Marijuana is a commonly ingested drug with a variety of health effects, some beneficial and some not so desirable. The smoke per se from joints is not healthy, but activation of the cannabinoid system (via THC and other chemicals in marijuana) may confer some beneficial effects.

This page features 637 unique references to scientific papers.

Confused about what actually Works?
MUST GET: Supplement Stack Guides - Saving You Money & Time


In Progress

This page on Marijuana is currently marked as in-progress. We are still compiling research.

You can help contribute by:



For the most part, the psychological effects of marijauna are mediated by THC content although variations in other cannabinoids (such as cannabidiol) can modify the percieved high and have other biological effects.

The primary mechanism of marijuana comes from THC's action on cannabinoid receptors, two receptors designated CB1 and CB2 which were discovered due to their interaction with extracts from Cannabis sativa (hence the name) and seem to mediate many of the effects of marijuana.

Roughly, the CB1 receptor is the 'psychoactive' receptor and mediates the feelings of a high whereas the CB2 receptor is the 'antiinflammatory' receptor expressed on immune cells and some brain cells that mediates any health benefits. Things that act on the CB2 receptor but not the CB1 receptor, such as Echinacea, do not have psychoactive effects.

THC is also known to interact with a superfamily of receptors characterized by a certain structural feature known as a Cysteine Loop (Cys-loop), with the superfamily being known as the Cys-loop ligand gated ion channel (LGIC) family. THC binds to a nonactive site on these receptors and, while not directly activating or blocking them, can modify the actions of the things which normally act on them.

The receptors that can be suppressed by THC in this family include receptors for a serotonin receptor (5-HT3A) while a glycinergic receptor (α3GlyR) is enhanced by THC, other members are either not affected by THC despite being regulated by endocannabinoids (α7-nicotinic) or the effect is either weak (muscarinic acetylcholine) or uninvestigated (GABAA).

The interaction with serotonin and glycine receptors are known to also contribute to the psychoactive effects of THC.

Major Benefits

Major Negatives

Tolerance, Addiction, Withdrawal

Tolerance to and withdrawal from marijuana is a well-known occurance, with the latter recently being recognized by the DSM-5, a major psychological publication which classifies mental disorders. Tolerance to marijuana, on a molecular level, is when the CB1 receptor, being overstimulated, gets internalized and signalling through it is thus hampered. Since CB1 and the NMDA receptor are both intimiately linked when it comes to marijuana, the NMDA receptor also gets internalized and its signalling hampered.

The internalization of the NMDA receptor, and reduced glutamate signalling, mediates a fair bit of tolerance effects when it comes to marijuana. This includes epilepsy (where the acute beneficial effects are thought to lessen), schizophrenic symptoms (where the increase in symptom intensity from marijuana usage is thought to be lessened), and memory loss (where usage during tolerance may be less amnesiac than a first time use).

Practically speaking, most of the effects of marijuana tolerance/withdrawal can be explained with the phrase "What the drug giveth, the drug taketh away" referring to how the benefits seen with acute usage are the same parameters which are then reduced later on.

Other Notables


When marijuana is administered by itself, it appears to be relatively safe, although there are case reports of sudden death due to cardiovascular complications attributed to marijuana use.

Marijuana inhalation is known to increase diastolic blood pressure and heart rate when taken acutely, and these adverse changes are soon normalized in most people when the high goes away. That being said, there are numerous case studies of marijuana usage 30-60 minutes before heart attacks which are thought to be due to when people who are at elevated risk already take "the toke that broke the camels back" pushing their blood pressure and heart rate to dangerous levels. There have also been reported drug interactions with where the combination resulted in a heart attack. Smoking marijuana may also lead to bronchitis.

Follow this Page for updates

Confused about Supplements?
Get the Stack Guides

Also Known As

Cannabis Sativa, Weed, Medical Marijuana, Marihuana, dope, ganja, hashish, Dronabinol (medical THC),

Do Not Confuse With

Hemp Protein (same plant, but this term tends to refer to a food product without THC)

Things to Note

  • Marijuana is highly psychoactive via both an oral and inhaled route
  • Marijuana can acutely reduce motor control and attention (and should not be inhaled prior to operating heavy machinery)
  • Marijuana is known to interact with many enzymes of drug metabolism of which include CYP3A4 and CYP2C19; see pharmacokinetic section for more information

Is a Form of

Does Not Go Well With

  • Caffeine (Tolerance to caffeine may cause an increased impairment of spatial memory formation when using marijuana)
  • Cardiac stimulants (due to an increase in diastolic blood pressure and heart rate seen with marijuana, the combination may be acutely dangerous for those at risk for a heart attack)

Caution Notice

Marijuana has a variable legal status depending on region, and may be illegal (to varying degrees) in your region if not for medicinal purposes.

Known drug and enzyme interactions. Medical Disclaimer

Although it is not currently clear whether the purported estrogenic properties of marijuana may affect results from an exercise program, heavy users take heed: if your current goals involve maximal fat-loss and/or muscle-gain, the possible pro-estrogenic effects should be a concern.

Bill Willis

Table of Contents:

  1. Sources and Composition
    1. Origin and Composition
    2. Physicochemical Properties
  2. Pharmacology
    1. Absorption
    2. Transportation in Serum
    3. Peripheral Distribution
    4. Metabolism
    5. Elimination
    6. Phase I Enzyme Interactions
  3. Molecular Targets
    1. Cannabinoid Receptors
    2. Other Receptors
    3. Ion Channels
    4. 15-LOX
  4. Neurology
    1. Adenosinergic Neurotransmission
    2. Adrenergic Neurotransmission
    3. Agmatinergic Neurotransmission
    4. Cannabidergic Neurotransmission
    5. Cholinergic Neurotransmission
    6. Dopaminergic Neurotransmission
    7. GABAergic Neurotransmission
    8. Glutaminergic Neurotransmission
    9. Glycinergic Neurotransmission
    10. Opioidergic Neurotransmission
    11. Serotonergic Neurotransmission
    12. Neurogenesis
    13. Neuroinflammation
    14. Headaches and Blood Flow
    15. Analgesia
    16. Appetite and Food Intake
    17. Attention and Focus
    18. Epilepsy and Convulsions
    19. Anxiety and Stress
    20. Depression
    21. Memory and Learning
  5. Cardiovascular Health
    1. Cardiac Tissue
    2. Atherosclerosis
    3. Blood Pressure
    4. Platelets and Viscosity
    5. Triglycerides
    6. Cholesterol
  6. Interactions with Glucose Metabolism
    1. Insulin
    2. Insulin Sensitivity
    3. Blood Glucose
    4. Glycogen
    5. Glycation
    6. Type I Diabetes
    7. Type II Diabetes
  7. Fat Mass and Obesity
    1. Adipokines
    2. Lipolysis
    3. Weight
  8. Skeletal Muscle and Physical Performance
    1. Muscular Power Output
    2. Aerobic Exercise
  9. Inflammation and Immunology
    1. Interleukins
    2. Natural Killer Cells
    3. B Cells
  10. Interactions with Hormones
    1. Estrogens
    2. Androgens
    3. Growth Hormone
    4. Luteinizing Hormone
    5. Follicle-Stimulating Hormone
    6. Cortisol
  11. Peripheral Organ Systems
    1. Intestines
    2. Liver
    3. Pancreas
    4. Lungs
    5. Eyes
    6. Male Sex Organs
  12. Interactions with Cancer Metabolism
    1. Lung
    2. Prostate
    3. Adjuvant Usage
  13. Longevity and Life Extension
    1. Rationale
  14. Sexuality and Pregnancy
    1. Fertility
    2. Spermatogenesis
  15. Other Medical Conditions
    1. Alzheimer's Disease
    2. Multiple Sclerosis
    3. Amyotrophic Lateral Sclerosis
    4. Parkinson's Disease
    5. Psychosis
    6. Inflammatory Bowel Disease
  16. Nutrient-Nutrient Interactions
    1. Alcohol
    2. Caffeine
    3. COX2 Inhibitors
    4. Nicotine
    5. High Fat Diet
  17. Safety and Toxicology
    1. Tolerance
    2. Withdrawal
    3. Dependency
    4. Case Studies

Edit1. Sources and Composition

1.1. Origin and Composition

Cannabis sativa is a plant from Traditional Chinese Medicine that also has a history of usage for various non-nutritional and non-medical purposes, such as fiber and textile manufacturing. Its history extends beyond mainland Asia, as it has been detected alongside Egyptian mummies (as hashish).[1]

The plant is called many names with the most common being marijuana (referring to the plant itself), bhang (referring to a drink produced in some Asian countries from the leaves and flowers[2]) and hashish (referring to a resinous solution). All parts of the plant tend to be used, usually the leaves and flower buds.[3]

Cannabis sativa (of the family Cannabaceae) is a somewhat broad plant species, and previous species in the Cannabis genus (Cannabis indica, which is usually the source of hemp, as well as Cannabis ruderalis) are now considered varieties of Cannabis sativa.[4] Beyond this there are distinct chemotypes of Cannabis sativa;a drug phenotype (defined by a Δ9THC exceeding 20%) a fiber type used to create hemp products (0.3% Δ9THC or less) and an intermediate type (0.3-1% Δ9THC).[4][5] The fiber type is used to create commercial Hemp Protein or hemp oil supplements to circumvent their potential for drug abuse.

Marijuana is currently the most widely used illicit substance in the world according to the UN[6] yet can legally be given as a medical treatment for various forms of cancer, AIDS/HIV, and neurological impairments either as therapy or as adjuvant (to increase appetite, food intake, and thus weight).[7][8]

Marijuana is a traditional Chinese medicine that was initially spread in part due to its medicinal properties but also for utilizing material from the hemp plant for manufacturing. Nowadays it is most well known and used for its psychoactive properties although it still has some medicinal importance.

In general, the Cannabis sativa plant contains a wide variety of bioactives but those of interest are the cannabinoids. Cannabinoids, in the context of Cannabis sativa, refer to molecules with a C21 terpenophenolic skeleton[9] of which over 86 unique molecules have currently been isolated.[9][4][10] Known constituents include:

Cannabinoids (aka. phytocannabinoids) including:

  • Tetrahydrocannabinol Δ9 (Δ9THC) type: this includes the major psychoactive (-)-trans-(6aR,10aR) Δ9-tetrahydrocannabinol (commonly shortened to Δ9THC, but specifically referred to as Δ9THC-C5[9]) but also includes; shortened sidechain variants such as tetrahydrocannabinol C49THC-C4[9]); acid variants tetrahydrocannabolic acid A9THCA-C5 A[9]), tetrahydrocannabinolic acid B9THCA-C5 B[9]), tetrahydrocannabivarinic acid A9THCVA-C3 A[9]), and tetrahydrocannabiorcolic acid9THCOA-C1 A/B[9]); and other variants tetrahydrocannabivarin9THCV-C3[9]) and tetrahydrocannabiorcol9THCO-C1[9])
  • Tetrahydrocannabinol Δ8 (Δ8THC) type: Differs from Δ9THC via position of the double bond, and only two variants of Δ8(6aR,10aR) tetrahydrocannabinolic acid A8-THCA-C5 A[9]) and Δ8(6aR,10aR) tetrahydrocannabinol8-THC-C5[9]) are known to exist currently
  • Cannabinol (CBN) type: created from full aromatization of THC type cannabinoids. This includes cannabinolic acid A (CBNA-C5 A[9]), cannabinol (CBN-C5[9]) and its methyl ether (CBNM-C5[9]), cannabinol-C4 (CBN-C4[9]), cannabinol-C2 (CBN-C2[9]), cannabiorcol-C1 (CBN-C1[9]), and cannabivarin (CBN-C3[9])
  • Cannabidiol (CBD) type: includes cannabidolic acid (CBDA-C5[9]), (-)-cannabidiol (CBD-C5[9]) and its monomethyl ether, cannabidiol C4 (CBD-C4[9]), cannabidivarinic acid (CBDVA-C3[9]), (-)-cannabidivarin (CBDVA-C3[9]), and cannabidiorcol (CBD-C1[9])
  • Cannabitriol (CBT) type: these include cannabitriol in (+)-cis, (+)-trans, and (-)-trans configurations (CBT-C5[9]) as well as (+)-trans-cannabitriol-C3 (CBT-C3[9]). Both 8,9-dihydroxy-Δ6a(10a)tetrahydrocannabinol (8,9-Di-OH-CBT-C5[9]) and 10-ethoxy-9-hydroxy variants[9][11][12] belong to this group
  • Cannabinodiol (CBND) type: formed during full aromatization of CBD type, only cannabinodiol (CBND-C5[9]) and cannabinodivarin (CBVD-C3[9]) are known to exist currently
  • Cannabigerol (CBG) type: not psychoactive in the classical sense (effects attributed to marijuana[13]) and include cannabigerolic acid A (E-CBGA-C5 A[9]) with its monomethyl ether, cannabigerol (E-CBG-C5[9]) and its monomethyl ether, cannabigerovarinic acid A (E-CBGVA-C3 A[9]), cannabigerovarin (E-CBGV-C3[9]), and cannabinerolic acid A (Z-CBGA-C5[9][14])
  • Cannabichromene (CBC) type: these mostly racemic cannabinoids include cannabichromenic acid (CBCA-C5 A[9]), cannabichromene (CDC-C5[9]), cannabichromevarinic acid (CBCVA-C3 A[9]), cannabichromenevarin (CBCV-C3[9]), cannabivarichromene (CBCV-iC3[9]), and 2-methyl-2(4-methyl-2-pentenyl)-7-propyl-2H-1-benzopyran-5-ol[9]
  • Cannabicyclol (CBL) type: Three known cannabinoids in the (+)-(1aS,3aR,8bR,8cR) configuration including cannabicyclolic acid (CBLA-C5 A[9]), cannabicyclol, (CBL-C5[9]) and cannabicyclovarin (CBLV-C3[9])
  • Cannabielsoin (CBE) type: These appear to be infrequently identified in natural sources and may be produced by photooxidation from the CBD type, these cannabinoids are all in the (5aS,6S,9R,9aR) configuration and include cannabielsoic acid A (CBEA-C5 A[9]), cannabielsoic acid B (both CBEA-C5 B and CBEA-C3 B[9]), and cannabielsoin (both CBE-C3 and CBE-C5[9])
  • (Other) Cannabinoids found in cannabis sativa not belonging to one of the above groups are known to include dehydrocannabifuran (DCBF-C5[9]), cannabifuran (CBF-C5[9]), cannabichromanone (CBCN-C5[9]), cannabichromanone-C3 (CBCN-C3[9]), cannabicoumaronone (CBCON-C5[9]), cannabicitran (CBT-C5[9]), 10-oxo-Δ6a(10a)tetrahydrocannabinol (OTHC[9]), a cis configuration of Δ9THC (cisΔ9THC-C5[9]), cannabiglendol (OH-iso-HHCV-C3[9]), and isotetrahydrocannabivarin C3 and C5[9]

The exact Δ9THC content of marijuana can vary widely. Many studies using Δ9THC containing cigarettes tend to use products with a 4.8% Δ9THC content, while modern common street marijuana contains 7-9% Δ9THC.[15][16] This content is significantly higher than in the past, since as early as 1980 marijuana has possessed a 1.5% Δ9THC content which has increased steadily as time progressed.[17][16] There have been strains of home-grown marijuana reporting 20% Δ9THC by weight,[15] and this time related increase in Δ9THC content of the average product also extends to hashish.[15]

Ultimately, there are well over 70 cannabinoids found within Cannabis sativa which may all contribute to the effects of administering the whole plant extract. Of these, the major cannabinoid is the first highly psychoactive one to be available in a pure form for research which is (-)-trans-(6aR,10aR) Δ9-tetrahydrocannabinol (henceforth simply Δ9THC).

Note: In the above acronyms for each molecule the bolded component (ie. CBT) refers to the structural subclass the cannabinoid belongs to while A refers to an acid (carboxylation) and M refers to a monoethyl ether addition. Cx refers to the length of a carbon chain on the backbone.
Other (noncannabinoid) possible bioactives including:

  • Volatile oils (airborne constituents usually implicated in Aromatherapy) usually contianing a high concentration of myrcene (29.4-65.8% total essential oil[18][19]) followed by Limonene (up to 16.3-17.7%[19] although sometimes trace) and various lesser components including linalool, trans-ocimene, α-pinene, β-pinene, and β-caryophyllene (which itself possesses cannabinoid activity[20])
  • Various phenanthrenes including 4,5-dihydroxy-2,3,6-trimethoxy-9,10-dihydrophenanthrene, 4-hydroxy-2,3,6,7-tetramethoxy-9,10-dihydrophenanthrene, and 4,7-dimethoxy-1,2,5-trihydroxyphenanthrene[21]
  • Cannabispiranols such as α-cannabispiranol[21] and β-acetyl cannabispiranol[21]
  • Cannaflavin A[21] and C[21]
  • Chrysoeriol (bioflavonoid)[21]
  • 6-prenylapigenin (prenylated Apigenin)[21]

The noncannabinoid constituents will vary depending on growing condition and the strain of marijauna used, but unlike Δ9THC they are not commonly quantified so their contribution to the biological effects of marijuana are uncertain. Δ9THC and other cannabinoids (primarily cannabidiol) remain the most active components.

1.2. Physicochemical Properties

The double bond isomer (-)-trans-6a,10a-Δ8THC is said to be a biologically active but weaker variant of (-)-trans Δ9-THC, differing only by the position of the double bond being between carbons 9 and 10 (Δ9THC) or 8 and 9 (Δ8THC).[22]

Tetrahydrocannabinol is a terpenoid compound that possesses a double bond that can change location depending on the particular isomer, which is labelled via a delta (Δ) designation.

Edit2. Pharmacology

2.1. Absorption

Passive inhalation refers to second-hand inhalation of smoke from marijuana, and is of concern since many athletes who cannot use marijuana for their sports may be friends with those who do use marijuana causing 'side-stream' smoke from marijuana and its relation to a urine test relevant.[23] Furthermore, the urinary detection of side-stream smoke is relevant due to it being the main excuse for when a urine test turns out to be positive for Δ9THC.[24]

A urine concentration of the Δ9THC metabolite tested (11-Nor-9-Carboxy-Δ9-Tetrahydrocannabinol or THCCOOH) to turn positive (greater than 15ng/mL) generally does not occur under realistic usage[25][26] and is not thought to be relevant to athletes.[23] Even in a nonventilated room, exposure to the smoke from four joints (2.8% Δ9THC) daily over six days does not seem to cause a reliable increase in urine THCCOOH.[26] This has been tested elsewhere, where four joints over an hour in a similar environment caused a single positive result (3.9ng/mL) out of 80 urinary samples[27] and three hours of exposure to recreational marijuana usage (joint passing) failed to cause any positive results.[28]

A positive result can be forced, since urinary THCCOOH correlates with the amount of Δ9THC in the air.[26] In a small (2.1 x 2.5 x 2.4 meters) nonventilated room, exposure to 16 joints of side-stream over an hour can cause a positive urine test[26][29][30] although this is a quantity of marijuana smoke where goggles are actually required due to the smoke being so dense.[26] Only in this latter example are psychoactive effects of marijauna felt by the nonuser.[26]

While it is possible to have a positive urine test from secondary (passive) marijuana inhalation by being near marijuana users, this requires the subject to essentially be sitting in a hotbox for an hour with smoke thick enough to require goggles to see properly. Any other condition of marijauna usage including all realistic situations do not seem to be enough exposure for a passive inhaler to test positive

Tetrahydrocannabinol (THC) appears to be absorbed through the skin when in an appropriate medium (as it is fat soluble), with some studies noting success in absorbing THC in vitro with solutions containing ethanol[31][32][33] or propylene glycol.[34][33] This increase in permeability applies to both THC and cannabidiol.[33] However, the latter appears to be more permeable than THC due to lower lipophilicity.[34] While mouse skin is more permeable than human skin,[31] there is no difference with guinea pig skin.[35]

Despite species-dependent differences in absorption, THC has been noted to be topically absorbed in vivo in the mouse[36] and guinea pig,[35] with the latter showing a 84 minute lag time to reach a plasma concentration of 4.4+/-0.9ng/mL (with a patch containing 8mg THC in a solution with ethanol and propylene glycol) which was maintained for 70 hours.[35]

THC can be absorbed through the skin, although its absorption is limited. Absorption can be increased like other agents, and at least in the guinea pig patches have been noted to expose the body to low but prolonged THC levels. Due to the low rates of absorption and no sizeable peak in serum, there is unlikely to be any appreciable psychoactive effects.

2.2. Transportation in Serum

When marijuana is smoked (toking), a maximum plasma value of cannabinoids and the onset of psychotropic effects occurs in a few minutes. The psychotropic effects are maximal 15-30 minutes after initial ingestion and taper off 2-3 hours after exposure.[37] Systemic bioavailability ranges from 10+/-7%[38] to 27+/-10%[39], with habitual users absorbing more of the active THC. The reason for the low bioavailability is due to a hypothesized maximum 30% loss from pyrolysis, poor lung absorption, and losses to sidestream smoke not being ingested.[37] Toking in the form of a pipe seems to eliminate sidestream losses, and absorption rates of up to 45% have been recorded.[40]

After oral ingestion (via brownies) peak serum levels are achieved at a variable 60-120 minutes after ingestion, due to varying digestive potencies inter-person.[37][41] Some studies have noted delays of peak values up to 4-6 hours post ingestion[42] and some showing multiple plasma peaks.[43] With a fatty acid vehicle, intestinal uptake of radiolabelled THC (of which includes both the active Delta-9 form and its acid hydrolysis Delta-8[44]) exceeds 90% in most cases[41], although after extensive hepatic first-pass metabolism the amount available to systemic circulation varies from 2-14%, with high interindividual differences.[45][37]

Ophthalmic (eye) administration has only been researched in rabbits, in which a light mineral solution resulted in 6-40% systemic bioavailability and a peak serum level 1 hour after application, which remained high for several hours.[46]

2.3. Peripheral Distribution

Tissue distribution of THC is assumed to be due to the molecule's physicochemical properties (traits denotes by the structure's shape), as there exists no THC-specific transport or barriers that affect tissue concentration.[47][37] Approximately 10% of assimilated THC is bound to red blood cells[48] while the otehr 90% floats freely in the blood. Of this 90%, 95-99% is bound to plasma proteins such as lipoproteins and, to a lesser extent, albumin.[49][50] Due to THC's lipophilicity (fat-solubility), it can diffuse through cell membranes.

THC, at times correlated near peak plasma levels or shortly after, rapidly enters highly vascularized (good blood supply) tissues and organs such as; muscle, spleen, heart, lungs, liver, and kidneys.[51] Due to its lipophilicity, it eventually almost exclusively settles into adipose tissue (body fat) where it can remain for long periods of time.[52][53]

THC can easily cross the placental barrier, and can appear in a child's blood if a mother ingests marijuana. This is seen across all species to varying degrees.[54][55][56] Human breastmilk can contain levels of THC up to 8.4 times that found in plasma, and thus a mother smoking 1-2 joints a day can expose their child to values ranging from 0.01-0.1mg active THC through breastmilk.[57]

THC may also accumulate in the testicles, where it may influence reproductive function.[51]

2.4. Metabolism

Although metabolism exists in the lungs and heart tissue, tetrahydrocannabinoids are metabolized primarily in the liver through the cytochrome P450 (CYP) enzyme system, via hydroxylation and oxidation reactions.[58][59] A member of the CYP2C subfamily seems to be the most active in humans.[60]

Although over 100 separate metabolites of THC have been identified[61], the major one is hydroxylation of THC at the C-11 (eleventh carbon) site to form 11-OH-THC, and further oxidation results in THC-COOH.[62] All mediated by liver P450 enzymes, the rate limiting step of which seems to be hepatic blood flow.[37][63]

THC metabolites are commonly excreted in the urine through the acid metabolite 11-nor-9-carboxy-THC glucuronide, a glucuronidated form of THC-COOH.[64] A proposed mechanism of long-term storage is when 11-OH-THC conjugates with fatty acids in the adipocyte.[65]

Excretion of THC compounds in the urine and feces begins after a pseudoequilibrium is met between tissues and plasma. The time of equilibrium changes based on dosage, with low dosage (16mg THC) tokes taking 3-12 hours, and high dosage (34mg) tokes taking 6-27 hours.[66] The carboxylated metabolite (THC-COOH) can be detected in the plasma for up to 7 days after both dosages.[66] This long duration for metabolism is partially explained by the slow release of THC conjugates from adipose and other body tissue into the bloodstream,[47] and partially due to the half-life of various THC conjugates, which although not accurately known, ranges from 12-36 hours for 11-OH-THC and 25-55 hours for THC-COOH; typically values in the 20-30 hour range are reported for the THC molecule itself.[67][39] Typically, the metabolites have longer half-lives than the parent THC molecules. Complications arise in measuring the half-life of Delta-9-THC due to interpersonal and interspecies differences, and some complications in distinguishing THC from its metabolites in vivo.

Excretion of THC occurs primarily as acid metabolites rather than the parent molecule, with 20-35% being excreted in the urine and 65-80% excreted in the feces.[41][63] Most being excreted in the feces due to the molecule's fat-solubility, extensive enterohepatic recirculation, and resorption from the renal tubules (which minimizes urine excretion)[41][68] Roughly 65% of THC and THC metabolites are excreted after 72 hours from both routes.[37][41] Full elimination of THC from the body may take up to two weeks to occur.[42] There also seems to be differences between chronic and first-time users, with chronic users taking much longer to fully metabolize all THC from the body; in some cases under urine analysis metabolites can be traced in the urine up to 46-77 days after administration[69] although averages were 12.9 days for light users and 31.5 days for chronic users.

2.5. Elimination

Despite the lipophilicity of cannabinoids, which usually suggest fecal elimination via the liver, cannabinoids tend to be reliably eliminated in the urine leading to urinalysis of Δ9THC metabolites as a reliable way to detect marijuana abstinence.[70] Blood testing[70] as well as hair testing[70][71] have both also been investigated.

Δ9THC is known to bioaccumulate in body fat (adipose), with one study noting that in heavy users who were given two joints daily for two days (an estimated intake of 56mg labelled Δ9THC) noted that the inhaled Δ9THC resulted in between 0.4-8.0ng/g more Δ9THC remaining in fat deposites for over four weeks.[52]

Δ9THC can be retained at a low concentration in body fat for a month.

2.6. Phase I Enzyme Interactions

Smoking (marijuana or tobacco) can lead to increases in CYP1A2 activity (CYP1A2 being a predominant enzyme CYP enzyme), and a cessation is known to normalize this abnormal induction. At times, it has been noted that the reduced aromatase activity from stopping marijuana smoking resulted in an overdose of some antipsychotics (clozapine and olanzapine) due to less metabolism.[72][73] The other two enzymes in the CYP1 class, CYP1A1 and CYP1B1, has both been noted to be induced from smoke (albeit cigarettes).[74]

When tested in vitro, all three enzymes (CYP1A1/2 and CYP1B1) are competitively inhibited by both cannabidiol (CBD) and Δ9THC with the most potent inhibition on CYP1A1 being seen with cannabidiol (IC50 of 537nM) while both CYP1A2 and CYP1B1 were inhibited by cannabinol (CBN) potently at 188nM and 278nM.[75] The actions of CBD on CYP1A1, however, were said to be related to enzymatic inactivation in an NADPH-dependent manner.[75]

Δ9THC was relatively weaker at inhibiting CYP1 isoforms, having a Ki for competitive inhibition in the 2.47μM (CYP1B1) to 7.54μM (CYP1A2) range.[75]

Smoking in general increases the expression of the CYP1 enzymes, and at least when tested acutely in vitro constituents of marijuana appear to quite potently inhibit these enzymes (with CYP1A1 being inactivated from cannabidiol).

Cannabidiol (CBD) appears to be an mixed inhibitor of CYP2C19 with an IC50 of 2.51-8.70µM (Ki value of only 793nM),[76] the enzyme that metabolizes it via 7-hydroxylation,[77] with more potency in inhibiting omeprazole metabolism (IC50 1.55-1.79µM) and more potent than Δ9THC at this inhibition (mixed inhibition with an IC50 value of 4.35µM[76]); the phenolic hydroxyl groups on the resorcinol moiety seem crucial for this inhibition, and CBD is thought to be more potent since the group is rotatable on this molecule (not so much on Δ9THC),[76] and cannabidivarin (minor constituent of Cannabis sativa) also had inhibitory activity.[76]

CYP2C19 appears to be inhibited by relatively low values of both Δ9THC and cannabidiol when tested in vitro, suggesting possible drug-drug interactions.

Cannabinoids appear to inhibit CYP2C9 potently when tested in vitro, with Δ9THC possessing a Ki of 937-1,500nM and IC50 in inhibiting warfarin hydroxylation of 2.29μM[78] while cannabidiol (CBD) has a Ki of 882-1,290nM and IC50 of 4.8μM;[78] cannabinol (CBN) and polyaromatic hydrocarbons are comparatively weaker and no cannabinoid exhibited metabolism-dependent inhibition.[78]

CYP2C9 is inhibited by all cannabinoids when tested in vitro and, relative to the IC50 values (proxy measurement of potency) of all the P450 enzymes this one as well as CYP1 isoforms appear to be most likely inhibited by marijuana.

CYP2D6 is inhibited by both Δ9THC (IC50 of 17.1-21.2μM in inhibiting various substrate metabolism[79]) and CBD (IC50 of 4.01-6.52μM[79]), with CBD being more potent and a competitive inhibitor again dependent on the resorcinol moiety.[79] This inhibition was significantly greater than tested polyaromatic hydrocarbons (PAHs; produced from the smoke in marijuana inhalation) which had IC50 values exceeding 100μM.[79]

In regards to the isoforms CYP2A6 and CYP2B6, cannabinoids appear to be noncompetitive inhibitors with comparatively weaker effects in inhibiting CYP2A6 in vitro (Ki ranging from 28.9-55μM in inhibiting the function of this enzyme) with appreciable inhibition of CYP2B6 by Δ9THC (2.81μM), cannabidiol (695nM), and cannabinol (2.55μM).[80]

Repeated exposure of a cell to cannabidiol and THC has been noted to result in an induction of CYP2B and 2C mRNA but without apparent changes in catalytic activity of these enzymes in vitro.[81]

CYP2D6 and CYP2A6 are both inhibited by cannabinoids, with competitive inhibition by cannabidiol on the former and noncompetitive inhibition by all three cannabinoids on the latter (the latter being relatively weak compared to the others). CYP2B6, however, is potently noncompetitive inhibited by all three cannabinoids in vitro.

The resorcinol moiety also plays a role with CYP3A4 (another enzyme involved in cannabidiol metabolism[82]) and CYP3A5 as cannabidiol has inhibited both with IC50 values of 11.7μM and 1.65μM respectively and in a competitive manner, significnatly higher than Δ9THC and cannabinol (both cannabinoids on both enzymes requiring over 35μM to reach their IC50 values).[83] CYP3A7 was inhibited in a mixed manner by all three to comparable degrees with an IC50 value in the range of 23-31μM.[83] Cannabidiol has also been reported to be an inactivatory of CYP3A4 among other P450 enzymes when tested in vitro.[84][85]

In contrast to the above information assessing acute enzyme interactions, induction of CYP3A isoforms has been noted with repeated exposure of cells to the inactivating cannabinoid (usually cannabidiol[81]) although the increase in CYP3A4 mRNA and protein content was met with no significant change in catalytic activity in vitro.[81]

One study in cancer patients given an oral Cannabis sativa supplement (1g prepared as tea containing 18% THC and 0.8% CBD) once daily in the evening for 15 days prior to testing of two chemotherapeutics metabolized by CYP3A (irinotecan[86] and docetaxel[87]) failed to find any significant alterations in clearance or AUC for either drug.[88]

Other human evidence is limited to a suspected acute inhibition of CYP3A4 due to a case study where the combination of Viagra and marijuana resulted in a myocardial infarction[89] and a study in people with HIV on antiretroviral therapy where two weeks supplementation of dronabinol (2.5mg) or inhalation of marijuana thrice daily resulting in nonsignificant reductions in drug area under the curve (AUC).[90]

All tested cannabinoids are acute inhibitors of the CYP3A isoforms of P450 when tested in vitro, with the most potent one being cannabidiol which also potently inhibits CYP3A7 and appears to inactivate CYP3A4. Subchronic treatment of cells with these cannabinoids appears to cause a refractory induction of CYP3A activity, and when tested in humans the limited evidence suggests that two weeks consistent marijuana usage does not affect drug kinetics much (and there is a suspected inhibitory effect of a single dose of marijuana on CYP3A prior to induction can occur).

Edit3. Molecular Targets

3.1. Cannabinoid Receptors

The main site of activity for the cannabinoid constituents of marijana are the cannabinoid receptors, named cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), with the former being the found mostly in the brain where it modulates psychoactive effects whereas the latter is found mostly immune tissue where it modulates inflammation and immune response.[91]

CB1 receptors are prominent in neural tissue but are also found in pituitary and peripheral tissue such as the thyroid, adrenals, gastrointestinal tract, and reproductive organs.[92] The affinity (as Ki) of Δ9THC towards the CB1 receptor is approximately 35-80nM, which is more potent than both the endogenous cannabinoids (or 'endocannabinoids') anandamide (60-540nM) and 2-AG (60-470nM).[91]

CB1 exerts its effects through coupling with G proteins.[91] Specifically, CB1 is coupled to:

  • Gi/o (also known as Gi which stands for G protein Inhibitory), known to have inhibitory actions on adenylyl cyclase (reducing cAMP).[93] Through this coupling, CB1 activation is known to reduce cAMP-activated Protein Kinase A (PKA) activity, as well as activating MAPK and mixed effects on nitric oxide signalling, and inhibition of voltage-gated calcium channels and activation of inwardly-rectifying potassium channels.[94] Na+K+ATPase activity can also be enhanced by CB1 activation.[95] One subtype, Gαi3, which is preferrentially coupled with CB1 is also involved in opiod signalling[96]
  • Gs (G protein Stimulatory), which has a stimulatory effect on adenylyl cyclase, although CB1 couples less selctively with this compared to Gi/o[97]
  • Gq/11 which is coupled to the phospholipase C pathway and leading to increased intracellular calcium, although Δ9THC only induces this particular pathway weakly as compared to other CB1 ligands[98][99]
Activation of the CB1 receptor by any ligand, which usually refers to Δ9THC when looking at marijuana, results in psychoactive effects of marijuana. This receptor acts by coupling with G proteins.

CB2 receptors are found mainly in immune cells of which include some brain cells (glial cells)and, like CB1 receptors, are coupled with pertussis toxin-sensitive Gi/o proteins which inhibit adenylyl cyclase formation and and affect the MAPK pathway.[91] CB2 has also been found in keratinocytes as well, where they facilitate the release of endorphins.[100] The affinity (as Ki) for Δ9THC towards CB2 is in the range of 4-75nM, which is more potent than both endocannabinoids anandamide (280-1,900nM) and 2-AG (150-1,400nM).[91]

CB2 receptors are also G-protein coupled receptors, and do not mediate psychoactive effects of marijuana but instead act mostly in regards to regulating the immune system, including immune cells in the brain such as glial cells.

The CB1 receptor has been noted to heterodimerize (pair with another, distinct, receptor) with multiple other receptors including the dopamine D2 receptor, adenosine A2A receptor, β2 adrenergic receptor, and the μ, κ, and δ opioid receptors, which leads to different signaling pathways being activated.[101]

3.2. Other Receptors

There are some actions of cannabinoids which still occur when CB1 or CB2 or blocked or deleted entirely in knockout mouse strains, yet are sensitive to pertussis toxin that inhibits any G-protein coupled receptor's actions, suggesting that cannabinoids act directly on receptors that are not one of the two aforementioned cannabinoid receptors; Δ9THC seems to have little effect on these receptors, however, and these effects are mainly seen from other endogenous and synthetic cannabinoids.[102][103] The former orphan receptor (receptors without fully known ligands) GPR55 is one such cannabinoid receptor, as it responds to some synthetic cannabinoids as well as most endocannabinoids such as 2-AG (EC50 of 3nM) and Oleoylethanolamide (440nM), as well as Δ9THC (8nM) while cannabidiol only acted as an antagonist.[104] It is expressed in the adreanal glands, some of the gastrointenstinal tract, and central nervous system (although at lower levels than CB1) in mice, and it is thought that GRP55 is coupled to the G-protein known as Gα13.[104] The receptor's function is not entirely clear, but preliminary evidence suggests it may play a role in vascular tone and have some anti-inflammatory effects. [104]

Some G-protein receptors, which were initially 'orphan' receptors due to no known ligands, such as GPR55 have affinity for molecules which the cannabinoid receptors also respond to; hence they may be involed in cannabinoid signalling.

Cannabinoids (not specifically Δ9THC) are known to influence a variety of other receptor functions including inhibitory actions on some serotonin receptors, cholinergic, glutaminergic, and mixed inhibitory or potentiation of GABAergic and glycinergic receptors;[105] each are elaborated more on in their respective neurotransmission subsections (in the Neurology section), and it seems that these receptors are common to one another as they are the members of the Cys-loop ligand-gated ion channel (LGIC) superfamily.[106]

The Cys-loop ligand-gated superfamily appears to respond to cannabinoids, with most members of the superfamily being allosterically inhibited by various cannabinoids (with exception for the glycine and GABA receptors which are sometimes potentiated).

3.3. Ion Channels

The effects of CB1 receptor activation on ion channels, and ultimately the electrical conduction and action potential, in neurons are mediated primarily through CB1's effects on PKA and G proteins. [91] Some evidence in guinea pigs suggests that the effect of CB1 on some ion channels may may be subject to sex-related differences.[107]

Specifically, CB1 receptors can activate A-type potassium channels (KV1.4[108] and KV4.2[91]), which is secondary to a decrease in cAMP via inhibiting adenylyl cyclase[109] and it appears that activation of CB1 is also capable of inhibiting L-type calcium channels (arterial cells[110]) and N-type calcium channels (neuronal cells) secondary to the Gi protein inhibiting adenylyl cyclase.[111][112] T-type calcium channels also appear to be inhibited by CB1 activation.[113]

Activation of CB1 receptors influences neurons by modifying ion influx and efflux, which modifies the frequency of neuronal 'firing' (action potentials) and thus their signalling. CB1 activation results in activation of potassium channels and inhibition of calcium channels, ultimately causing a generally 'suppressive' or 'downer' effect (similar to GABA or adenosine signalling).

A family of ion channels called the transient receptor potential (TRP) channels depolarize the cell membrane upon activation, and play a wide role in sensory perception, including pain.[114] Cannabinoids have been noted to interact with TRP channels including activating both TRPA1[115] and TRPV1[116] depending on the cannabinoid investigated. Δ9THC, specifically, appears to be an agonist of TRPA1 differing in potency based on cellular localization as it is comparatively weak when external to a cellular membrane (Ki greater than 20µM) and more potent when acting internally (Ki of 700nM).[117] The latter affinity of 700nM is close to the levels seen acutely after inhalation.[118] As TRPV1 is known to be involved in neuropathic pain[119] it is a plausible target for marijuana's pain killing effects. In vitro evidence suggests that several cannabinoids from marijuana, including cannabidiol and cannabinol (a degradation product of THC) are able to desensitize TRPV1 and TRPA1, which could possibly lead to analgesia.

Cannabinoids interact with a kind of ion channel called TRP channels, some of which are involved in pain. Some cannabinoids have been shown to desensitize these channels in cell models, which could in part explain marijuana's analgesic benefits beyond their effects at the cannabinoid receptors.

3.4. 15-LOX

The 15-lipoxygenase (15-LOX) enzyme, which is known to play a role in oxidizing low density lipoprotein (LDL) which is a key step in the development of atherosclerosis, appears to be inhibited by Δ9-THC with an IC50 of 2.42μM in vitro, along with one of its metabolites (Δ9-THC-11-oic acid, with another metabolite, 11-hydroxy-THC being inactive).[120] It is uncertain if this is biologically relevant, however, since THC has been noted to accumulate in tissues up to a concentration of around 1uM with standard usage[52] while the active metabolite tends to be detected in plasma up to 200nM only.[120]

Cannabidiol also has the ability to directly inhibit 15-LOX,[121] with its metabolite cannabidiol-2',6'-dimethyl ether (CBDD) being significantly more potent with near complete inhibition at 2μM[120] and an IC50 of 280nM,[121] while the other metabolite cannabielsoin is wholly inactive at these concentrations.[120]

None of the above tested cannabinoids appear to inhibit 5-LOX, the molecular target of Boswellia serrata, in the range where they were effective on 15-LOX[120] and the selectivity of CBDD towards 15-LOX (relative to 5-LOX) was greater than 700.[121]

While numerous cannabinoids show the ability to inhibit 15-LOX, an enzyme that plays a role in inflammation and atherosclerosis, this mechanism is of uncertain status in regards to marijuana use.

Edit4. Neurology

4.1. Adenosinergic Neurotransmission

The CB1 cannabinoid receptor is G protein coupled receptor that signals through G proteins of the Gαi/o subfamily to inhibit adenylyl cyclase.[91] In this way CB1[122] and adenosine A1[123] receptors have much in common; both are located presynaptically and in similar brain regions, where they exert collective suppressive effects on glutamate release.[124][125] Furthermore, CB1 and A1, along with GABAB, signal through a common pool of G proteins. Activation of both CB1 and A1 result in less-than-additive G protein activation,[126] while stimulation of the A1 pathway with Caffeine reduces the activation of G proteins through CB1.[127]

While both cannabinoid CB1 receptors and adenosine A1 receptors clearly share common second messengers in their respective signaling cascades, the exact nature of their crosstalk is complex, and not completely understood. During tolerance to cannabinoids, A1 mediated G protein activation is not affected,[128] while CB1-dependent activation is suppressed.[129] Moreover, there is mixed evidence as to whether adenylyl cyclase inhibition by the A1 receptor is affected upon tolerance to cannabinoids, with one study finding no effect,[130] and another finding a reduction in inhibition upon stimulation of A1 and GABAB of around 18%.[126] One study assessing motor coordination also noted cross tolerance with A1 and CB1 receptors.[131]

Conversely, tolerance to Caffeine (which increases A1 receptor density in neurons[132]) decreases CB1 receptor density. [127] The simultaneous increase in A1 receptors and decrease in CB1 receptors led to a condition where A1 activation suppressed activity of CB1 presynaptic receptors in an in vitro assay, where A1-dependent activation of the common Gαi/o pool limited signaling through the CB1 receptor.[127]

The CB1 receptor (the psychoactive target of Δ9THC) and the adenosine A1 receptor (activated by caffeine) are located in similar regions of the brain and signal through common secondary messengers (inhibitory G-proteins) to inhibit adenylyl cyclase. This may confer an element of negative cross-talk between these pathways, as some studies suggest.

4.2. Adrenergic Neurotransmission

One study has found that acute oral ingestion of 30-70mg (a high dose) of Δ9THC may have an influence on urinary catecholamines, with noradrenaline not being affected but with adrenaline being increased by 57% at the two hour mark (returned to baseline after four hours).[133]

4.3. Agmatinergic Neurotransmission

Agmatine is a neurotransmitter derived from L-Arginine[134] that appears to interact with cannabinoid signalling, in particular the CB1 receptor[135][136] and imidazoline receptors[137] (which agmatine can act upon) and may act as a co-transmitter released alongside glutamate. [138]

The analgesic properties of agmatine appear to partially depend on imidazoline receptors, as the ability of mice to tolerate pain caused by heat decreases when given both imidazoline and CB1 receptor blockers.[139] Since agmatine also synergistically enhanced the analgesia of test cannabinoids (WIN 55212-2 and CP55,940), it seems that agmatine can augment the analgesic properties of cannabinoids.[139] Agmatine has also been noted to augment cannabinoid-induced hypothermia.[140][141]

Evidence suggests that agmatine is is associated with cannabinoid signalling in the brain, where it appears to synergistically augment pain and hypothermic responses in animal testing, although this remains to be tested in humans.

4.4. Cannabidergic Neurotransmission

The cannabinoid receptors CB1 and CB2 are named after the plant Cannabis sativa, since its main psychoactive componetn, Δ9THC, was the first potent ligand discovered for this class of receptors; since then, endogenous cannabinoids (endocannabinoids) such as the Arachidonic acid derivative anandamide have been discovered.[142] These receptors are G protein-coupled, with CB1 coupled to Gi/o[95][143] and CB2 coupled only to Gi.[143] Internalization (drawing a receptor into a cellular membrane) and externalization (shuttling the receptor to the cell surface) of the receptors help to regulate activity.[144][145]

Δ9THC is a partial agonist of CB1, and does not maximally activate either G protein coupled to it.[143]

Cannabidiol is known to be an inverse agonist of both CB1[146][147] and CB2[148][147] receptors in vitro, and is active as an inverse agonist on CB2 at 1µM with a potency comparable to 1µM rimonabant.[147] It appears to be able to block the activation of these receptors by other agonists at a lower concentration though, blocking the nonselective agonist CP55940 with a KB of 79nM and the CB1 agonist WIN55212 with a KB of 138nM. The ability of cannabidiol to block agonists seems to occur at around a 64.5-fold lower concentration than its inverse agonist ability.[147] Cannabidiol is also able to block the effects of Δ9THC.[149]

Cannabidiol (CBD) appears to block the effects of ligands binding to the cannabinoid receptors, and as such negatively interacts with the actions of Δ9THC on these receptors.

Subchronic exposure to marijuana is known to downregulate the CB1 receptor in humans[150] and a downregulation has been noted as acutely as after three days of exposure in rats.[151] In the case of the CB2 receptor, at least in rats, exposure to marijuana results in an increase in cerebral mRNA for the CB2 receptor after cessation.[152]

4.5. Cholinergic Neurotransmission

Δ9THC does not appear to influence α7-nicotinic acetylcholine receptors in vitro at concentrations up to 1μM, despite the endocannabinoid 2-AG being a noncompetitive inhibitor with an IC50 of 168nM.[153] This inhibition is also seen with anandamide[154] which is additive with Alcohol in vitro,[155] and anandamide also inhibits α4β2 nicotinic receptors which is not seen with Δ9THC at concentrations up to 1μM.[156] When this inhibition occurs, it seems to be independent of the CB1 receptor[156][154] or CB2 receptor.[154]

At the level of the muscarinic acetylcholine receptors, anandamide has shown weak (and possibly not biologically relevant) inhibition of M1 and M4 receptors with an IC50 value ranging between 10-50μM.[157][158][159]

While endocannabinoids seem to have an inhibitory role on Nicotine receptors, this inhibitory property does not appear to be replicated with Δ9THC as it doesn't seem to interact with nicotinic acetylcholine receptors.

4.6. Dopaminergic Neurotransmission

The dopamine D2 receptor in the prefrontal cortex, which have the potential to couple with 5-HT2A receptors via forming heteromers (thereby enhancing the actions of 5-HT2A[160][161]), seem to have this heteromer formation enhanced after cannabinoid treatment in vivo following a week of treatment as well as increased membrane localization of individual 5-HT2A, D2S, and D2L receptors.[162]

Activation of cannabinoid signalling in neurons for a subchronic length of time (week) has been noted to increase D2 dopamine receptors alongside the serotonin receptor 5-HT2A, and has been noted to encourage their ability to fuse together to enhance 5-HT2A signalling

The increase in 5-HT2A expression appears to be due to CB2 activation[162] which has been noted elsewhere[163][164] while the suppression of D2 mRNA is due to CB1 activation;[162] this suppression of D2 mRNA has been suggested in utero with mothers who use marijuana,[165] and the receptor or mechanism underlying the heteromerization was not specified.

Low D2 receptor content and the resulting lower dopamine release from drugs is implicated in various drug dependency situations including Alcohol,[166] amphetamines,[167] and cocaine.[168] Chronic marijuana usage, despite the above in vitro study noting reduced D2 mRNA, does not appear to be associated with any abnormalities in dopamine D2 or D3 receptor availability or dopamine release in any tested brain region relative to controls.[169][170][171][172]

While evidence is limited, it seems possible that activation of the CB1 receptor for a subchronic period (week) can reduce the mRNA and transcription for the D2 receptor. With a combined CB1/CB2 agonist (such as Δ9THC) this may occur alongside an increase in receptor content on the cell membrane and an increase in dopamine signalling. A reduced expression of the D2 receptor seen with chronic usage of marijuana has failed to be demonstrated thus far

4.7. GABAergic Neurotransmission

The CB1 receptor is expressed to a large relative degree on GABAergic interneurones in the hippocampus and cerebellum, usually to a larger relative degree than glutaminergic neurons.[173][174] These interneurones (around 10% of total neurons in this brain region[175]) appear to be the target for some CB1 actions in the hippocampus[176] where Δ9THC can act as a full agonist on its own receptors[177] ultimately influencing GABA signalling.[178] Endocannabinoids are known to act on GABAA receptors as positive allosteric modulators (enhancing the actions of GABA agonists without having inherent actions)[179] and due to Δ9THC allosterically modifying all other members of the Cys-loop ligand-gated superfamily (5-HT3A, α7 nicotinic, and glycine receptors[106]) it is thought that THC also acts on these receptors.

When looking at GABA transmission itself, there appears to be an inhibition of hippocampal GABA mediated transmission associated with cannabinoids.[180] Of the two forms of inhibition (phasic inhibition follows a high release of GABA presynaptically while tonic inhibition refers to a slow asynchronous release of ambient GABA), activation of the CB1 receptor results in tonic inhibition.[178] Prolonged exposure to CB1 activation, due to interanalization of CB1 receptors (seen during tolerance), attenuates this inhibition[181] and has been noted to make the local cells relatively more susceptable to excitotoxicity[181] and reduce possible therapeutic effects of cannabinoids for epilepsy (the benefits being mediated secondary to GABA).[182]

Δ9THC appears to influence GABA in an inhibitory manner, secondary to acting on CB1 receptors; there may also be a direct interaction between Δ9THC and GABAA receptors (as this is noted with endocannabinoids) but that has not been elucidated as much. Chronic administration of cannabinoids appears to attenuate this response

During tolerance to Δ9THC in rats, the G-protein activation seen from GABAB receptors does not appear to be altered.[129]

4.8. Glutaminergic Neurotransmission

Glutamate (a major excitatory neurotransmitter) appears to be implicated in the impairments to working memory seen with marijuana usage, specifically Δ9THC.

Initially, Δ9THC appears to act on astrocytes (the CB1 receptors directly on GABA and glutamate dominant neurons are not mandatory for a reduction in long term depression or LTD[183]) and signals through one particular subset of glutamate receptor known as NMDA (NR2B subunit);[183] this is thought to be due to how CB1 activation of astrocytes releases glutamate into the synapse.[184] This activation of NMDA receptors acutely contributed to a reduction in LTD since it caused acute internalization of an AMPA receptor (Glu1/Glu2, comprises over 80% of hippocampal AMPA[185]) and it is thought that Δ9THC reduced signalling through this promnesic receptor since preventing AMPA from being internalized prevented Δ9THC from acutely impairing memory.[183]

Subchronically (one week of THC infusion at 5-10mg/kg in rodents), it appears that Δ9THC causes a downregulation in NMDA receptor expression (specifically the GluR1, NR2A and Nr2B subunits[186][187]) secondary to a dose and time dependent upregulation of COX2[188] while the common glutaminergic target CREB (its activation downstream of both NMDA and AMPA and pivotal for memory formation[189]) has its activation reduced relative to baseline[186] due to less calcium influx from NMDA receptor activation.[187] Physically, the reduced expression of NMDA is likely due to how activation of CB1 bound the two receptors via HINT1 expression[190][191] and subchronic Δ9THC exposure will internalize CB1 bringing NMDA into the cytosol alongside CB1.[192][186]

This results in a reduction in hippocampal plasticity, which is noted in vitro and seen in vivo with subchronic Δ9THC administration,[193][186][183] and thought to underlie long term memory impairment from chronic usage of marijuana. This is a mechanism that is due to tolerance, and is likely reversible upon cessation of marijuana.

Δ9THC is implicated in impairments to working memory related to glutamate signalling, and while this extends to both acute (one time use) and subchronic (week long) usage they are mediated by different means. Acute usage is met with an increase in glutamate overall but altered signalling towards NMDA and away from AMPA (resulting in less synaptic plasticity) whereas for subchronic usage the NMDA receptor gets internalized and isn't available to the same degree for signalling

When looking at the neurons themselves rather than astrocytes, in both the ventral tegmental area (VTA) dopaminergic neurons[194] and hippocampal slices[195] activation of CB1 receptors presynaptically appears to attenuate glutamate release from neurons. Since in mixed cultures (containing both glial cells such as astrocytes alongside neurons) incubated with Δ9THC results in an increase in synaptic glutamate[183] it seems the suppressed release of presynaptic glutamate may not be directly practically relevant.

Although activating presynaptic CB1 receptors would suppress glutamate release, the increase in glutamate release from astrocytes appears to be larger and overrides this possible protective effect (this information is thought to be relevant in understanding the interactions of caffeine and marijuana on memory)

There may be interactions between CB1 and NMDA at the receptor level rather than via glutamate, by the two receptors forming a heterodimer (pairing via a protein known as HINT1 which binds the two receptors,[196] which is thought to bind to the NR1 subunit of NMDA promoting its internalization with no affect on NR2[191][196]) resulting in less glutaminergic activity via NMDA.[191][190] This is thought to be relevant to the actions of Δ9THC since noncompetitive NMDA antagonists can block CB1-mediated analgesia[197][191] and reduce zinc mobilization (involved in epilepsy),[191] both functions known to be relevant to inhalation of marijuana, and in mice lacking the binding protein HINT1 this effect is not observed.[191]

The coupling of CB1 with NMDA ultimately seems to reduce signalling via NMDA.[196][191]

This reduction in NMDA signalling due to an association with CB1 is also thought to underlie some of the neuroprotective aspects of marijuana, since mice lacking HINT1 do not experience protection by CB1 agonists from glutamate-induced neurotoxicity[196] which is known to be mediated by uncontrolled NMDA signalling.

There is a possible interaction between CB1 and NMDA at the level of the receptors on neurons leading towards less NMDA signalling, which may be another possible explanation for some of the side-effects (memory loss and possible increased risk of schizophrenia) and benefits (reduction in epilepsy and neurodegeneration) of marijuana which seem to be linked to a long-term suppression of reduced glutamate signalling via NMDA

4.9. Glycinergic Neurotransmission

Glycinergic neurotransmission (referring to the signalling properties of Glycine and D-Serine) appears to interact with cannabinoids,[198][199] with Δ9THC having a direct potentiating role.[200] The ionic currents activating by glycine in vitro appear to be enhanced by Δ9THC with an EC50 value in the range of 73-115nM depending on the structure of the receptor,[201] are replicated albeit a bit less potent with anandamide,[201] and is unlike both alcohol and volatile anaesthetics (which also potentiate glycinergic neurotransmission) as it is thought to be a direct allosteric modification[201] via hydrogen bonding from the hydroxyl groups on the cannabinoids towards the α1 subunit of glycine receptors.[202][203]

This potentiation has been noted to contribute in part to analgesic properties of marijuana with or without psychoactive effects, since the effects of marijuana are lessened in mice lacking a glycine receptor (α3GlyR).[202]

Glycinergic neurotransmission (a normally sedative neurotransmission that has roles in schizophrenia) appears to be potentiated with cannabinoids, and THC has been noted to exert some pain relieving effects in part due to this pathway in mice

4.10. Opioidergic Neurotransmission

The CB1 receptor is known to participate in crosstalk with opioid signalling, where animal evidence initially noted that administration of an μ-opioid agonist augmented the effects of Δ9THC in rodents[204] and primates[205] where blocking μ-opioid signalling decreases cannabis self-administration in rodents[206][207] and primeates.[208]

Mechanistically, CB1 activation and µ-opioid receptors are synergistic in a manner dependent on the A2A receptor as blocking this adenosine receptor prevents synergism between the two receptors in regards to drug seeking behaviour.[209]

Blocking μ-opioid signalling has been noted to precipitate withdrawal from Δ9THC or other CB1 agonists in chronically treated rats,[206][210] but similar designs failed to find this effect in primeates[211] or heavy marijuaan smoking humans[212] suggesting species differences.

At least when looking at animal evidence, the opioid signalling system and the cannabinoid signalling system seem to positively influence each other in regards to drug self-administration and reward

In heavy smokers, administration of naltrexone (opioid antagonist) alongside marijuana inhalation appeared to increase the percieved high and was also noted to cause impairment to psychomotor function (in a study which marijuana alone was insufficient to do so).[213]

4.11. Serotonergic Neurotransmission

Δ9THC appears to be able to noncompetitively inhibit the effects of serotonin on 5-HT3A receptors (a serotonin receptor subset involved in pain[214] and mood disorders[215]) with an IC50 of 1.2μM, with stronger inhibitory actions in vitro in oocytes when there are less overall 5-HT3A receptors (and accordingly, less inhibitory effects when receptors are abundant)[216] similar to the endocannabinoid anandamide which has similar inhibitory actions on this receptor.[217][218] As inhibiting this receptor confers pain relief[214] and marijuana seems to have a similar clinical profile as 5-HT3A antagonists it is thought this receptor plays a role, further supported by colocalization of 5-HT3 and CB1 receptors in interneurons.[219]

It has been noted that, despite glycine and serotonin receptors both being allosterically modified by Δ9THC, that the hydrogen bonding necessary for glycine receptor interactions does not extend to 5-HT3A receptors.[203]

Noncompetitive inhibition of one serotonin receptor subset (5-HT3A) has been noted with endocannabinoids as well as a low concentrations of Δ9THC, and this is thought to be biologically relevant since the effects of clinical 5-HT3A antagonists seem to have overlap with the properties of marijuana

In regards to other receptor subsets, it has been noted that activation of cannabinoid signalling in the hypothalamus (PVN) causes an upregulation of 5-HT2A receptors[220][163] which is likely mediated by the CB2 receptor activating ERK1/2 signalling, since this upregulation can be blocked by CB2 receptor antagonists[220] and by blocking ERK1/2 signalling.[221]

Subchronic, but not acute, exposure to CB2 agonists has been noted to cause anxiety in rodents.[164] This was noted to occur alongside a downregulation of GABA receptors (and prevented by blocking the CB2 receptor[164]) but was replicated elsewhere where the increase in cannabinoid-induced anxiety was also associated with increased 5-HT2A receptor density.[163] The actions of 5-HT2A are also thought to be increased in vivo, since production of prolactin and corticosterone (increased in part by 5-HT2A activation[222]) are increased in response to weeklong cannabinoid treatment.[163]

Activation of the CB2 receptor subchronically (at least a week) has been noted to increase the receptor density of 5-HT2A in the hypothalamic PVN and subsequent signalling through this receptor

Subchronic (12 day) administration of the synthetic cannabinoid HU-120 has been noted to, while upregulating the aforementioned 5-HT2A receptor by inceasing the actions of its agonists while suppressing the activity of the 5-HT1A receptor subset[223] and the release of corticosterone from a 5-HT1A agonist appeared to be blunted with pretreatment of cannabinoid.[223]

It is possible that, alongside an increase in 5-HT2A receptor activity there is a suppression of 5-HT1A receptor activity induced by cannabinoids in a subchronic manner

4.12. Neurogenesis

Δ9THC is known to have interactions with brain-derived neurotrophic factor (BDNF), having been noted in vitro to upregulate transcription of this protein which is thought to be due to activating the TrkB receptor seen with endocannabinoids.[224]

In vivo, administration of Δ9THC to rats for seven days has been noted to increase the mRNA and protein content of BDNF in several brain regions in particular the nuclear accumbens (NAc; 5.5-fold increase in protein content[225]), the ventral tegmental area (VTA; 4-fold[225]) and the paraventricular nuclei (PVN; 1.7-fold[225]) with no influence in the hippocampus.[225]

CB1 agonists which are not Δ9THC have been noted to reduce BDNF expression in some brain regions (frontal cortex and hippocampus) following chronic exposure.[226] Reduced BDNF expression, which subsequently reduces its signalling through its receptors (including TrkB), causes reduced ERK signalling[226] which is also reduced during cannabinoid tolerance with Δ9THC in the rat hippocampus[227] despite acutely increasing activation of ERK signalling.[228]

The above seems to be intertwined with glutaminergic signalling, as the initial stimulation of ERK and other MAPKs by Δ9THC has once been found to be partially dependent on NMDA receptors[229][228] while fully dependent on CB1 receptors[230][229] and D1 dopamine receptors;[229] the stimulation of ERK itself is known to increase BDNF mRNA transcription while mediating the effects of synthesized BDNF.[231][232]

It appears that cannabinoids can, acutely, increase the transcription of brain-derived neurotrophic factor (BDNF) and its content in brain cells since it can activate ERK dependent on CB1, D1, and NMDA receptors; the tolerance to cannabinoids and internalization of these two receptors seems to precede a subsequent tolerance

Endocannabinoids, via acting on CB1 (and thus thought to apply to Δ9THC), seem to additively promote interneuron migration alongside BDNF in a manner dependent on the TrkB receptor and Src which lay downstream of it;[224] the interneurons in this study used were the cholecystokinin expressing GABAergic interneurons.[224]

The BDNF-induced morphogenesis of interneuons, however, appears to be suppressed in the presence of CB1 activation in a manner also dependent on TrkB-Src signalling.[224]

Activation of CB1 receptors appear to have some effects on interneurones migration and morphogenesis; practical relevance unknown

Injections of Δ9THC into participants has been noted to have differential effects on serum BDNF based on marijuana tolerance, with users (at least 10 times in the last month) having lower baseline BDNF in serum.[233] The nonusers, aside from having a higher baseline BDNF, experienced an acute increase in serum BDNF 20 minutes after injections which was normalized after an hour.[233]

The influence of Δ9THC on BDNF appears to be one that is subject to marijuana tolerance, and chronic tolerance is thought to be a contributing factor to reduced baseline BDNF. The changes seem in serum seem to reflect what is thought to occur in the human brain (based on rodent evidence)

4.13. Neuroinflammation

Marijuana is known to have components that control inflammation in the brain via acting on glial cells, which are macrophage-like brain cells that support neuronal function and highly involved in neurodegenerative disorders when overactivated.[234][235]

Δ9THC can suppress inflammation in these cells secondary to acting on CB2 receptors,[236] and despite cannabidiol (CBD) not activating CB2 receptors it appears to suppress the inflammatory genomic response to LPS[237] (an inflammtory stimuli) and has been noted to reduce the expression of IL-1β by 81% at 10µM.[237] The mechanism of cannabidiol may be secondary to PPARγ, as it has been noted to act on this nuclear receptor to exert antiinflammatory effects on glial cells not related to cannabinoid receptors.[238][239]

Cannabinoids appear to acutely suppress inflammation in the brain, and both Δ9THC and CBD appear to be active although by different mechanisms

4.14. Headaches and Blood Flow

Orthostatic hypotension/dizziness upon reaching a standing position from a supine position has been noted with intravenous administration of isolated Δ9THC in otherwise healthy persons[240][241][242] (around 28% of users[243]) thought to be related to decreased cerebral blood velocity as assessed by transcranial Doppler measures seen with marijuana inhalation.[244] This orthostatic hypotension appears to be subject to tolerance with chronic Δ9THC administration, which was noted alongside edema and thought to be related to a counterregulatory increase in blood volume.[240]

Naive users to marijuana may experience orthostatic hypotension upon standing up, and this orthostatic hypotension appears to not be a significant concern to those tolerant to marijuana

The decrease in middle cerebral blood velocity is seen with mild and major instances of orthostatic hypotension associated with marijuana after 10 minutes[244][243] and not related to plasma THC content.[243]

When looking at the hemispheres of the brain there appears to be an increase in cerebral blood flow relative to placebo inhalation between 30-120 minutes (no longer present at the two hour mark) in both hemispheres and globally which is dose-dependent.[245][246] This increase in cerebral blood flow is mediated by CB1 receptors[247][248] (despite the CB1 receptors not being highly involved in blood flow regulation under baseline conditions[247]) and has been noted in humans subject to positron emission tomography with intravenous Δ9THC[249][245] favoring the frontal lobes, right hemisphere, and specifically the anterior cingulate (highly involved in cardiovascular functions such as heart rate).[249]

Persons with orthostatic hypotension shortly after inhaling marijuana experience reductions in blood flow velocity which is thought to be the cause of said orthostatic hypotension, while in other situations there appears to be an increase in overall blood flow to the brain for up to an hour after inhalation

4.15. Analgesia

Marijuana inhalation appears to have a dissociative effect on pain, not necessarily reducing percieved intensity of the pain[250] but reducing the reported unpleasantness of the pain[250] due to CB1 activation from Δ9THC.

The efficacy of the dissociation from CB1 activation seems to be related to pain severity as it is more prominent in hyperalgesic states,[251][252] it can occur in people who have never used marijuana before,[250] and is dose-dependent[250] occurring within 45 minutes of inhalation.[251]

At least one study using an active dose of 20mg Δ9THC failed to find any pain relieving effects 2.5 hours after oral ingestion of a capsule despite that being in the range of peak plasma concentrations.[253]

There appears to be an acute analgesic effect of Δ9THC when administered either as capsules or as inhalation seen in most evidence, and this appears to be best tested with the capsaicin model (neuropathic pain)

The dissociation of pain seen in otherwise healthy volunteers (naive to Δ9THC and given 15mg) where pain was induced by topical Capsaicin appears to be associated with right amygdala activity;[250] a brain region that preferentially processes highly salient stimuli[254] and is known to be involved in pain perception.[255][256] This is thought to partially explain the analgesic effects, since some peripheral mechanisms may also contribute to the observed analgesic effects from CB1 activation.[257]

The dissociation of sensing pain and being bothered by its severity appears to be related to the amygdala, specifically the right hemisphere.

Marijuana has been tested in the treatment of neuropathic pain, and found to be effective in reducing pain when smoked compared to placebo (0% THC content).[258][259] Vaporized marijuana was also found to be effective in reducing pain relative to placebo, including in patients whose neuropathic pain was resistant to traditional treatments.[260] Smoking marijuana was also found to be effective specifically in HIV-related neuropathic pain in placebo-controlled trials, providing benefit similar to other therapies for neuropathic pain[17296917] and providing additional relief when added on top of other therapies to manage pain.[261]

Vaporized and smoked marijuana appears effective in reducing neuropathic pain due to various causes, including physical trauma and HIV.

4.16. Appetite and Food Intake

Marijuana is well known to increase hunger, initially being known to cause 'munchies' in users but later used medicianlly for cachectic states where weight loss from little food intake is medicinally concerning (AIDS/HIV as well as cancer related cachexia).[262] These actions of marijuana are traced back to Δ9THC acting upon the CB1 receptor, and intimately intertwined with the hormone ghrelin which is normally secreted from the stomach and intestines in response to food deprivation in order to increase hunger.[263]

Ghrelin ultimately increases food intake via acting in the hypothalamus, and this is usually indicated by an increase in hypothalamic AMPK activity (locus point for nutrient sensing[264][265]). This action is dependent on both the CB1 receptor[266] and the ghrelin (GHS-R1a) receptor[267] while the same holds true for cannabinoids such as Δ9THC.[267] It is also known that ghrelin can increase synthesis of the endocannabinoid 2-arachidonoylglycerol dependent on CB1.[266]

Interestingly, this requirement for CB1 activation from ghrelin is due to peripheral rather than central CB1 receptors as antagonists that cannot reach the brain are still highly effective in blocking the effects of centrally administered ghrelin.[268] Since CB1 antagonists that reach the periphery but not the brain are not associated with anxiety,[269] and are being tested as antiobesity agents.[270]

The appetite increasing properties of marijuana (cannabinoids in general) is not only dependent on activating its CB1 receptor, but is also highly intertwined with the signalling of the 'gut-brain' hunger hormone known as ghrelin.

Inhalation of cannabis in HIV patients (blinded) has been noted to suppress serum PYY concentrations[271] and increase serum ghrelin,[271] both changes seen as favorable towards hunger.

An increase in serum ghrelin has been noted in humans who smoke marijuana

4.17. Attention and Focus

In heavy marijuana users (average six sessions weekly with 5.4+/-1 joints each) who are given cigarettes containing 800mg marijuana (5.5% or 6.3% Δ9THC) and then given an attention test involving tracking an item on a computer screen for 10 minutes, marijuana did not appear to worsen attention relative to placebo inhalation.[272]

Chronic marijuana usage has been associated with a reduction in motivation (ie. apathy), which has been associated in humans (PET imaging) with a reduction in dopamine synthesis seen with chronic marijuana usage.[273]

A reduction in motivation seen in chronic cannabis use may be associated with a reduction in dopamine synthesis

4.18. Epilepsy and Convulsions

Endocannabinoids were initially thought to have a protective effect in epilepsy, since they are released from neurons when a seizure occurs[274] and control seizure frequency and duration via acting on CB1[275][276] (preventing them from doing so will increase the severity of the seizure,[274][277] and the downregulation of CB1 receptors seen with subchronic exposure in vitro results in less tonic inhibition[181] and anticonvulsant activity[182]).

The anti-epileptic function is known to be due to CB1 activation,[276] and is thought to be specifically due to the heterodimer formed between CB1 and NMDA (a glutamate receptor) which suppresses glutamate signalling.[191]

Excessive glutamate signalling will promote seizures due to acting on NMDA, which then causes a high amount of calcium influx and production of Nitric Oxide within the cell (via increasing nNOS activity) which gets oxidized to form peroxynitrate; the subsequent release of Zinc in these neurons from peroxynitrate then greatly exacerbates the excitatory signalling from glutamate leading to disregulated neuronal firing.[278][279] Activation of CB1 reduces the aforementioned pathway by blocking the initial stage of NMDA being activated to such a high degree,[191][280] and CB1 is thought to be the endogenous regulator that best hinders excessive NMDA signalling.[190][187]

The antiepileptic actions of THC are known to be secondary to its actions on the CB1 receptor, and it is further thought to be due to how CB1 activation will reduce too much activity from the excitatory neurotransmitter glutamate; this appears to be a mechanism that is subject to tolerance

4.19. Anxiety and Stress

One meta-analysis of numerous cohort studies assessing the association of marijuana usage or marijuana use disorders in the general population (noninstitutionalized)[281] assessing various states of anxiety such as trait/state anxiety,[282][283][284] anxiety disorders (social, general, and other),[285][286][287][288][289][290][291][292][293][294][295][296][297][298] anxiety and mood disorders (AMD),[299][300][301][302][303][304][305] post-traumatic stress disorder (PTSD) and panic disorders,[306][307][308] and other types of anxiety diagnoses (at times with other neurological disorders such as anxiety during obsessive compulsive disorder)[309][310][290] observed that while there appeared to be an overall positive relationship with long-term marijuana usage that it was relatively small in magnitude. This included associations between anxiety and marijuana (Odds Ratio (OR) of 1.24 with a 95% confidence interval (CI) of 1.06-1.45), anxiety and marijuana use disorders (OR of 1.68; CI of 1.23-2.31), and marijuana use with combined anxiety and depression (OR of 1.68; CI of 1.17-2.40).[281]

While only five studies were available for establishing a temporal relationship (by measuring the same individuals at two time points) it does seem that people who used marijuana early on had an increased risk of developing anxiety later on compared to users who did not use marijuana (OR of 1.28; CI of 1.06-1.54).[281] This study also extracted the higher doses and usage times of marijuana but used the more conservative ORs from each study, and controlled for confounds when possible[281] since some other drugs commonly ingested alongside marijuana (such as Nicotine via tobacco products) may increase longterm risk of anxiety symptoms.[311]

Marijuana appears to be associated with an increased risk of developing anxiety and panic symptoms (to the degree where a disorder can be diagnosed) over the course of numerous years of continuous usage, although the increased risk seen with long-term marijuana use appears to be relatively small not usually exceeding an odds ratio of 2.00 (meaning double risk)

4.20. Depression

In heavy adolescent and adult marijuana users (approximately daily usage) there does not appear to be any increased risk for depression in later in life when compared to non-smokers.[291][312] Although at times a positive association has been noted between marijuana use and depressive symptoms,[313][314] unlike anxiety this is eliminated after controlling for confounding factors.[315][316] Moreover, when intentionally seeking out heavy marijuana users with significant depression, marijuana use appeared to be associated with less depressive symptoms relative to those who did not use marijuana.[317]

There is however a mildly increased risk for diagnosis of combined depression and anxiety in subjects who chronically use marijuana, as noted in a recent meta-analysis (Odds Ratio of 1.68 with a 95% confidence interval of 1.17-2.40).[281] Importantly, combined depression and anxiety is a distinct diagnosis from solely depression.

Long-term marijuana use does not appear to be associated with increased long term risk for developing depressive symptoms when compared to nonusers. Although some positive associations have been noted, there are often confounding factors present in people who use marijuana (such as social status or other drug usage) that contribute to the development of depression.

4.21. Memory and Learning

Memory function is known to be impaired in healthy individuals who smoke marijuana regularly,[318][319][320] and the degree of memory impairment has been correlated with self-reported frequency of smoking.[321][322] The memory-impairment effects of marijuana have been attributed to its Δ9THC content, since this cannabinoid in its pure form has been shown to suppress working memory in research animals.[323]

Δ9THC induced memory impairment occurs via CB1 mediated induction of cyclooxygenase-2 (COX-2),[188] an enzyme that converts arachidonic acid to prostanoids in the brain. Cox-2 induction downstream of CB1 appears to be necessary for memory impairment by Δ9THC,[188] as inhibiting either the CB1 receptor[324][183][186] or COX-2[188] can limit the effects of CB1 activation on memory impairment.

Chronic administration of Δ9THC may also negatively effect memory by impairing synaptic plasticity. CB1 receptor agonists have been shown to suppress NMDA glutamate receptor-mediated calcium influx,[187] resulting in less CREB phosphorylation and decreased synaptic plasticity that may ultimately impair memory formation.[186]

Δ9THC appears to impair memory via CB1 receptor activation, which affects multiple downstream signaling pathways important for memory. CB1 activation has been shown to impair memory by activating COX-2, suggesting that COX-2 inhibitors may ameliorate some of the negative effects of marijuana on working memory. CB1 activation has also been shown to limit NMDA glutamate receptor-mediated calcium influx that is important for memory formation.

In regards to working memory (the ability to store and manipulate information for a few seconds at a time in order to execute a task[325]) there have been reductions in working memory relative to controls in a dose-dependent manner when given a battery of tests.[321] This is commonly referred to as a 'residual' effect, which is seen in near daily users but not in once monthly users.[326][327] While marijuana may affect multiple parameters of cognition, the one that appears to be most frequently affected in an adverse manner is the attention/working memory domain,[318] with an increase in forgetting and decrease in motor control also being common.[318]

When abstaining from marijuana for one month, heavy users (94+/-15 joints a week) do not return to baseline working memory and cognition whereas moderate (42+/-18 joints a week) and light (11+/-4 joints a week) users appear to fully normalize.[321]

Heavy marijuana usage (near daily), rather than light usage (once monthly), appears to be associated with reduced working memory and performance on various tasks that require working or spatial memory. This effect may persist for months after marijuana cessation for very heavy users, but it is otherwise temporary.

In marijuana users who have since abstained, at least one twin study has failed to find a long-term impairment to cognition (with a median 20 years of marijuana cessation)[328] and a meta-analysis assessing shorter term studies suggested that possible impairment is limited to 25 days as it failed to find any impairment for periods longer than that.[329]

Chronic memory impairment from marijuana appears to be more of a "sustained transient" state due to the long half-life of THC in the body, and users of marijuana do not appear to have any long-term impairment to memory function after cessation

In studies of heavy users given marijuana under acute conditions, inhalation has been noted to impair immediate word recall as assessed by a digit recall task.[272]

Edit5. Cardiovascular Health

5.1. Cardiac Tissue

Inhalation of marijuana smoke is known to increase heart rate at rest.[330][331] This increase in resting heart rate varies from 20-100% greater than baseline (when measured supine; it is lower when standing), occurs within 10 minutes of inhalation, and persists for two to three hours.[332] Although marijuana increased heart rate relative to control during submaximal exercise,[330] no differences were noted at intensities that exceeded 80% maximum, nor were there any differences in maximal exercise-induced heart rate between groups.[330]

Increases in heart rate upon smoking marijuana can occur even in heavy users[213] and have been suggested to correlate with the percieved high.[213] In contrast, one study noted that attenuation in subjective intoxication with oral synthetic Δ9THC adminstration over the course of a week was not met with an attenuation of heart rate, suggesting that heart rate may increase independently of psychotropic effects.[333] More prolonged usage of Δ9THC is associated with not only a normalization of heart rate, but a refractory decrease in heart rate relative to baseline.[240]

There is an increase in heart rate associated with both marijuana smoking and oral ingestion of pure Δ9THC. The increase seems to scale with the psychoactive effects of marijuana acutely, but the increase in heart rate does not attenuate with tolerance to the psychoactive effects over longer periods of time. Heart rate may in fact decrease below baseline with longer-term exposure to Δ9THC.

Marijuana-induced increases in heart rate can be attenuated with beta-blockers[242][241] or atropine[241], the combination of which nearly abolish any changes in heart rate[241] or other cardiac measures.[334] This suggests that the heart-rate increasing effects of marijuana are mediated by both cholinergic (atropine) and adrenergic (beta-blockers) mechanisms.

These effects may originate from the central nervous system,[334] since Δ9THC has been noted to increase blood flow to the anterior cingulate cortex in a manner correlating with the depersonalization effects of this drug.[249] The activity of this brain region, which is enhanced with marijuana inhalation,[335] is also involved in the regulation of cardiovascular function.[336][337] The anterior cingulate cortex has also been observed to develop hypoactivity with chronic usage[338] (possibly resulting in atrophy[339]), correlating with the time course of the effects of marijuana on heart rate.

Marijuana's actions on the heart seem to occur through central (brain-mediated) means rather than directly, and are correlated with increased activity of the anterior cingulate cortex.

The cannabinoid receptor CB1 has been detected in endothelial cells from the human aorta[340] where its activation leads to increased free radical production and Mitogen-Activated Protein Kinase (MAPK) activation which leads to cell death.[340][341] These tissues also express CB2 receptors which appear to have antiinflammatory actions when activated resulting in less immune cell adhesion to these tissues as the adhesion factors (induced by inflammation) are suppressed.[342][343]

The cannabinoid receptors CB1 and CB2 are expressed throughout the cardiovascular system. Neither the degree to which marijuana consumption may activate them, nor the resulting physiological responses are well- understood.

5.2. Atherosclerosis

Atherosclerosis is a disease that is driven by chronic inflammation, where fatty deposits and immune cells enter the walls of blood vessels causing progressive narrowing and restriction of blood flow. It has been noted that cannabinoids have both immunosuppressive and anti-inflammatory properties,[344][345][346] suggesting they may have potential as therapeutics for atherosclerosis.[347] CB2 has been found to be upregulated in diseased arteries due to the accumulation of immune cells expressing this receptor on the diseased arterial wall.[347] Notably, signaling through the CB2 receptor is both immunosuppressive and anti-inflammatory, suggesting that cannabinoid signaling through CB2 receptors may be part of a negative feedback mechanism that suppresses the formation of atherosclerotic plaques.

Consistent with this idea, human foam cells, which are damaged macrophages that develop after engulfing oxidized lipids,[348] have been found to have greater amounts of CB2 than the macrophages from which they are derived.[349] In vitro evidence also has indicated that activation of the CB2 receptor on macrophages could be protective against atherosclerosis by reducing macrophage recruitment[350] and suppressing the accumulation of oxidized lipid droplets,[349] resulting in reduced accumulation of foam cells.[348] The anti-atherosclerotic effects of the CB2 receptor have also been confirmed in vivo, where Δ9THC orally at 1mg/kg (peak effective dose) daily in ApoE-/- mice hindered progression of atherosclerosis via the CB2 receptor.[347] Notably, the concentration of Δ9THC in serum from this study was well- below levels required for psychoactive effects.

In vitro and animal data suggest that activation of the CB2 receptor via Δ9THC confers an antiinflammatory effect that reduces the progression of atherosclerosis. This occurs at serum concentrations lower than required for psychoactive effects.

Activation of the CB2 receptor appears to work via reducing the amount of oxidized LDL cholesterol (oLDL) that is accumulated by macrophages, secondary to downregulating the binding protein CD36 (aka. the macrophage binding receptor).[349] CD36 is central to accumulating oLDL and initiating the production of foam cells, and is known to have its own expression enhanced during the inflammatory process initiated when binding to oLDL;[351][352] this inflammation is reduced by CB2 activation as evidenced by a subsequent reduction in the inflammatory cytokines TNF-α, IL-10, and IL-12.[349]

There may be an efflux of cholesterol out of already-formed foam cells secondary to CB2 activation, since it has been noted that CB2 activation has caused an increase in ATP-Binding Cassette sub-family G member 1 (ABCG1) protein levels,[349] which is responsible for transporting excess cholesterol out of cells.[353] It is hypothesized that the 15-lipoxygenase inhibition seen with some cannabinoids (most notably the cannabidiol metabolite CBDD) may have a role in reducing LDL oxidation[121] as this enzyme is able to oxidize LDL when active[354][355] and cannabinoids are highly lipophilic and carried in plasma by these lipoproteins.[70]

Uptake of oxidized LDL cholesterol into macrophages produces foam cells, a critical factor for atherosclerotic buildup. Activation of CB2 via Δ9THC appears to prevent oxidized LDL from binding to the macrophage, reducing its uptake and ultimately reducing foam cell production.

In contrast to CB2, activation of the cannabinoid signaling system through the CB1 receptor is proatherogenic[356][357] (although some compounds that inhibit CB1 also have confounding actions which may also be beneficial (direct acyl CoA:cholesterol acyltransferase inhibition[358][359]). CB1 receptor activation has been shown to promote cholesterol accumulation in macrophages, leading to foam cell formation.[360] This has been confirmed in vivo, where the CB1 receptor antagonist rimonobant inhibited atherosclerosis in LDL receptor-deficient mice.[361] Although marijuana activates CB1 and CB2 receptors with similar affinity, cells of the immune system tend to have much higher levels of CB2, which may explain why the mixed agonist Δ9THC ultimately has protective effects in mice when orally ingested.[347] Moreover, the negative effects of CB1 activation may explain why the benefits of Δ9THC are not dose dependent.[347]

Although macrophages are traditionally considered as the source of foam cell formation, resident vascular smooth muscle cells are also capable of developing into foam cells.[362][363] The Transient Receptor Potential Vanilloid Type 1 (TRPV1) receptor, a protein widely expressed in vascular smooth muscle cells that also reduces lipid accumulation,[364] is known to be activated by components found in marijuana.[365][366] This is known to reduce foam cell formation.[367] This receptor is also found in macrophages and is downregulated in foam cells derived from them, although activation in these cells may actually increase lipid droplet accumulation.[349]

5.3. Blood Pressure

Marijuana smoking is known to increase resting systolic and diastolic blood pressure in otherwise healthy subjects who do not identify as heavy users[331] whereas heavy users experience either no changes or a potential decrease in diastolic blood pressure when given Δ9THC.[333] Changes in blood pressure seem to be more marked with diastolic pressure, and occur alongside alterations in heart rate.[331][330] Increased blood pressure may be partly driven by the action of THC on CB1 receptors in the brain, which is known to increase heart rate and produce acute increases in blood pressure.[368] Marijuana-induced increases in blood pressure may be limited to more occasional users, as one study in heavy users with isolated Δ9THC administered continuously over six days did not see such an effect, instead observing a consistent hypotensive effect.[333]

Acute usage of marijuana leads to an increase in both systolic and diastolic blood pressure alongside an increased heart rate. This occurs quite rapidly after oral ingestion of Δ9THC or inhalation. These increases are subject to tolerance and may result in a refractory decrease in resting blood pressure in heavy users.

Abrupt cessation of marijuauna usage (usage at least 25 times monthly for minimum of one year) was associated with an increase in systolic (7.8%), diastolic (9.3%) and mean arterial blood pressure (8.7%) for the first three days of cessation in a manner that was not associated with heart rate. These changes were normalized when marijuana was resumed,[369] and most subjects (69%) in this study did not experience increases large enough to meet hypertension criteria.[369]

Abruptly stopping chronic marijuana usage can result in a refractory increase in blood pressure.

5.4. Platelets and Viscosity

In vitro evidence suggests that some components of marijuana may inhibit platelet aggregation by blocking ADP-induced platelet aggregation.[370] The ADP-induced aggregation was inhibited in a dose-dependent manner, with cannabigerol being the most potent, followed in decreasing potency by cannabidiol, olivetol, Δ1THC and cannabinol.[371] The inhibition caused by cannabidiol and Δ1THC is countered by adding higher levels of ADP.[372]

Serotonin is taken up and stored by platelets; when these platelets are activated, serotonin is released, which functions both as a vasoconstrictor as well as an activator of additional platelets.[373] Pure Δ9THC at 30-70mg acutely does not appear to modify platelet serotonin concentration relative to baseline two hours after administration,[133] as the noncompetitive inhibition of Δ9THC on platelet serotonin uptake occurs at very high concentrations (IC50 of 139 µM).[374] Serotonin release from the platelets of migraine sufferers was also inhibited at similar levels[375]. An in vitro study found that the inhibition of serotonin release by cannabinoids was not correlated to their ability to inhibit platelet aggregation.[371] Despite this, male moderate marijuana users (3-7 joints per week for 2-12 years) appeared to have a slightly increased Vmax for serotonin uptake in platelets when compared to nonsmoking controls (this effect was not observed in females).[374]

5.5. Triglycerides

Intraperitoneal injection of 10mg/kg body weight cannabidiol into Wistar rats did not affect triglyceride levels, although injection of 5mg/kg THC was seen to significantly raise them.[376]

Although present in rats, the effects of marijuana on triglycerides do not appear to occur in humans. A large longitudinal study examining marijuana usage found a correlation between marijuana use and elevated triglyceride levels in young users, although this correlation disappeared when concurrent alcohol use was taken into account.[377] A smaller case-control study found no association between marijuana use and triglyceride levels.[378] An additional study which examined self-reported past or present use of marijuana in adults found no association with triglyceride levels.[379]

Based on observational human evidence, there seems to be no correlation between marijuana use and triglyceride levels once confounders are taken into account.

5.6. Cholesterol

Intraperitoneal injection of 10mg/kg body weight cannabidiol into Wistar rats was observed to reduce HDL levels, while a 5mg/kg injection decreased both HDL and total cholesterol.[376]

Observational studies have failed to note changes in total cholesterol levels among marijuana users,[377] and either a decrease,[378] increase,[380] or no change[377][379] in HDL-C. No interventional research concerning the effects of active components of marijuana on cholesterol has been performed to date.

When total cholesterol and LDL-C are investigated, similar mixed results are noted, with one study reporting a possible decrease[380] and another reporting no significant changes.[377]

Current research on the effects of marijuana on cholesterol levels is inconclusive.

Edit6. Interactions with Glucose Metabolism

6.1. Insulin

Current usage of marijuana appears to be associated with a reduction in fasting insulin concentrations (16% after adjusting for multiple possible confounders) relative to those who report having never used marijuana.[379] This reduction is not thought to be due to pancreatic damage since a different case-control study failed to find any association with marijuana usage and β-cell function.[378]

Although not currently well understood, the mechanisms responsible for marijuana-induced reduction in fasting insulin may occur via attenuation CB1 receptor signaling that could increase adiponectin levels,[381] resulting in increased insulin sensitivity[382] and therefore reduced production of insulin.[379] Consistent with this idea, CB1 receptor knockout mice are resistant to diet induced obesity,[383] which is suggestive of an important role for this receptor in glucose homeostasis. Moreover, in addition to containing the cannabinoid receptor agonist THC, marijuana also contains cannabidiol, which is a cannabinoid receptor antagonist. Thus, it is plausible that known or yet-to be identified components of marijuana may reduce fasting insulin concentrations via an adiponectin-mediated mechanism that is driven by decreased signaling through the CB1 receptor.

6.2. Insulin Sensitivity

Insulin sensitivity as calculated by the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was observed to be higher in current users of marijuana (used at least once in the past 30 days) when compared to controls who never used marijuana. No dose-dependency between marijuana use and insulin sensitivity was noted, however.[379] This increase in insulin sensitivity was not observed in another study of long-term heavy marijuana users (average of six joints daily over 9.5 years),[378] although this study used calculations of insulin sensitivity which differed from the previous study. However, the study of chronic users did reveal an increase in adipocyte insulin resistance despite no change in the other measures of insulin sensitivity.[378]

Observational studies have yielded mixed results concerning marijuana's effect on insulin sensitivity. One study noted that recent use may increase sensitivity, while another study found no effect in long-term heavy users. Thus, the effects of marjijuana on insulin sensitivity in different populations are not well-understood.

6.3. Blood Glucose

Data from the National Health and Nutrition Examination Survey (NHANES III) showed that past and current marijuana users appear to have lower concentrations of fasting glucose (92.3-93.1mg/dL) when compared to those who have never used marijuana (97.8mg/dL).[380] In contrast, a small study examining the acute effects of marijuana on carbohydrate metabolism saw no evidence of hypoglycemia in the fasted for fed state in chronic marijuana users after smoking,[384] suggesting that the effects of marijuana on blood glucose may manifest over time, rather than acutely.

6.4. Glycogen

There are no clinical studies on the effects of marijuana on glycogen. However, some data from animal models and in vitro experiments do exist.

In animal models, acute administration of cannabis extract to rats decreases glycogen stores in the liver,[385] while repeated exposure to cannabis extract decreases uterine glycogen stores in rats.[386]

Indirect in vitro evidence using human tissue suggests that the cannabinoid system may affect glycogen levels. AMP-activated protein kinase (AMPK) functions as a cellular energy sensor, inhibits glycogen synthesis in muscle cells, and is involved in a number among other metabolic processes associated with energy homeostasis.[387] The endocannabinoid system is present in human skeletal muscle and plays a role in oxidative energy metabolism, with CB1 antagonism affecting the expression of several proteins including AMPK. However cellular and molecular control of energy homeostasis is quite complex, requiring a number of other receptors and signaling pathways that also play a role and complicate the picture.[388] Some of these additional receptors include Transient Receptor Potential channel-Vanilloid sub-family member 1 (TRPV1) and CB2.[389] Rat studies indicate that CB1 agonism using Δ9THC did not affect AMPK activity, however.[390]

6.5. Glycation

Data from NHANES III suggests that current and past usage of marijuana appears to be associated with a significantly reduced prevalence of elevated HbA1c in serum (3.2-4.2% of users having an HbA1c exceeding 6.0%) when compared to persons who have never used marijuana (8.7% of the sample exceeding an HbA1c of 6.0%).[380] However, another study using NHANES III data found that, while unadjusted average HbA1C levels were significantly lower in current and past users, this effect disappeared once the data were adjusted for possible confounders.[379]

6.6. Type I Diabetes

A collection of case studies has suggested that marijuana usage may 'mask' ketoacidosis, with less than expected increases in blood acidity relative to ketone concentration and symptoms. This ketonuria was remedied with intravenous insulin.[391] It has also been noted that marijuana given to obese rats, was associated with weight reduction and an increase in pancreas weight, suggesting that it may have conferred a protective effect to pancreatic beta cells.[392] This suggests that marijuana may prevent the onset type I diabetes in certain animal models.

6.7. Type II Diabetes

In a cross-sectional analysis of NHANES data, it appears that current or past marijuana users were at a lower risk of having type II diabetes when compared to those who never used marijuana (overall OR 0.42 and a 95% CI of 0.33-0.55). In this study past users, (OR 0.44, 95% CI 0.33-0.59), light current users (OR 0.29, 95% CI 0.13-0.65), and heavy current users (OR 0.47, 95% CI 0.22-0.98) were all found to be at lower risk for type II diabetes.[380] These protective effects occured alongside reductions in serum C-reactive protein, which is suggestive of a mechanism related to inflammation.[380] Another study also using NHANES data found reductions in fasting insulin (16%) and improved insulin sensitivity (17%) in marijuana users.[379]

Self-reported usage of marijuana appears to be associated with a significantly reduced risk of developing type II diabetes when compared to those who do not use marijuana.

Edit7. Fat Mass and Obesity

7.1. Adipokines

Both marijuana[393] and the endogenous cannabinoid anandamide[394][395] have orexigenic (appetite increasing) effects. It was noted in one study that the appetite-increasing effects of ghrelin, an orexigenic peptide, were blocked by the cannabinoid receptor antagonist rimonabant,[396] suggesting the some of the appetite increasing effects of marijuana occur via increased ghrelin levels. Moreover, rimonabant also reduced ghrelin secretion, leading to reduced food intake in food deprived rats.[397]

The hypothalamus is highly enriched in CB1 receptors,[398][396] and it has been demonstrated in rodents that rimonabant blocks the appetite-stimulating effects of ghrelin when infused directly into this region of the brain.[396] Thus, the appetite stimulating effects of marijuana appear to occur via increased ghrelin levels that activate CB1 receptors in regions of the hypothalamus important for appetite control.

Marijuana also has been shown to directly increase ghrelin levels in humans. In a prospective subgroup analysis of a trial investigating the effect of smoked cannabis on neuropathic pain in HIV-positive men,[261] inhalation of marijuana was noted to increase circulating ghrelin by 42.4% (range of 27-59%).[271]

Inhalation of marijuana increases ghrelin levels, which is partly responsible for its appetite-increasing effects.

Inhalation of marijuana over a week has also been noted to increase circulating levels of leptin to a large degree in one preliminary trial in an HIV-infected population (67.1% relative to 11.7% in placebo).[271] Considering that marijuana stimulates appetite via increased ghrelin levels, this result was counterintuitive, as leptin normally acts to suppress appetite by upregulating the production anorexigenic (appetite-reducing) neuropeptides[399][400] and downregulating the production of orexigenic ones.[401]

It is not clear whether the counterintuitive marijuana-induced increase in leptin levels may be population-specific, or even of functional significance. Given the effects of marijuana on ghrelin, it is possible that leptin levels may increase as part of a negative feedback mechanism. Because calorie intake was not monitored in the HIV study,[271] it also cannot be ruled out that the increase in leptin levels may have occurred via increased food intake, a known stimulus for leptin production.[402][403]

One study noted that marijuana increased leptin levels. While large in magnitude, this has not been replicated in other studies. Thus, the reproducibility and practical significance of this result is not clear.

7.2. Lipolysis

It has been noted that cannabinoids, similar to the peptide ghrelin,[404][405] can directly suppress lipolysis in adipocytes via CB1 activation resulting in an increase in lipid accumulation. This causes a shift in energy utilization away from fatty acids and towards glucose.[406] Localized activation of CB1 receptors may also explain the increase in adipocyte insulin sensitivity observed in marijuana users despite no alterations in whole-body insulin sensitivity.[378] In vitro studies suggest that this phenomenon may indeed be due to CB1 activation.[407] This effect appears to be dependent on cannabinoid concentration as well as the presence of insulin; in vitro studies have shown that 5μg/mL Δ9THC increases triglyceride accumulation whereas 2.5-10μg/mL Δ9THC in the presence of insulin suppresses triglyceride accumulation and adipogenesis.[408]

Glucose uptake into adipocytes also appears to be enhanced subsequent to CB1 activation,[409] despite decreased AMPK activity.[390] This appears to occur via increased PI3K signaling, leading to enhanced GLUT4 mobilization and glucose uptake.[409] Notably, PPARγ does not play a role here.[410] Both insulin-stimulated as well as basal glucose uptake are enhanced by cannabinoids in vitro.[409][410]

Other studies assessing the anti-lipolytic effects of cannabinoids have found a suppression of peripheral AMPK (mostly in visceral fat tissue)[390] as well as carnitine palmitoyltransferase 1 (CPT1)[411][412] in adipose and hepatic tissue despite both being elevated in neuronal tissues.[390][413]

Activation of the CB1 receptor in fat cells appears to reduce fat oxidation rates, switching energy utilization away from lipids and towards carbohydrates.

Beyond suppressing lipolysis, CB1 activation can also increase lipogenesis via increasing the expression of proteins such as SREBP-1c,[414][415] fatty acid synthase (FAS),[414] and lipoprotein lipase (LPL)[416] while inhibiting adenylyl cyclase.[417] This has also been noted to increase adipocyte maturation and triglyceride content[417] due to increased activity of the nuclear receptor PPARγ.[417][409] Because adipocyte proliferation is abolished when PPARγ is blocked, CB1 activation also appears to have a proliferative effect in adipocytes.[418]

7.3. Weight

The endocannabinoid system appears to have a location-specific influence, and during the state of obesity subcutaneous body fat exhibits a relative decrease in endocannabinoid (anandamide and 2-AG) concentrations[419][420][421] whereas visceral body fat exhibits an increase.[422][423] While it is thought that this difference may play a role in imbalances in a viceral:subcutaneous body fat ratio by favoring deposition of lipids in the former,[424] studies investigating weight circumference (a proxy measure of visceral fat content) have found both increases[378] and decreases[379] in marijuana users relative to controls.

Current marijuana use appears to be associated with a lower BMI[425][426] (also at times a comparable BMI[377]) and reduced prevalence of obesity.[380] Interestingly, this observation coexists with increased caloric intake and lower reported quality of food intake,[426][377] suggesting that marijuana use may somehow confer the ability to consume more unhealthy foods while gaining less weight as a consequence.

Marijuana use is correlated with an increase in self-reported caloric intake and possible reduction in body weight.

In contrast, body weight has been shown to increase with marijuana use in hospitalized settings (where food intake is controlled) over the course of a week or two. This was associated with increased body water which was reversible within 48 hours of marijuana cessation.[427]

Short term marijuana use may alter water balance in the user, resulting in a rapid increase in non-adipose weight that can be lost equally rapidly following cessation.

Edit8. Skeletal Muscle and Physical Performance

8.1. Muscular Power Output

The inhibitory effect of marijuana on motor control may be attenuated in heavy users (near daily), as a dose of 800mg marijuana (3.7% Δ9THC) is insufficient to impair psychomotor performance[213] while 5.5-6.4% Δ9THC of the same amount of marijuana is.[272]

Inhalation of marijuana (1.4g conferring 18.2mg Δ9THC) acutely, in self-reported marijuana smokers relative to Δ9THC depleted marijuana, was unable to beneficially or negatively influence power output as assessed by a grip strength test.[331]

8.2. Aerobic Exercise

Marijuana usage is prevalent in athletes, with upwards of 10% of Olympic athletes reporting usage prior to its status as a prohibited substance by the IOC (1998-2003) with it being the second most used prohibited substance in the Olympics behind anabolic agents.[23] While its usage is not seen as physically ergogenic, it is thought to be used primarily due to its psychoactive effects of relieving anxiety and tension[23][428] and due to its impairment to learning also applying to adversive learning (conditioned fear[429][430]) it is thought that marijuana is also used to reduce fear associated with competition.[23][428] This function, to some,[431] has been described as ergogenic since the end result is an increase in performance.

In regards to exercise usage (both aerobic and anaerobic, but in this section due to it being first) the usage of marijuana in athletes may be due to reducing fear and anxiety with competing rather than any inherent ergogenic effect.

Inhalation of marijuana (20-25 tokes of 1.4g marijuana, conferring 18.2mg Δ9THC) has been noted to acutely increase heart rate and diastolic blood pressure at rest which resulted in an acute 25% reduction in steady state performance on a bicycle ergometer (maintaining cycling at 170 BPM);[331] smoking the placebo, relative to the control, did not influence performance.

Edit9. Inflammation and Immunology

9.1. Interleukins

Interleukin 6 (IL-6) is an inflammatory and immunostimulatory cytokine produced by the immune system which normally increases with age.[432] Self-reported usage of marijauna in middle-aged African-Americans appears to be associated with lower resting IL-6 concentrations when compared to similarly-aged nonsmoking cohorts (58% of control value).[433] Although this cohort was on average obese (another possible reason for elevated IL-6[434]) and their BMI was also correlated with IL-6 in serum, IL-6 levels were still lower in the marijuana users even after adjustment for these and other social and physical factors.[433]

9.2. Natural Killer Cells

The cannabinoid system appears to affect natural killer cells (NK cells), as the endocannabinoid 2-arachidonoylglycerol (2-AG) which is involved in immunological signalling[435] has been noted to induce the migration of NK cells partially via CB2 receptors;[436] when Δ9THC was tested, it not only failed to induce migration of NK cells at 1µM but blocked 2-AG from doing so at the same concentration.[436] While not specifically demonstrated, these differences may be due to differences in binding strength to CB2, since Δ9THC and anandamide, which also failed, are partial CB2 receptor agonists while 2-AG is a full agonist.[435][437]

In contrast to the inability of Δ9THC to induce cell migration, intravenous administration of 2.5mg/kg cannabidiol (CBD) for two weeks appears to increase the total count and percentage of NK cells in rats despite reductions in other lymphocytes (B and T cells).[438]

While the cannabinoid system is involved in natural killer cell migration, Δ9THC does not induce cell migration at moderate concentrations.

Usage of bhang in youth (around 1.5-3g daily) appears to be associated with a reduced amount of natural killer cells in serum (26%) relative to youth who did not report usage of cigarettes or marijuana; this association was noted in those using for 6-24 months yet was not present in those who reported usage for longer periods.[439]

One study assessing an association between immunological parameters and Cannabis sativa usage (as bhang) noted a reduction in NK cell count associated with bhang.

9.3. B Cells

B Lymphocytes (B cells) express CB2 receptors to a degree greater than NK cells, macrophages, neutrophils, and T cells (descending order of receptor abundance[440][441]) and the mRNA for this receptor appears to be responsive to various cytokines in vitro with lipopolysaccharide potentially suppressing CB2 mRNA[442][441] and stimulation of STAT6 via IL-4 increasing CB2 receptor expression.[443]

Activation of this receptor in B cells by increasing differentiation,[444] migration,[445] and activation[446] with at least one study implicating this receptor in antibody class switching since incubation of B cells with cannabinoid agonists can increase immunoglobulin E (IgE) at the cost of IgM secretion in a manner blocked by CB2 antagonists.[447] An increase in IgE without allergic reaction has been noted in a few cases given marijuana inhalation.[448]

When tested in vitro, Δ9THC caused a dose-dependent increase in B cell proliferation with an EC50 of 2nM when in the presence of costimulatory agents depsite anandamide being ineffective up to 1µM.[449]

The antiinflammatory cannabinoid receptor (CB2) appears to be expressed to a relatively large degree on the particular kind of white blood cell known as B cells, which are involved in adaptive immunity. When this receptor is activated, B cells appear to generally be activated and secretion of IgE may be preferred over other immunoglobulins.

When investigating chronic marijuana smokers, baseline B cell count appeared to be lower than nonsmoking controls[448] (lower baseline B cell count has also been noted in chronic bhang users relative to nonusers[439]) but over the course of 64 days of marijuana usage in hospitalized settings this was normalized.[448] These trends, both the initial reduction[448][439] and restoration to baseline levels with marijuana usage[448] are also seen with T cells.

There are no controlled interventions comparing the effects of marijuana against placebo in regard to B cell mediated immunity, but it seems that chronic users have lower baseline B cell count than do abstainers, although these drops in B cell levels may not persist in longer term use.

Edit10. Interactions with Hormones

10.1. Estrogens

Many case studies have reported that heavy marijuana usage often precedes the development of gynecomastia (breast tissue growth in males) suggesting that marijuana may have intrinsic estrogenic properties that may disrupt normal hormonal balance in males.[450][451] Some in vitro studies corroborate this; both an ethanolic Cannabis sativa extract and marijuana smoke condensate with a THC content equivalent to 24µM competes with estradiol for binding to the estrogen receptor.[452] This may not be due to THC, however; neither pure Δ9THC nor ten of its metabolites were noted to have any estrogenic activity, and cannabidiol showed estrogenic activity only at very high concentrations.[452] Moreover, marijuana smoke condensate and several components of marijuana showed neither estrogenic nor anti-estrogenic activity in an in vivo animal uterine tissue model, bringing the biological relevance of in vitro studies into question.[452] Failure of phytocannabinoids from Cannabis sativa to either stimulate or suppress the estrogen receptor of breast cancer cells in culture has been noted elsewhere, further questioning the purported estrogenic activity of marijuana.[453]

A more recent study using in vitro as well as in vivo methods found that marijuana smoke condensate has an estrogenic effect that can be traced to phenolic compounds generated upon the combustion of plant materials. Thus, marijuana smoke may have intrinsic estrogenic properties that occur via estrogenic polyphenols, rather than cannabinoids as previously assumed.[454]

It has also been noted that Apigenin in Cannabis sativa is an estrogen antagonist at 500-5,000nM[452] while both formononetin[453] and 4,4,dihydroxy-5-methoxybibenzyl from Cannabis sativa[455] are agonists.

Human case studies suggest that marijuana possesses estrogenic activity. If an estrogenic effect does exist, this is likely attributed to combustion products from natural polyphenols found in marijuana, rather than cannabinoids.

10.2. Androgens

In a study on rats fed Cannabis sativa as aqueous Bhang solution (at 6mg/mL), 36 days of administration decreased testosterone by almost half at a dose of 3mg/kg bodyweight, with further decreases noted at 6mg/kg bodyweight.[2] This decrease in testosterone was thought to be due to inhibitory effects on 3β-Hydroxysteroid Dehydrogenase (3βHSD), the final enzyme in testosterone synthesis.[2] Another study found that THC can inhibit gonadotropin-induced testosterone synthesis even in abundance of gonadotropins, suggesting inhibition at the level of testicular tissue.[456]

Another study also found that while cannabinoids do not prevent gonadotropins from binding to receptors, they still lower testosterone by inhibiting cholesterol esterase, an enzyme needed for testosterone synthesis.[457] These effects are also seen with cannabidiol and cannabinol, and are more effective than THC.[458]

In research animals and animal tissue, several cannabinoid components of Cannabis sativa such as THC can suppress testosterone levels.

In humans, infusion of 10mg THC over 50 minutes (as 0.02% solution) showed a time-dependent decrease in testosterone over a 6-hour interval. Whereas the control group fluctuated at around 5.5+/-0.5ng/mL testosterone, the THC group dropped to around 3.5+/-0.5ng/mL at 4-6 hours despite THC concentrations in the blood disappearing by 1 hour post-test.[459] A decrease in testeosterone was also noted after subjects smoked a marijuana cigarette, where testosterone levels appeared to reach about 66% of baseline values after 3 hours (time after not recorded).[459] Other studies suggest nonsignificant reductions in testosterone levels after 1-2 2.8% THC joints,[460] including a slight (8%) transient decreased in testosterone after 20mg THC as a joint.[461] Both of these studies controlled for marijuana use prior to the study, whereas aforementioned studies that noted larger testosterone decreases did not.[459] Interestingly, a study using isolated THC did not find any effect on testosterone level, suggesting that other compounds in the Cannabis sativa plant may be affecting testosterone levels.[462]

Two studies found that chronic users of marijuana did not display significantly different baseline levels of testosterone (either gender, tested under non-smoking conditions) up to daily smoking sessions, or 7 joints weekly.[463][464] However, another study noted depressed testosterone levels in men who used marijuana at least 4 days a week for at least 6 months compared to age-matched controls that did not smoke marijuana.[465]

It has been noted[466] that all human studies showing decreases are still within the normal biological range, suggesting that marijuana use is unlikely to influence behavior secondary to testosterone.

Human studies the effects of marijuana on testosterone levels have yielded mixed results. Smoking marijuana probably causes an acute decrease in circulating testosterone levels, but the effect of chronic, heavier use on testosterone is much less clear. The clinical relevance of depressed testosterone levels is not clear; although most studies indicate that although circulating hormone levels may drop, they remain within the normal range.

Another possible mechnanism by which testosterone is depressed is through reducing hypothalamic and pituitary output of gonadotropin hormones, as administration of hCG (Human chorionic gonadotropin) in one study that noted marijuana-induced testosterone suppression also noted that the admistrration of hCG reversed it.[465]

Other possible mechanisms of testosterone suppression include decreased testosterone synthesis in the testes (extrapolated from mouse studies)[2], increased liver conjugation and metabolism of testosterone,[467] or direct antagonism at the level of the androgen receptor,[468][469] with Δ9THC possessing the ability to prevent DHT from binding to the androgen receptor. [470] The last possible mechanism was noted in in vivo animal studies, as castrated rats still experience anti-androgenic effects from THC and this effect is independent of circulating testosterone levels.[469] Many of the testosterone-related effects may be due to marijuana's action on the pituitary gland, as endocannabinoids cannot suppress testosterone in rats lacking a CB1 receptor.[471]

The possible mechanisms by which marijuana can suppress testosterone synthesis are quite numerous, but are mostly due to decreased synthesis of testosterone in the testicles.

Marijuana use may suppress testosterone levels for up to 48 hours, as based on a mathematical simulation.[459] Most time curves, however, indicate maximal suppression of testosterone 4-6 hours after consumption, which is well after THC has been cleared from circulation.[459][460][459]

10.3. Growth Hormone

Acute smoking of two 2.8% joints is associated with a slight, statistically insignificant increase in circulating growth hormone levels 2 hours after smoking in men, from about 1ng/mL to 2ng/mL when compared to control (smoking placebo).[460] Abnormally high oral doses (210mg) of Δ9THC have been noted to acutely suppress circulating growth hormone concentrations.[472]

10.4. Luteinizing Hormone

Marijuana smoking causes an acute reduction Luteinizing Hormone (LH) levels in males. [460] Chronic use is not associated with depressed LH levels, although moderate use (5-6 tokes weekly) is associated with a nonsignificant increase in baseline LH levels.[464]

10.5. Follicle-Stimulating Hormone

Chronic usage of marijuana, when tested under non-smoking conditions, is not associated with significant changes in follicle-stimulating hormone levels in men or women.[464]

10.6. Cortisol

One study found that inhalation of marijuana smoke (from 1-2 cigarettes containing 2.8% Δ9THC) acutely increased cortisol alongside the psychoactive effects in healthy men.[460] This effect has been confirmed elsewhere to occur with intravenous Δ9THC in naive users in a dose-dependent manner, but is subject to tolerance as chronic users do not appear to have increased cortisol at similar doses.[473]

The magnitude of change noted with doses of marijuana corresponding to recreational use is not thought to be of a clinically relevant magnitude,[474] and there is no alteration in the diurnal rhythm of cortisol when comparing chronic users of marijuana to nonusers.[462]

Very high doses (210mg) Δ9THC can reduce the cortisol response to low blood glucose in hospitalized patients.[472] A plausible mechanism for this effect is via suppressed ACTH activity, which has been observed in rats with the CB1 agonist HU-120 at high doses. In contrast, lower doses have been found to have a mild stimulatory effect, suggesting that this mechanism may be subject to tolerance subchronically.[475]

Inhalation of marijauna seems to promote an acute spike in cortisol, which is attenuated with chronic use. The overall size of the cortisol spike noted with normal use does not appear to be of a clinically relevant magnitude.

Edit11. Peripheral Organ Systems

11.1. Intestines

It can aid gut/intestinal disorders by direct suppression of proinflammatory mediators, inhibition of intestinal motility and diarrhoea, and attenuation of visceral sensitivity.[476][477]

11.2. Liver

Marijuana usage is thought to be a contributing factor in the development of nonalcoholic fatty liver disease (NAFLD)[411] as activation of the CB1 receptor in the liver (hepatic tissue) seems to promote lipogenesis in the liver[414] and CB2 receptors appear to be expressed in the NAFLD-affected liver but not healthy livers.[478]

Mechanistically, when CB1 is activated in vitro the expression of the lipogenic factor SREBP-1c and the target enzymes ACC1 and fatty acid synthase (FAS) are increased[414] and injections of CB1 agonists causes lipogenesis in the liver of mice correlating with subsequent weight gain.[414]

11.3. Pancreas

Inhalation of marijuana has been noted to account for some instances of acute pancreatitis, albeit less than 2% of what is seen in emergency settings (as a more common cause is Alcohol).[479] While causation has not been placed on marijuana causing this condition, it is known that the CB1 receptor exacerbates preexisting pancreatitis and blocking this receptor can prolong survival in rats.[480]

Marijuana is associated with a few instances of pancreatitis (acute inflammation causing pain. Causation has not been placed on marijuana for this, but it is possible that marijuana could have a role (as the cannabinoid system is implicated)

In rats exposed to a standard western diet, injections of marijuana (equivalent to 5mg/kg Δ9THC) increased ab libitum food intake in lean rats yet not obese rats and reduced weight in both groups;[392] this observation was noted alongside protection of pancreatic β-cell function.[392] This study did use a marijuana extract containing cannabidiol, which independently (at 5mg/kg i.p.) can reduce the incidence of diabetes in rats at the level of the pancreas.[481]

In diabetic mice (streptozotocin induced) with pancreatic inflammation, Δ9THC given alongside the inflammatory stressor at 150mg/kg appeared to partially prevent inflammation of the pancreas resulting in preserved insulin content of this organ and less of an increase in blood glucose.[482]

The limited animal evidence at this moment in time assessing the effects of marijuana on the pancreas varies a bit from one study to another, and while there may be a protective effect with marijuana usage chronically the acute protective effects seen with Δ9THC require much too high a dose

11.4. Lungs

Marijuana has effects on the lungs secondary to both the plant constituents but also due to the act of inhalation per se, since any combustable organic material (regardless of its constituents) inhaled may have a damaging effect on lung tissue.[483]

The act of chronic marijuana inhalation has been associated with acute and chronic bronchitis as well as cases of cellular dysplasia, which are thought to be related to volatiles produced during combustion similar to tobacco containing cigarettes.[483]

The act of inhalating marijuana (via a joint), due to the combustible material released from the burnt organic material, has similar properties to tobacco smoke in how the smoke itself can damage lung tissue and possibly has a carcinogenic role

In self-reported heavy smokers (four times a week minimum) while one study failed to note any abnormalities in pulmonary function or lung power when tested[484] an assessment of marijuana dependent adults noted that the percentage of subjects with a FEV1/FVC less than 80% was higher in users (36%) than nonusers (20%).[485]

The state of marijuana tolerance (assessed by surveying dependent adults) is also associated with higher baseline sputum production in the morning, waking during the night with chest pains, wheezing (outside of sickness), and exercise-induced shortness of breath were also increased in frequency relative to nonsmokers;[485] these effects were also noted in tobacco users, and hypothesized to be related to the inhalation of smoke per se.[485]

Baseline lung power in marijuana users, relative to nonusers, does not appear to be significantly altered

Marijuana has a bronchodilation effect, and is able to increase FEV1 and airway conductance when inhaled by otherwise healthy persons acutely[330][486] with actions present within 20 minutes and persisting for up to an hour;[486] this appears to be due to the Δ9THC since oral supplementation is also effective albeit slower acting[486] and inhalation of placebo or cigarettes acutely impair airway conductance.[486]

The bronchodilation seen with marijuana does not appear to be additive with exercise when inhalted at 7mg/kg (1.7% Δ9THC).[330]

Acute inhalation of marijuana appears to have a slight bronchodilating effect, and is significantly more effective than oral supplementation of Δ9THC due to the direct application to the airway via inhalation. This effect lasts for approximately one hour

11.5. Eyes

Marijuana is seen as a treatment for glaucoma via retinal CB1 receptors.

Activation of CB1 receptors has various actions in this organ thought to the therapeutic including inhibition of glutamate-mediated cytotoxicity, as glutamate acting on NMDA can cause cell death in the retina (a process known as excitotoxicity[487]) and this process is increased in instances of increased intraocular pressire (IOP) seen during glaucoma. Marijuana components can reduce this toxicity directly in vitro[488][489] and an additional benefit may occur secondary to reducing IOP.

When given to subjects with glaucoma sublingual (5mg Δ9THC),[490] intravenous,[491] and inhalation[492] of Δ9THC via marijuana has been shown to decrease IOP more than placebo. The decrease in IOP seen with marijuana peaks 60-90 minutes after inhalation[492] although a decrease may occur before 30 minutes[493] with these changes parallelling a decrease in peripheral blood pressure at a concenration which coincides with the psychoactive effects of marijuana.[492] This effect may be subject to tolerance, since a low dose of Δ9THC (12mg) has once shown efficacy in only those naive to marijuana usage.[493]

The reduction in IOP has been noted in young adults who do not suffer from glaucoma as well.[493]

Marijuana appears to be able to reduce intraocular pressure (IOP) in subjects with glaucoma associated with the reduction in peripheral blood pressure, and the dose required for this is similar to the one required to have a psychoactive effect. This decrease in IOP may be subject to tolerance

11.6. Male Sex Organs

The testicles are known to express both CB1 and CB2 receptors in the rat[2] and also express the fatty acid hydrolase (FAAH) enzyme of cannabinoid metabolism.[2]

Bhang (leaf/flower extract of cannabis sativa with over 25% Δ9THC content) orally at 3-6mg/kg daily in rats for 36 days has been noted to reduce testicular weight in a dose-dependent manner by 14-27%. This was associated with a reduction in 3βHSD and FAAH activity alongside reduced serum testosterone, thought to be related to testicular toxicity as assessed by histology.[2]

Edit12. Interactions with Cancer Metabolism

12.1. Lung

When assessing rates of marijuana usage and lung cancer incidence (survey research) and investigating research that exludes tobacco usage, there was no increased risk for habitual (frequent) users relative to either nonhabitual (infrequent) or nonusers in regards to developing lung cancer.[494] This has been noted elsewhere where no association was noted after tobacco was controlled for,[495][496] although increased biomarkers that would suggest lung damage (tar exposure, alveolar macrophage dysfunction, etc.) were noted[496] likely due to the inhalation of smoke per se.

A lack of association between marijuana usage and development of adenocarcinoma has been noted with marijuana usage despite a positive (nonsignificant) trend[494] although there may be some premalignant changes in the respiratory tract.[496]

Marijuana usage, either light or heavy, does not appear to be associated with an increased incidence of lung cancer when compared to nonusers after tobacco has been controlled for; tobacco usage is higher in marijuana users than nonusers. There may still be some procarcinogenic effects due to inhaled smoke which require further study as it applies to marijuana (smoke is known to be carcinogenic)

12.2. Prostate

The healthy prostate normally expresses the cannabinoid system including both CB1 and CB2 receptors, as well as some TRPV/TRPA channels which marijuana constituents are also known to target.[497][498] The expression of the cannabinoid receptors in cancerous prostate cells such as LNCaP, PC3, and DU145 appears to be higher than in normal prostate cells (PZ-HPV-7 and PrEC)[499] and activating these receptors in cancerous cells appears to cause a dose and time-dependent reduction in cell viability and increase in apoptosis in a manner blocked by receptor antagonists;[499] higher CB1 immunoreactivity seems to be associated with worse prognosis in prostate cancer,[500] although this is thought to be a consequence of rather than a cause of the worsening state.[500][501]

Δ9THC may be an androgen receptor antagonist, antagonizing DHT binding with a dissociation constant of 210nM[470] and is active in prostate tissue of the rat where a week-long administration of 10mg/kg hindered the effects of testosterone injections on DNA synthesis in this tissue[469] which has been noted elsewhere.[468] Due to the therapeutic role inhibiting DHT signalling through the androgen receptor plays in prostate cancer,[502] it is thought that this property of marijuana be beneficial.[501]

It should also be noted that, in cancerous prostate cells, activation of cannabinoid receptors decreases the protein expression of the androgen receptor and decreases the production and secretion of PSA[499] suggesting dual effects on the androgen receptor.

The cannabinoid receptor appears to be expressed on prostate cells, and its expression increases during cancer and seems to be correlated with the severity of the cancer prognosis. Activating the cannabinoid receptor can cause apoptosis and decreases androgen receptor content, and due to Δ9THC also blocking DHT binding to the androgen receptor it is thought to have two possible (unexplored) therapeutic roles in prostate cancer

Other components of marijuana beyond Δ9THC may have anticancer effects at the level of the prostate,[503] and in one study assessing 12 cannabinoids found in marijuana it was found that cannabidiol (CBD) was the most potent inhibitor of prostate cancer cell growth and marijuana extracts (varying between 24.1-67.5% pure compound) tended to be similar potency in vitro while depleting cannabinoids eliminates efficacy.[497] These cannabinoids were additive with the chemotherapeutics docetaxel and bicalutamide in vitro.[497]

1-100mg/kg injections of a CBD-rich marijuana extract in vivo in mice appeared to inhibit the growth of LNCaP (androgen dependent) cells in a manner equipotent to 5mg/kg docetaxel but antagonist it it, and while inherently ineffective in DU-145 (androgen independent) cells it augmented docetaxel's growth inhibitory effects.[497] These inhibitory effects are associated with increased p53 expression and increased ROS production leading to apoptosis[497] and the estrogen receptor known as G-protein coupled oestrogen receptor 1 (GPER) significantly hindered these effects.[497]

Other cannabinoids in marijuana appear to have a role in promoting apoptosis of prostate cancer cells and may confer some therapeutic effects

12.3. Adjuvant Usage

Marijuana has been investigated for its usage in treating pain associated with chemotherapy[504][505] although currently trials tend to be of relatively low quality (based on a GRADE approach) and are mostly conducted in chronic pain in general.[506] In an assessment of 18 trials (four scoring a 4 or above on JADAD) totally 809 patients it was noted that usage of marijuana or oral Δ9THC was associated with a significant reduction in chronic pain intensity with a standardized mean difference (SMD) of -0.61 (95% CI of -0.84 to -0.37) alongside psychoactive effects.[505]

While marijuana is at times used for reducing pain associated with chemotherapy, there does not appear to be much evidence specific for this usage. There is evidence for the benefits of marijuana in chronic pain in general, which is thought to extend to pain during chemotherapy

Marijuana is also reported to be used as adjuvant in chemotherapy for its appetite stimulating effects, since weight loss from reduced food intake per se may worsen the prognosis of some cancers and any attempt to circumvent weight loss is seen as protective.[504][507]

The appetite stimulating properties of marijuana may also be of benefit to cancer therapy as an adjuvant, since preventing weight loss during chemotherpay is a therapeutic goal

Edit13. Longevity and Life Extension

13.1. Rationale

The endocannabinoid system is involved in food and appetite regulation,[508] and has been shown to be involved in increasing lifespan under dietary restriction in a nematode model by reducing endogenous N-acylethanolamines (NAEs) (signalling molecules that activate the endocannabinoid system).[509] Artificially increasing levels of the enzyme Fatty Acid Amide Hydrolase (FAAH), an enzyme which breaks down NAEs, mimics the life extension effects of dietary restriction, while supplementing a particular NAE (eicosapentaenoyl ethanolamide) abolishes these effects, lending further support to the idea that NAEs play a role in longevity in nematodes.[509]

It has been noted in transgenic mice possessing a mutated superoxide dismutase gene to model amyotrophic lateral sclerosis (ALS), abolishing the FAAH enzyme fails to modify lifespan despite an increase in anandamide, but abolishing the CB1 receptor promotes lifespan.[510]

Dietary restriction has been shown in a worm model to increase lifespan, and the endocannabinoid system seems to play a role. The endocannabinoid system also plays a role in the lifespan of a mouse model of ALS. No studies to date have examined the relevance of these animal studies in humans.

Edit14. Sexuality and Pregnancy

14.1. Fertility

Oral ingestion of 3-6mg/kg bodyweight liquid Bhang (aqueous Cannabis Sativa) is able to dose-dependently decrease testicle weight in rats over 36 days, by 17% at 3mg/kg and 33% at 6mg/kg.[2]

14.2. Spermatogenesis

Histologically, an absence of spermatozoa has been seen after oral administration of 3-6mg/kg Bhang ingestion in up to 40% of tubules observed.[2] Spermatozoa apoptosis (sperm death) appeared to increase as observed via staining.[2]

Edit15. Other Medical Conditions

15.1. Alzheimer's Disease

Alzheimer's disease is a neurodegenerative disease which, on a biochemical level, is characterized by an accumulation of plaques composed mainly of β-amyloid and 'tangles' usually comprised of a protein known as tau.[511] Neuroinflammation around these plaques and tangles is associated with neuronal damage,[512] with a critical intermediate in the process being inflammatory activation of neuroglial cells.[513][514] The cannabinoid system, particularly CB2 (the receptor that mediates antiinflammation but not psychoactive effects), appears to be involved in this pathology since a deficiency of this receptor aggravates amyloid pathology[515] and activation of the system reverses pathology.[516]

The CB2 receptor is expressed in various immune cells[517] including microglia[518] The gene which expresses the CB2 receptor, CNR2, it may have its transcription upregulated during Alzheimer's disease relative to control,[519] which is correlated with cognitive impairment[520]) resulting in more CB2 receptors (demonstrated in vivo in humans[521]) alongside a reduction in endogenous cannabinoid activity, thought to be due to upregulation of Fatty Acid Amide Hydrolase (FAAH), which is an enzyme that breaks down endogenous cannabinoids such as anandaminde.[522]

There appears to be dysregulation of the endocannabinoid system in Alzheimer's disease. One facet of this is a reduction in endocannabinoid activity, at least in part due to the upregulation of FAAH, an enzyme that breaks them down. Additionally, CB2 receptors are overexpressed in brain tissue afflicted with Alzheimer's disease.

It is known that Aβ1-40 (amyloid beta) fibrils activate microglial immune cells localized near neurons[523][524] by acting upon surface receptors such as scavenger receptor A, CD36, α6β1 integrin, CD47, and TLRs.[525][526] This overall process is blocked when CB2 is activated in vitro.[527]

In rats injected with Aβ1-40 fibrils to mimic Alzheimer's pathology, activation of CB2 (via the synthetic cannabinoid MDA7[528]) is able to near-fully preserve memory relative to control, which is thought to be due to reduced microglial activation in the hippocampal CA area.[516] It was also observed that CB2 activation promoted Aβ1-40 clearance in the hippocampal CA1 area as well. [516] Treatment with MDA7 also prevented abnormalities in this region such as CB2 receptor upregulation or impaired glutaminergic signalling.[516] The toxic effects of injected Aβ have been ablated by various other cannabinoids in rodents.[527]

Activation of CB2 by various cannabinoids has been seen to reduce many of the toxic effects of induced Alzheimer's disease in rodent models.

15.2. Multiple Sclerosis

Marijuana has been investigated for the treatment of multiple sclerosis (MS) in part due to self-reports that it improves several physical and pain symptoms associated with MS.[529] In places where medical marijuana is prescribed, such as The Netherlands, MS is one of the more common medicinal uses for marijuana.[530] Some evidence for its possible usefulness in MS also comes from animal data; for instance, cannabinoids have been shown in mice to modulate the immune response in a manner that could be beneficial to MS.[531]

In terms of the overall efficacy of marijuana in MS, a systematic review of the evidence to date by the American Academy of Neurology found that oral cannabis extract is effective in reducing spasticity and central pain or painful spasms in MS; smoked marijuana was of uncertain efficacy in both of the previous symptoms and marijuana overall was possibly or probably ineffective for other symptoms of MS.[532]

According to a systematic review of the evidence, oral marijuana extract is probably effective in reducing pain and spasms in MS, although smoked marijana has less good evidence to support its efficacy for any symptoms.

Clinical trials have been performed to examine the effects of oral cannabis extract on MS. Oral ingestion of a cannabis extract or pure Δ9THC (up to 25mg based on weight) in people with MS over 15 weeks failed to improve physical mobility as reported by a physician/physiotherapy using the Ashworth scale,[533] although patient-reported spasticity and pain was significantly reduced relative to placebo, and secondary improvements in sleep were also noted (with no change in fatigue or mood).[533] However, this study (the CAMS study) has been followed up after a year and in those who chose to maintain therapy, a small therapeutic effect as assessed by the Ashworth scale and self-reported benefits to spasticity and pain were noted with no major safety concerns.[534] Another large trial (MUSEC) in persons with MS given oral Cannabis sativa (two weeks used to titrate up to 25mg Δ9THC daily) for ten weeks noted that the percent of patients reporting significant reductions in muscle stiffness reached 29.4% with cannabis despite only reaching 15.7% in placebo, giving an odds ratio (OR) of beneficial effects of 2.26.[535]

Clinical trials of oral cannabis extract or oral Δ9THC have found that daily usage can reduce self-reported levels of pain, spasticity, and stiffness associated with MS.

The cognitive effects of marijuana on patients with MS have also been examined. In people with MS who report (mostly daily) marijuana smoking, following at least 12 hours cessation the smoking group appears to perform worse on tests of acute recall and working memory relative to those with MS who do not use marijuana;[335] fatigue and depression did not differ between groups.[335] Similar negative associations have been noted in one study of 10 subjects who inhaled or ingested street marijuana who performed slower on an Symbol Digit Modalities Test (SDMT) for working memory and sustained attention (with no differences on a Neuropsychological Battery for MS, or NPBMS)[536] and in a cross-sectional study where 25 cannabis-using people with MS performed worse than disease controls on information processing, working memory, and executive function.[537]

When looking at placebo-controlled trials (the aforementioned studies being correlations), those with MS who took Cannabis sativa (personally titrated to the optimal dose to reduce muscle spasticity) for eight weeks at different times did not experience memory impairment with the former relative to placebo.[538]

Usage of cannabis in those with multiple sclerosis, relative to those with MS but with no reported usage of cannabis, appears to be associated with impaired working memory and acute recall with at least one study noting reduced executive function. One double-blind controlled study involving marijuana, while small in size, failed to replicate these observations.

While less commonly reported, marijuana usage appeared to be associated with self-reported improvements in incontinence in people with MS[529] and in a substudy of a major study (CAMS) it was noted that the 18% of subjects in placebo who reported significant improvements in incontinence (specifically urgency incontinence) were outperformed by both Cannabis sativa capsules and pure Δ9THC (33-38%) both dosed at 25mg Δ9THC equivalents for fifteen weeks.[539] it should be noted that the primary CAMS trial failed to find any influence on bladder symptoms unlike the substudy,[533] but is still considered an up-and-coming treatment option requiring further evidence.[540]

Based on limited evidence, it appears that the side-effect of incontinence seen in multiple sclerosis may be beneficially influenced by usage of marijuana capsules or Δ9THC, particularly in the urgency thereof.

15.3. Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurological disorder in which glials cells may play a role, with human post-mortem evidence suggesting that spinal cord damage in this disorder is associated with CB2-positive microglial activity, suggesting that cannabinoids could in theory affect the progression of the disease.[541] This possibility has been supported in a mouse model of Δ9THC improved symptoms when administered either before or during the onset of symptoms.[542]

Marijuana has been noted to have effects which may be beneficial in the treatment and palliation of ALS.[543] A survey of people with ALS revealed self-reports of improvements of appetite loss, depression, pain, spasticity, and drooling, although other symptoms of ALS were not affected, and the sample size was very small.[544]

Animal data suggests that the cannabinoid system may be involved in the disease progression of ALS, and Δ9THC in these models can delay progression. ALS patients have also reported relief from some symptoms of ALS with marijuana use, although there have been no clinical trials to date to assess the effect of marijuana or its components to support these claims.

15.4. Parkinson's Disease

While marijuana was historically given to patients with tremor associated Parkinson's disease, a small pilot study treating 5 Parkinson's patients with a cigarette in the morning containing 1g of marijuana with a THC content of 2-9% found no benefit in subjective relief or tremor severity.[545] A small double-blind crossover trial using oral cannabis extract to alleviate levodopa-induced dyskinesia in Parkinson's patients trial also found no improvements in dyskinesia or in the symptoms of Parkinson's disease.[546] However, an open-label study of smoked marijuana in Parkinson's disease patients found a signficant decrease in the Unified Parkinson Disease Rating Scale in patients after use, including a reduction in tremors.[547]

Despite this, a larger survey of Parkinson's patients from Prague revealed that almost half of patients who used marijuana reported that marijuana general improvement of their symptoms with about 30% reporting an improvement in tremor.[548]

The evidence of marijuana's efficacy on Parkinson's disease is mixed at this time; while sometimes patients report subjective symptom relief, some studies have found litte to no effect.

15.5. Psychosis

Usage of marijuana recreationally is consistently correlated with various forms of mental illness, particularly psychosis,[549] but it is not entirely clear whether or not there exists a causal relationship; some reviews claim that more evidence exists for marijuana exacerbating existing schizophrenia rather than causing a "cannabis psychosis,"[550] while others suggest causation.[551] The evidence to date seems to rule out the hypothesis that increased cannabis use can be attributed to attempts at self-medication of previously-existing psychotic symptoms.[552][553] It also appears there may be a common genetic component which can predispose people to both cannabis use and schizophrenia, although the genetic contribution is small.[554]

Because case-control studies may be prone to recall bias,[555] and since randomized controlled trials of medicinal marijuana use would not be applicable to populations which use the drug recreationally,[549] the best evidence for a causal link between marijuana use and symptoms of psychosis would be from longitudinal cohort studies. Several such studies have been performed and seem to demonstrate a link between marijuana use and the development of psychotic symptoms. A follow-up to the first such study examining a large all-male cohort of Swedish conscripts found a dose-dependent increase in risk of developing schizophrenia in those who used marijuana without using other illicit substances (OR 1.9, 95% CI 1.1-3.1) even after adjusting for multiple confounders.[556] Such a dose-dependent relationship for the development of any psychotic symptoms in marijuana users was also found in a Dutch sample from the general population over 3 years when adjusted for multiple confounders (adjusted overall OR 2.76, 95% CI 1.18-6.74).[557]. A New Zealand sample also showed an positive association with dose-dependence between marijuana use and psychotic symptom development even after statistically taking into account symptoms previous to marijuana use, which ruled out pre-existing psychotic symptoms as the cause for marijuana use and other confounders.[558] A separate New Zealand study using a different sample confirmed an increased risk of schizophrenic symptoms in those who used marijuana, with early age of first use leading to worsening risk.[559] Finally, a German cohort study of marijuana use in adolescents over 10 years also confirmed a link between marijuana use and psychotic symptoms even after taking into account other variables including other psychiatric diagnoses; this study also noted that the self-medication hypothesis was unlikely as psychotic symptoms previous to marijuana use did not predict future marijuana use.[560]

While no long-term controlled trials of marijuana use have been done due to practical and ethical concerns, there have been placebo-controlled trials of intravenously-infused Δ9THC and its effects on certain psychotic symptoms. In one study, an 2 mg/mL IV infusion administered over 20 minutes in both healthy and frequent users of marijuana to mimic Δ9THC blood levels obtained during recreational marijuana use found that increases in both the Positive and Negative Syndrome Scale (PANSS), a measure of psychosis, over placebo, but no change in "panic" or "anxious" visual rating scales; the subjective experience of the infusion was reported to be similar to that of recreational marijuana use.[561] A similar experiment in stabilized schizophrenics being treated with antipsychotics a significant transient increase in positive and negative psychotic symptoms.[562] Another placebo-controlled study using IV-infused Δ9THC in individuals who had at least one paranoid thought in the past month and assessing paranoia via a realistic virtual reality simulation and focusing on which congnitive components contributed to paranoia found that paranoia was increased over placebo, and found that an increase in negative affect and anomalous experiences such as thought echoing, hallucinations, and unusual changes in sensory experiences.[563]

Several observational studies have suggested that marijuana use, especially at a young age, may be associated with an increase in the risk of developing psychotic symptoms later in life, and short-term placebo-controlled studies have verified that Δ9THC can briefly increase psychotic symptoms in both healthy and schizophrenic individuals. It is important to note, however, that association does not show causation, and more research is needed to establish a definitive link. Although the body of evidence leans toward causation, it is not currently clear whether this may occur in certain populations predisposed to psychosis.

While the mechanisms of psychosis are not completely clear, it is biologically plausibild that marijuana may have a causative role in the development of psychosis and schizophrenic symptoms.[564][565] The general mode of hypothetical causation involves the effects of THC on CB1 receptors, which is distributed in brain regions implicated in psychosis such as the frontal regions of the cerebral cortex, basal ganglia, hippocampus, cerebellum, and anterior cingulate cortex.[564] The primary general role of the CB1 receptor is to presynaptically modulate the release of various neurotransmitters upon being stimulated, which suggests the general mechanism by which THC could induce its psychological effects.[564] In particular, THC has been seen to enhance doapamenergic activity in the striatal and mesocorticolimbic areas of the brain, which may explain how marijuana use could induce some of the positive symptoms of psychosis, which are thought to be related to increased dopaminergic activity.[565]

A second mechanism by which THC may induce psychotic symptoms may be through reducing glutamate activity. Starting in 1980, hypoglutamatergic (reduced glutamate) neurotransmission has been implicated in schizophrenia,[566] specifically due to reduced activity of the NMDA receptor.[567] The Δ9THC content found in marijuana can also decrease NMDA receptor activity by activating the CB1 receptor which can then bind to the NMDA glutamate receptor and acutely reduce signalling via NMDA.[190] Cannabinoids can do this through the internalization of CB1 receptors, which can co-internalize NMDA receptors into the cytosol.[191] In addition, subchronic administration of Δ9THC has been seen to reduce expression of NMDA receptors subunits (NR1 and NR2 subunits in the hippocampus in animal models.[186]

It is biologically plausible that marijuana could cause psychotic symptoms. The mechanisms by which it may do so may involve the dopamine and glutamate systems.

15.6. Inflammatory Bowel Disease

In survey of people with inflammatory bowel disease (IBD) found that those who used cannabis (17.6% of the sample, almost entirely through inhalation) noted that usage of cannabis was associated wtih improvements in abdominal pain and cramping with semifrequent reports of improving joint pain and diarrhea, although usage of cannabis for six months was a predictor (95% CI OR 1.45-17.46) for requiring surgery those with Chohn's disease.[568] Another retrospective observational study in patients specifically with Crohn's disease found improvement in self-reported symptoms; a significant reduction in the Harvey-Bradshaw index was seen in patients after they began cannabis use as opposed to before use.[569]

Small prospective trails have also shown some benefit. An uncontrolled pilot study involving 13 individuals showed self-reported improvement in patients with IBD receiving cannabis showed signficant improvements in several areas of well-being and a reduction in Harvey-Bradshaw index.[570] Additionally, a small placebo-controlled trial in Crohn's patients administering cannabis cigarettes twice daily containing 115mg Δ9THC (with the placebo having the THC removed) found a significant clinical response in the treatment group, although the primary endpoint of complete remission was not reached.[571]

Preliminary evidence suggests that marijuana may help improve symptoms of IBD, although the evidence to date is only in the form of observational data or very small studies.

Edit16. Nutrient-Nutrient Interactions

16.1. Alcohol

Alcohol is a drug commonly used alongside marijuana, and both are known to interact with one another.

The dopamine-releasing effects of alcohol appear to be dependent on the CB1 receptor (as blocking it can reduce dopamine activity induced by alcohol[572]) and blocking this receptor has been noted to reduce voluntary alcohol intake in various rodent strains[573][574][575][576] (likely due to the suppressive effect of blocking CB1 on dopamine release, since dopamine involved in the motivational effects in alcohol-seeking behaviors[577]).

Alcohol's effects on dopamine release in rats appears to depend on activation of the CB1 receptors, since blocking it can reduce the dopamine release induced by alcohol in the nucleus accumbens and subsequent self-adminstration of alcohol in rats.

16.2. Caffeine

Tolerance to caffeine is known to increase density of adenosine A1 receptors in several brain regions,[132] and activation of this receptor is similar to activation of the CB1 receptor in the sense that they use are coupled to a similar pool of G-proteins[578] to subadditively suppress adenyl cyclase activity;[126] the mechanism for crosstolerance may exist downstream of the receptor-G-protein interface of the two signalling pathways.[126][131]

In mice tolerant to caffeine (which increases A1 receptor density) who were then given a single dose of Δ9THC acutely before cognitive testing noted that, relative to Δ9THC alone, that the caffeine-tolerant mice exhibited worse spatial memory deficits from the cannabinoid despite not worsening performance in mice which were not tolerant to caffeine.[127]

A possible explanation for this may be linked back to glutamate, which is released from CB1 activation of astrocytes,[579] and its activation of glutaminergic signalling and subsequent downregulation and internalization of NMDA and AMPA receptors[186] via a COX-2-dependent mechanism.[188] This could underlie memory impairments from marijuana usage since reduced receptor density impairs the ability of glutamate to improve synaptic plasticity, which is a key feature of marijuana-induced memory impairment.[183][186][193] While activation of CB1 on neurons (rather than astrocytes) normally suppresses glutamate release,[195] an increase in A1 receptor density is associated with less neuronal suppression and a relative increase in synaptic glutamate in hippocampal cells, as A1 activation attenuates CB1-mediated suppression of glutamate release.[127]

Animal data suggests that tolerance to caffeine may enhance the negative impact of Δ9THC on acute spatial memory formation.

16.3. COX2 Inhibitors

NSAID drugs (such as indomethacin, aspirin, and ibuprofen) appear to be able to inhibit some of the neurological effects of marijuana, including the percieved 'high',[580][581] by inhibiting COX2, which is induced by CB1 receptor activation and leads to downregulation of glutamate receptors.[188] This COX2 inhibition concurrent with Δ9THC administration appears to prevent memory impairment from Δ9THC while it preserves the ability of Δ9THC to reduce β-amyloid pigments and attenuate neurodegeneration.[188]

16.4. Nicotine

Nicotine is the main stimulatory component of cigarettes, and its signalling in the brain appears to interact with the main cannabinoid receptor (CB1).

It appears that activation of the CB1 receptor can potentiate the reinforcement stimulus for nicotine and lead to nicotine-seeking behavior in mice withdrawn from nicotine.[582] In contrast, blocking the actions of the CB1 receptor can reduce dopamine release into the nuclear accumbens from nicotine and decrease nicotine self-adminstration and motivation for nicotine-seeking.[572] CB1 antagonists do not require preadministered CB1 agonists to be effective at reducing motivation for nicotine.[583][584] Nicotine also seems to enhance some of the acute physiological responses to THC in rodents such as withdrawal effects.[585]

Activation of cannabinoid receptor appears to be able to enhance some of the addictive features of nicotine in mice. Conversely, rodent experiments have also shown that nicotine potentiates some of the physiological effects of THC, including withdrawal.

16.5. High Fat Diet

In rats, a high fat diet has been noted to reduce the effects of Δ9THC thought to be due to a desensitization of the CB1 receptor due to elevated levels of the endogenous cannabinoids (endocannabinoids) anandamide and 2-arachidonoylglycerol.[586]

Edit17. Safety and Toxicology

17.1. Tolerance

The body can become tolerant to marijuana usage and Δ9THC[587][588] which can be attributed to a desensitization of the CB1 receptor which mediates the psychoactive properties of Δ9THC.[128]

The G proteins to which CB1 is coupled (Gi and Go[95]), which mediate signalling of the receptor, are activated to a lesser degree in a desensitized receptor due to chronic exposure of tissue to Δ9THC,[128][129] and this desensitization is seen with most cannabinoid agonists of the CB1 receptor rather than solely due to Δ9THC (although differences exist between ligands).[95][589][143] The major reason the G proteins are activated to a lesser degree is due to an loss of surface CB1 receptors which occurs in a time- and dose-dependent manner[128] with more rapid internalization by more potent agonists,[145] and this decrease in receptor concentration is likely due to receptor internalization (which underlies agonist-induced desensitization for many G-protein coupled receptors).[145][590]

Exposure of the CB1 receptor to any agonist, including Δ9THC, can cause the receptor to eventually be removed from the cell membrane. This results in less activation of the receptor from Δ9THC, less signalling within the cell, and tolerance to the drug.

Such a phenomena has been confirmed in chronic marijuana users who reported 10+/-6 joints a day for numerous years (12+/-7) with more suppression in those who reported a longer smoking history.[591] Abstinence from marijauna for approximately four weeks is sufficient to normalize CB1 receptor activity.[591]

Reduction in CB1 receptor availability has been noted in numerous brain regions including the angular singulate cortex, the prefrontal cortex, and parahippocampal gyrus among others such as the parietal, posterior cingulate, and occipital cortices.[591] In general, downregulation affects cortical regions more than subcortical regions[592] reaching up to a 20% reduction in cortical regions[591] while subcortical regions more readily recovere after cessation (based on mouse data[593]).

A reduction in CB1 receptor availability has been noted in chronic marijuana users. This reduction in CB1 availability is normalized after four weeks abstinence.

17.2. Withdrawal

Withdrawal from marijuana exists but appears to differ from other drugs as it is not associated with any major medical or psychiatric problems that are seen with withdrawal from Alcohol, benzodiazepines, or opioids; cannabis withdrawal tends to involve significant physical and mental impairments to well-being with risk of relapse.[594]

In terms of withdrawal symptoms' role in the risk of relapse, marijuana is comparable to tobacco in severity[595][596] although withdrawing from both simultaneously has been reported as being more severe than either alone.[595] Symptoms of withdrawal occur almost immediately and decline over the course of approximately a week to a month.[597][598] Similarly to Nicotine being able to treat tobacco withdrawal, oral supplementation of Δ9THC appears to confer some benefit to marijuana withdrawal.[599][600][601]

Symptoms of marijuana withdrawal include difficulties with sleep, restlessness, decreased appetite, depressed mood, nervousness or anxiety, irritability, and physical symptoms/discomfort; at least three of the aforementioned seven would be present for a diagnosis of cannabis withdrawal syndrome (DSM-V).[602]

Physical symptoms refer to symptoms such as stomach pain, shakiness, sweating, chills, and/or headaches but are generally less frequently reported than other symptoms.[603] Major psychological withdrawal symptoms include decreased appetite, difficulty sleeping, irratibility and anger, strange dreams, restlessness, and marijuana cravings.[604][597] The time course of these symptoms can vary significantly.[605][597]

Marijuana withdrawal lasts for approximately a week to a month. The symptoms are both physical and mental, with physical symptoms being less prevalent. Major symptoms include insomnia and trouble sleeping, restlessness, irratibility, change in appetite, alongside cravings for marijuana.

Impared sleep is a commonly-reported symptom of marijuana withdrawal[606][607][598][597][608][604][603][609] and the intensity of this impairment is higher shortly after marijuana cessation gradually decreasing with time.[610][597] The exact time course of intensity is variable, as while two studies using self-reported side-effects noted a decrease in symptom intensity[597][610] one study assessing sleep quality via polysomnogram noted that sleep quality was impaired (slight worsening) over the first 13 days of marijuana cessation,[611] although subjective ratings of sleep disturbance in adults have seen to return to baseline in a week, although strange dreams persisted throughout the 45-day course of the study.[597]

Impaired sleep quality seem with marijuana cessation is one of the more commonly reported withdrawal effects, and while it appears to be most intense in severity for the first week of cessation it declines in intensity but is still present for up to a month of cessation, while strange dreams can persist even longer.

The cluster of symptoms of nervousness, irritability, and anger are commonly reported with marijuana cessation.[606][607][598][597][608][603][609][612] While nervousness appears to follow the same time course of sleep impairment and physical restlessness in returning to baseline in under two weeks,[610][597] irritability appears to have an earlier onset and may persist for longer than other symptoms.[597] Anger also lasts longer than usual, although it has a later onset.[597]

Nervousness, irratibility, and anger often appear as a cluster of symptoms in marijuana withdrawal, and have variable times of onset and cessation.

Animal models have provided some insight into the mechanism leading to some of the motor symptoms of marijuana withdrawal. After ceasing adminstration of THC twice daily for five days and abruptly injecting rats with rimonabant to precipitate withdrawal,impairments in motor control relative to controls were seen which seemed to be dependent on downregulation of CB1 receptors (specifically in parallel fibers), microglial activation, and signalling through the IL-1 receptor.[152] Stimulation of the IL-1 receptor is able to induce ataxia, as assessed by injections of IL-1β.[613][614] The underlying mechanism has been hypothesized[615] to be traced back to how stimulation of CB1 receptors downregulate glutaminergic activity;[195] a downregulation of these receptors exacerbates glutamate signalling resulting in inflammatory toxicity.

IL-1β is known to directly excite Purkinje cells,[614] although no overt neuronal damage was noted in rats during withdrawal[152] suggesting that neurotransmission towards these cells (from parallel fibers, which were implicated in the process[152]) were altered during withdrawal.

A reduction in motor control is noted during marijuana withdrawal in rats, which is traced back to a short-lived state of increased inflammation and excitotoxicity (from excess glutamate) causing alterations in Purkinje neuron firing.

17.3. Dependency

Marijuana dependence was defined in the DSM IV-TR as having 3 or more of the following symptoms occuring at any time during the same 12-month period: tolerance, taking marijuana in larger amounts or longer than intended, having a desire to or unsuccessful attempts at reducing use, spending a lot of time obtaining the drug or using or recovering from its use, continued use despite being aware of its adverse consequences, and giving up important activities because of use.[616] By these criteria, approximately 4.3 percent of Americans have been dependent on marijuana at some point in their lives.[617] However, a newer edition, the DSM V, has eliminated this specific category of dependence and replaced it with a substance use disorder category[616] as well as a specifically recognized cannabis withdrawal syndrome.[605]

The occurrence rate of marijuana dependence disorder amongst users is estimated to be 9%, which for comparison is less than the amount of tobacco users who are dependent on the product (32%).[618]

Marijuana does have habit-forming properties similar to all neuroactive drugs, but the amount of users who meet the criteria for a dependency disorder is less than the other commonly inhaled drug (tobacco) and is said to be an easier dependency to break

Neurobiologically, common occurrence in drug dependency is reduced dopamine receptor availability, specifically the D2/D3 subsets, in a brain region known as the striatum resulting in lower dopamine neurotransmission. Such an occurrence has been noted in dependency to alcohol,[166] amphetamines,[167] cocaine,[168] heroin,[619] and opioids[620] but despite this dependency to marijauna has repeatedly failed to demonstrate any impairment to dopaminergic signalling or receptor availability in this brain region.[169][170][171][172]

Neurobiologically, a classical sign of dependency in the brain, a reduction in dopamine signalling in the striatum and local brain regions, does not appear to extend to marijuana despite most other common drugs of abuse sharing this mechanism.

17.4. Case Studies

Marijuana has been associated with numerous side-effects in case studies with varying degrees of implied causation.

Case studies include pancreatitis,[479][621][622] enlarged gums,[623] mania,[621] nausea and vomiting,[624] transient ischemic attacks,[625][626] and atrial fibrillation .[627]

There have been a few case studies of youth with no history of cardiovascular problems experience nonlethal[628] and lethal[629][630] heart attacks (from coronary thrombosis) associated with marijuana usage, and other various coronary syndromes[631][632] and combine cerebral and myocardial infarctions.[633] In some cases symptoms have arisen near the time of marijuana ingestion which at least suggests a causal link,[628][634][635][636][636] It has been hypothesized that marijuana inhalation may serve as an acute 'trigger' exacerbating previously existing symptoms (which were initially benign)[634][636] although at times adverse effects have also been seen in people with no prior known symptoms or complications.[636]


  1. Balabanova S1, Parsche F, Pirsig W. First identification of drugs in Egyptian mummies. Naturwissenschaften. (1992)
  2. Banerjee A1, et al. Effects of chronic bhang (cannabis) administration on the reproductive system of male mice. Birth Defects Res B Dev Reprod Toxicol. (2011)
  3. Sharma P1, Murthy P, Bharath MM. Chemistry, metabolism, and toxicology of cannabis: clinical implications. Iran J Psychiatry. (2012)
  4. Ahmed SA1, et al. Cannabinoid ester constituents from high-potency Cannabis sativa. J Nat Prod. (2008)
  5. Piluzza G, et al. Differentiation between fiber and drug types of hemp (Cannabis sativa L.) from a collection of wild and domesticated accessions. Genet Resour Crop Ev. (2013)
  6. World Drug Report 2010
  7. Cinti S. Medical marijuana in HIV-positive patients: what do we know. J Int Assoc Physicians AIDS Care (Chic). (2009)
  8. Seamon MJ. The legal status of medical marijuana. Ann Pharmacother. (2006)
  9. Elsohly MA1, Slade D. Chemical constituents of marijuana: the complex mixture of natural cannabinoids. Life Sci. (2005)
  10. Radwan MM1, et al. Isolation and characterization of new Cannabis constituents from a high potency variety. Planta Med. (2008)
  11. Elsohly MA, El-Feraly FS, Turner CE. Isolation and characterization of (+)-cannabitriol and (-)-10-ethoxy-9-hydroxy-delta 6a{10a}-tetrahydrocannabinol: two new cannabinoids from Cannabis sativa L. extract. Lloydia. (1977)
  12. Elsohly MA, Boeren EG, Turner CE. (+/-)9,10-Dihydroxy-delta6a(10a)-tetrahydrocannabinol and (+/-)8,9-dihydroxy-delta6a(10a)-tetrahydrocannabinol: 2 new cannabinoids from Cannabis sativa L. Experientia. (1978)
  13. Grunfeld Y, Edery H. Psychopharmacological activity of some substances extracted from Cannabis sativa L (hashish). Electroencephalogr Clin Neurophysiol. (1969)
  14. Taura F, Morimoto S, Shoyama Y. Cannabinerolic acid, a cannabinoid from Cannabis sativa. Phytochem. (1995)
  15. Pijlman FT1, et al. Strong increase in total delta-THC in cannabis preparations sold in Dutch coffee shops. Addict Biol. (2005)
  16. Mehmedic Z1, et al. Potency trends of Δ9-THC and other cannabinoids in confiscated cannabis preparations from 1993 to 2008. J Forensic Sci. (2010)
  17. ElSohly MA1, et al. Potency trends of delta9-THC and other cannabinoids in confiscated marijuana from 1980-1997. J Forensic Sci. (2000)
  18. Malingré T, et al. The essential oil of Cannabis sativa. Planta Med. (1975)
  19. Ross SA1, ElSohly MA. The volatile oil composition of fresh and air-dried buds of Cannabis sativa. J Nat Prod. (1996)
  20. Gertsch J1, et al. Beta-caryophyllene is a dietary cannabinoid. Proc Natl Acad Sci U S A. (2008)
  21. Radwan MM1, et al. Non-cannabinoid constituents from a high potency Cannabis sativa variety. Phytochemistry. (2008)
  22. Abrahamov A1, Abrahamov A, Mechoulam R. An efficient new cannabinoid antiemetic in pediatric oncology. Life Sci. (1995)
  23. Huestis MA1, Mazzoni I, Rabin O. Cannabis in sport: anti-doping perspective. Sports Med. (2011)
  24. ElSohly MA. Practical challenges to positive drug tests for marijuana. Clin Chem. (2003)
  25. Mulé SJ1, Lomax P, Gross SJ. Active and realistic passive marijuana exposure tested by three immunoassays and GC/MS in urine. J Anal Toxicol. (1988)
  26. Cone EJ, et al. Passive inhalation of marijuana smoke: urinalysis and room air levels of delta-9-tetrahydrocannabinol. J Anal Toxicol. (1987)
  27. Perez-Reyes M, et al. Passive inhalation of marihuana smoke and urinary excretion of cannabinoids. Clin Pharmacol Ther. (1983)
  28. Law B, et al. Passive inhalation of cannabis smoke. J Pharm Pharmacol. (1984)
  29. Cone EJ. Marijuana effects and urinalysis after passive inhalation and oral ingestion. NIDA Res Monogr. (1990)
  30. Cone EJ, Johnson RE. Contact highs and urinary cannabinoid excretion after passive exposure to marijuana smoke. Clin Pharmacol Ther. (1986)
  31. Touitou E, et al. Transdermal delivery of tetrahydrocannabinol. Int J Pharm. (1988)
  32. Touitou E, Fabin. Altered skin permeation of a highly lipophilic molecule: tetrahydrocannabinol. Int J Pharm. (1988)
  33. Stinchcomb AL1, et al. Human skin permeation of Delta8-tetrahydrocannabinol, cannabidiol and cannabinol. J Pharm Pharmacol. (2004)
  34. Challapalli PV1, Stinchcomb AL. In vitro experiment optimization for measuring tetrahydrocannabinol skin permeation. Int J Pharm. (2002)
  35. Valiveti S1, et al. In vitro/in vivo correlation studies for transdermal delta 8-THC development. J Pharm Sci. (2004)
  36. Fabin B, Touitou E. Localization of lipophilic molecules penetrating rat skin in vivo by quantitative autoradiography. Int J Pharm. (1991)
  37. Grotenhermen F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet. (2003)
  38. Lindgren JE, et al. Clinical effects and plasma levels of delta 9-tetrahydrocannabinol (delta 9-THC) in heavy and light users of cannabis. Psychopharmacology (Berl). (1981)
  39. Ohlsson A, et al. Single dose kinetics of deuterium labelled delta 1-tetrahydrocannabinol in heavy and light cannabis users. Biomed Mass Spectrom. (1982)
  40. Agurell S, Leander K. Stability, transfer and absorption of cannabinoid constituents of cannabis (hashish) during smoking. Acta Pharm Suec. (1971)
  41. Wall ME, et al. Metabolism, disposition, and kinetics of delta-9-tetrahydrocannabinol in men and women. Clin Pharmacol Ther. (1983)
  42. Law B, et al. Forensic aspects of the metabolism and excretion of cannabinoids following oral ingestion of cannabis resin. J Pharm Pharmacol. (1984)
  43. Hollister LE, et al. Do plasma concentrations of delta 9-tetrahydrocannabinol reflect the degree of intoxication. J Clin Pharmacol. (1981)
  44. Garrett ER, Hunt CA. Physicochemical properties, solubility, and protein binding of Δ9 -tetrahydrocannabinol. J Pharm Sci. (1974)
  45. Ohlsson A, et al. Plasma delta-9 tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking. Clin Pharmacol Ther. (1980)
  46. Chiang CW, Barnett G, Brine D. Systemic absorption of delta 9-tetrahydrocannabinol after ophthalmic administration to the rabbit. J Pharm Sci. (1983)
  47. Leuschner JT, et al. Pharmacokinetics of delta 9-tetrahydrocannabinol in rabbits following single or multiple intravenous doses. Drug Metab Dispos. (1986)
  48. Widman M, et al. Binding of (+)- and (-)-Δ1-tetrahydrocannabinols and (-)-7-hydroxy-Δ1-tetrahydrocannabinol to blood cells and plasma proteins in man. J Pharm Pharmacol. (1974)
  49. Wahlqvist M, et al. Binding of delta-1-tetrahydrocannabinol to human plasma proteins. Biochem Pharmacol. (1970)
  50. Fehr KO, Kalant H. Fate of 14C-delta1-THC in rat plasma after intravenous injection and smoking. Eur J Pharmacol. (1974)
  51. Ho BT, et al. Distribution of tritiated-1 delta 9tetrahydrocannabinol in rat tissues after inhalation. J Pharm Pharmacol. (1970)
  52. Johansson E, et al. Determination of delta 1-tetrahydrocannabinol in human fat biopsies from marihuana users by gas chromatography-mass spectrometry. Biomed Chromatogr. (1989)
  53. Kreuz DS, Axelrod J. Delta-9-Tetrahydrocannabinol: Localization in Body Fat. Science. (1973)
  54. Hutchings DE, et al. Plasma concentrations of delta-9-tetrahydrocannabinol in dams and fetuses following acute or multiple prenatal dosing in rats. Life Sci. (1989)
  55. Martin BR, et al. 3H-delta9-tetrahydrocannabinol distribution in pregnant dogs and their fetuses. Res Commun Chem Pathol Pharmacol. (1977)
  56. Abrams RM, et al. Plasma delta-9-tetrahydrocannabinol in pregnant sheep and fetus after inhalation of smoke from a marijuana cigarette. Alcohol Drug Res. (1985-1986)
  57. Perez-Reyes M, Wall ME. Presence of delta9-tetrahydrocannabinol in human milk. N Engl J Med. (1982)
  58. Matsunaga T, et al. Metabolism of delta 9-tetrahydrocannabinol by cytochrome P450 isozymes purified from hepatic microsomes of monkeys. Life Sci. (1995)
  59. Narimatsu S, et al. Cytochrome P-450 isozymes involved in the oxidative metabolism of delta 9-tetrahydrocannabinol by liver microsomes of adult female rats. Drug Metab Dispos. (1992)
  60. Watanabe K, et al. Involvement of CYP2C in the metabolism of cannabinoids by human hepatic microsomes from an old woman. Biol Pharm Bull. (1995)
  61. Harvey DJ, Brown NK. Comparative in vitro metabolism of the cannabinoids. Pharmacol Biochem Behav. (1991)
  62. Widman M, Halldin M, Martin B. In vitro metabolism of tetrahydrocannabinol by rhesus monkey liver and human liver. Adv Biosci. (1978)
  63. Hunt CA, Jones RT. Tolerance and disposition of tetrahydrocannabinol in man. J Pharmacol Exp Ther. (1980)
  64. Williams PL, Moffat AC. Identification in human urine of delta 9-tetrahydrocannabinol-11-oic acid glucuronide: a tetrahydrocannabinol metabolite. J Pharm Pharmacol. (1980)
  65. Leighty EG. Metabolism and distribution of cannabinoids in rats after different methods of administration. Biochem Pharmacol. (1973)
  66. Huestis MA, Henningfield JE, Cone EJ. Blood cannabinoids. I. Absorption of THC and formation of 11-OH-THC and THCCOOH during and after smoking marijuana. J Anal Toxicol. (1992)
  67. Lemberger L, et al. Delta-9-tetrahydrocannabinol: metabolism and disposition in long-term marihuana smokers. Science. (1971)
  68. Garrett ER, Hunt CA. Physicochemical properties, solubility, and protein binding of Δ9 -tetrahydrocannabinol. J Pharm Sci. (1974)
  69. Ellis GM Jr, et al. Excretion patterns of cannabinoid metabolites after last use in a group of chronic users. Clin Pharmacol Ther. (1985)
  70. Musshoff F1, Madea B. Review of biologic matrices (urine, blood, hair) as indicators of recent or ongoing cannabis use. Ther Drug Monit. (2006)
  71. Auwärter V1, et al. Hair analysis for Delta9-tetrahydrocannabinolic acid A--new insights into the mechanism of drug incorporation of cannabinoids into hair. Forensic Sci Int. (2010)
  72. Zullino DF, et al. Tobacco and cannabis smoking cessation can lead to intoxication with clozapine or olanzapine. Int Clin Psychopharmacol. (2002)
  73. Lowe EJ, Ackman ML. Impact of tobacco smoking cessation on stable clozapine or olanzapine treatment. Ann Pharmacother. (2010)
  74. Kim JH1, et al. Expression of cytochromes P450 1A1 and 1B1 in human lung from smokers, non-smokers, and ex-smokers. Toxicol Appl Pharmacol. (2004)
  75. Yamaori S1, et al. Characterization of major phytocannabinoids, cannabidiol and cannabinol, as isoform-selective and potent inhibitors of human CYP1 enzymes. Biochem Pharmacol. (2010)
  76. Jiang R1, et al. Cannabidiol is a potent inhibitor of the catalytic activity of cytochrome P450 2C19. Drug Metab Pharmacokinet. (2013)
  77. Jiang R1, et al. Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes. Life Sci. (2011)
  78. Yamaori S1, et al. Comparison in the in vitro inhibitory effects of major phytocannabinoids and polycyclic aromatic hydrocarbons contained in marijuana smoke on cytochrome P450 2C9 activity. Drug Metab Pharmacokinet. (2012)
  79. Yamaori S1, et al. Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP2D6. Drug Metab Dispos. (2011)
  80. Yamaori S, et al. Differential inhibition of human cytochrome P450 2A6 and 2B6 by major phytocannabinoids. Forensic Toxicol. (2011)
  81. Bornheim LM1, et al. Induction and genetic regulation of mouse hepatic cytochrome P450 by cannabidiol. Biochem Pharmacol. (1994)
  82. Watanabe K1, et al. Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes. Life Sci. (2007)
  83. Yamaori S1, et al. Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: role of phenolic hydroxyl groups in the resorcinol moiety. Life Sci. (2011)
  84. Bornheim LM1, Correia MA. Selective inactivation of mouse liver cytochrome P-450IIIA by cannabidiol. Mol Pharmacol. (1990)
  85. Bornheim LM1, et al. Characterization of cannabidiol-mediated cytochrome P450 inactivation. Biochem Pharmacol. (1993)
  86. Mathijssen RH1, et al. Clinical pharmacokinetics and metabolism of irinotecan (CPT-11). Clin Cancer Res. (2001)
  87. Shou M1, et al. Role of human cytochrome P450 3A4 and 3A5 in the metabolism of taxotere and its derivatives: enzyme specificity, interindividual distribution and metabolic contribution in human liver. Pharmacogenetics. (1998)
  88. Engels FK1, et al. Medicinal cannabis does not influence the clinical pharmacokinetics of irinotecan and docetaxel. Oncologist. (2007)
  89. McLeod AL1, McKenna CJ, Northridge DB. Myocardial infarction following the combined recreational use of Viagra and cannabis. Clin Cardiol. (2002)
  90. Kosel BW1, et al. The effects of cannabinoids on the pharmacokinetics of indinavir and nelfinavir. AIDS. (2002)
  91. Howlett AC1, et al. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev. (2002)
  92. Pagotto U, et al. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev. (2006)
  93. Steffens M1, et al. Cannabinoid CB1 receptor-mediated modulation of evoked dopamine release and of adenylyl cyclase activity in the human neocortex. Br J Pharmacol. (2004)
  94. Howlett AC1, Blume LC, Dalton GD. CB(1) cannabinoid receptors and their associated proteins. Curr Med Chem. (2010)
  95. Araya KA1, David Pessoa Mahana C, González LG. Role of cannabinoid CB1 receptors and Gi/o protein activation in the modulation of synaptosomal Na+,K+-ATPase activity by WIN55,212-2 and delta(9)-THC. Eur J Pharmacol. (2007)
  96. Yao L1, et al. Activator of G protein signaling 3 regulates opiate activation of protein kinase A signaling and relapse of heroin-seeking behavior. Proc Natl Acad Sci U S A. (2005)
  97. Glass M1, Felder CC. Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors augments cAMP accumulation in striatal neurons: evidence for a Gs linkage to the CB1 receptor. J Neurosci. (1997)
  98. Lauckner JE1, Hille B, Mackie K. The cannabinoid agonist WIN55,212-2 increases intracellular calcium via CB1 receptor coupling to Gq/11 G proteins. Proc Natl Acad Sci U S A. (2005)
  99. McIntosh BT1, et al. Agonist-dependent cannabinoid receptor signalling in human trabecular meshwork cells. Br J Pharmacol. (2007)
  100. Ibrahim MM1, et al. CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc Natl Acad Sci U S A. (2005)
  101. Hudson BD1, Hébert TE, Kelly ME. Ligand- and heterodimer-directed signaling of the CB(1) cannabinoid receptor. Mol Pharmacol. (2010)
  102. Wiley JL1, Martin BR. Cannabinoid pharmacology: implications for additional cannabinoid receptor subtypes. Chem Phys Lipids. (2002)
  103. Begg M, et al. Evidence for novel cannabinoid receptors. Pharmacol Ther. (2005)
  104. Ryberg E, et al. The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol. (2007)
  105. Oz M. Receptor-independent actions of cannabinoids on cell membranes: focus on endocannabinoids. Pharmacol Ther. (2006)
  106. Sine SM1, Engel AG. Recent advances in Cys-loop receptor structure and function. Nature. (2006)
  107. Tang SL1, Tran V, Wagner EJ. Sex differences in the cannabinoid modulation of an A-type K+ current in neurons of the mammalian hypothalamus. J Neurophysiol. (2005)
  108. Binzen U1, et al. Co-expression of the voltage-gated potassium channel Kv1.4 with transient receptor potential channels (TRPV1 and TRPV2) and the cannabinoid receptor CB1 in rat dorsal root ganglion neurons. Neuroscience. (2006)
  109. Childers SR1, Deadwyler SA. Role of cyclic AMP in the actions of cannabinoid receptors. Biochem Pharmacol. (1996)
  110. Gebremedhin D1, et al. Cannabinoid CB1 receptor of cat cerebral arterial muscle functions to inhibit L-type Ca2+ channel current. Am J Physiol. (1999)
  111. Pan X1, Ikeda SR, Lewis DL. Rat brain cannabinoid receptor modulates N-type Ca2+ channels in a neuronal expression system. Mol Pharmacol. (1996)
  112. Mackie K1, Devane WA, Hille B. Anandamide, an endogenous cannabinoid, inhibits calcium currents as a partial agonist in N18 neuroblastoma cells. Mol Pharmacol. (1993)
  113. Ross HR1, Napier I, Connor M. Inhibition of recombinant human T-type calcium channels by Delta9-tetrahydrocannabinol and cannabidiol. J Biol Chem. (2008)
  114. Nilius B1, Owsianik G. The transient receptor potential family of ion channels. Genome Biol. (2011)
  115. Akopian AN, et al. Cannabinoids desensitize capsaicin and mustard oil responses in sensory neurons via TRPA1 activation. J Neurosci. (2008)
  116. Szallasi A1, Di Marzo V. New perspectives on enigmatic vanilloid receptors. Trends Neurosci. (2000)
  117. Cavanaugh EJ1, Simkin D, Kim D. Activation of transient receptor potential A1 channels by mustard oil, tetrahydrocannabinol and Ca2+ reveals different functional channel states. Neuroscience. (2008)
  118. Huestis MA. Human cannabinoid pharmacokinetics. Chem Biodivers. (2007)
  119. Morales-Lázaro SL1, Simon SA, Rosenbaum T. The role of endogenous molecules in modulating pain through transient receptor potential vanilloid 1 (TRPV1). J Physiol. (2013)
  120. Takeda S1, et al. Δ9-tetrahydrocannabinol and its major metabolite Δ9-tetrahydrocannabinol-11-oic acid as 15-lipoxygenase inhibitors. J Pharm Sci. (2011)
  121. Takeda S1, et al. Cannabidiol-2',6'-dimethyl ether, a cannabidiol derivative, is a highly potent and selective 15-lipoxygenase inhibitor. Drug Metab Dispos. (2009)
  122. Pacheco MA1, Ward SJ, Childers SR. Identification of cannabinoid receptors in cultures of rat cerebellar granule cells. Brain Res. (1993)
  123. Wojcik WJ, Cavalla D, Neff NH. Co-localized adenosine A1 and gamma-aminobutyric acid B (GABAB) receptors of cerebellum may share a common adenylate cyclase catalytic unit. J Pharmacol Exp Ther. (1985)
  124. Takahashi M1, Kovalchuk Y, Attwell D. Pre- and postsynaptic determinants of EPSC waveform at cerebellar climbing fiber and parallel fiber to Purkinje cell synapses. J Neurosci. (1995)
  125. Shen M1, et al. Cannabinoid receptor agonists inhibit glutamatergic synaptic transmission in rat hippocampal cultures. J Neurosci. (1996)
  126. Selley DE1, et al. Long-term administration of Delta9-tetrahydrocannabinol desensitizes CB1-, adenosine A1-, and GABAB-mediated inhibition of adenylyl cyclase in mouse cerebellum. Mol Pharmacol. (2004)
  127. Sousa VC1, et al. Regulation of hippocampal cannabinoid CB1 receptor actions by adenosine A1 receptors and chronic caffeine administration: implications for the effects of Δ9-tetrahydrocannabinol on spatial memory. Neuropsychopharmacology. (2011)
  128. Breivogel CS1, et al. Chronic delta9-tetrahydrocannabinol treatment produces a time-dependent loss of cannabinoid receptors and cannabinoid receptor-activated G proteins in rat brain. J Neurochem. (1999)
  129. Sim LJ1, et al. Effects of chronic treatment with delta9-tetrahydrocannabinol on cannabinoid-stimulated 35S-GTPgammaS autoradiography in rat brain. J Neurosci. (1996)
  130. Fan F1, et al. Cannabinoid receptor down-regulation without alteration of the inhibitory effect of CP 55,940 on adenylyl cyclase in the cerebellum of CP 55,940-tolerant mice. Brain Res. (1996)
  131. DeSanty KP1, Dar MS. Involvement of the cerebellar adenosine A(1) receptor in cannabinoid-induced motor incoordination in the acute and tolerant state in mice. Brain Res. (2001)
  132. Jacobson KA1, et al. Adenosine receptor ligands: differences with acute versus chronic treatment. Trends Pharmacol Sci. (1996)
  133. Hollister LE, et al. 1 -tetrahydrocannabinol, synhexyl and marijuana extract administered orally in man: catecholamine excretion, plasma cortisol levels and platelet serotonin content. Psychopharmacologia. (1970)
  134. Raasch W1, et al. Agmatine, the bacterial amine, is widely distributed in mammalian tissues. Life Sci. (1995)
  135. Tsou K1, et al. Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience. (1998)
  136. Pettit DA1, et al. Immunohistochemical localization of the neural cannabinoid receptor in rat brain. J Neurosci Res. (1998)
  137. Ruggiero DA1, et al. Immunocytochemical localization of an imidazoline receptor protein in the central nervous system. Brain Res. (1998)
  138. Reis DJ1, Yang XC, Milner TA. Agmatine containing axon terminals in rat hippocampus form synapses on pyramidal cells. Neurosci Lett. (1998)
  139. Aggarwal S1, et al. Agmatine enhances cannabinoid action in the hot-plate assay of thermal nociception. Pharmacol Biochem Behav. (2009)
  140. Compton DR1, et al. Aminoalkylindole analogs: cannabimimetic activity of a class of compounds structurally distinct from delta 9-tetrahydrocannabinol. J Pharmacol Exp Ther. (1992)
  141. Rawls SM1, Tallarida RJ, Zisk J. Agmatine and a cannabinoid agonist, WIN 55212-2, interact to produce a hypothermic synergy. Eur J Pharmacol. (2006)
  142. Console-Bram L1, Marcu J, Abood ME. Cannabinoid receptors: nomenclature and pharmacological principles. Prog Neuropsychopharmacol Biol Psychiatry. (2012)
  143. Glass M1, Northup JK. Agonist selective regulation of G proteins by cannabinoid CB(1) and CB(2) receptors. Mol Pharmacol. (1999)
  144. Leterrier C1, et al. Constitutive endocytic cycle of the CB1 cannabinoid receptor. J Biol Chem. (2004)
  145. Hsieh C1, et al. Internalization and recycling of the CB1 cannabinoid receptor. J Neurochem. (1999)
  146. Pertwee RG, et al. Pharmacological characterization of three novel cannabinoid receptor agonists in the mouse isolated vas deferens. Eur J Pharmacol. (1995)
  147. Thomas A, et al. Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol. (2007)
  148. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. (2008)
  149. Niesink RJ1, van Laar MW. Does Cannabidiol Protect Against Adverse Psychological Effects of THC. Front Psychiatry. (2013)
  150. Villares J. Chronic use of marijuana decreases cannabinoid receptor binding and mRNA expression in the human brain. Neuroscience. (2007)
  151. Romero J1, et al. Effects of chronic exposure to delta9-tetrahydrocannabinol on cannabinoid receptor binding and mRNA levels in several rat brain regions. Brain Res Mol Brain Res. (1997)
  152. Cutando L1, et al. Microglial activation underlies cerebellar deficits produced by repeated cannabis exposure. J Clin Invest. (2013)
  153. Oz M, et al. Differential effects of endogenous and synthetic cannabinoids on alpha7-nicotinic acetylcholine receptor-mediated responses in Xenopus Oocytes. J Pharmacol Exp Ther. (2004)
  154. Oz M1, et al. The endogenous cannabinoid anandamide inhibits alpha7 nicotinic acetylcholine receptor-mediated responses in Xenopus oocytes. J Pharmacol Exp Ther. (2003)
  155. Oz M1, et al. Additive effects of endogenous cannabinoid anandamide and ethanol on alpha7-nicotinic acetylcholine receptor-mediated responses in Xenopus Oocytes. J Pharmacol Exp Ther. (2005)
  156. Spivak CE1, Lupica CR, Oz M. The endocannabinoid anandamide inhibits the function of alpha4beta2 nicotinic acetylcholine receptors. Mol Pharmacol. (2007)
  157. Lanzafame AA1, Guida E, Christopoulos A. Effects of anandamide on the binding and signaling properties of M1 muscarinic acetylcholine receptors. Biochem Pharmacol. (2004)
  158. Christopoulos A1, Wilson K. Interaction of anandamide with the M(1) and M(4) muscarinic acetylcholine receptors. Brain Res. (2001)
  159. Lagalwar S1, et al. Anandamides inhibit binding to the muscarinic acetylcholine receptor. J Mol Neurosci. (1999)
  160. Albizu L1, et al. Functional crosstalk and heteromerization of serotonin 5-HT2A and dopamine D2 receptors. Neuropharmacology. (2011)
  161. Borroto-Escuela DO1, et al. Dopamine D2 and 5-hydroxytryptamine 5-HT(₂A) receptors assemble into functionally interacting heteromers. Biochem Biophys Res Commun. (2010)
  162. Franklin JM1, Carrasco GA. Cannabinoid-induced enhanced interaction and protein levels of serotonin 5-HT(2A) and dopamine D₂ receptors in rat prefrontal cortex. J Psychopharmacol. (2012)
  163. Franklin JM1, Mathew M, Carrasco GA. Cannabinoid-induced upregulation of serotonin 2A receptors in the hypothalamic paraventricular nucleus and anxiety-like behaviors in rats. Neurosci Lett. (2013)
  164. García-Gutiérrez MS1, et al. Chronic blockade of cannabinoid CB2 receptors induces anxiolytic-like actions associated with alterations in GABA(A) receptors. Br J Pharmacol. (2012)
  165. Wang X1, et al. In utero marijuana exposure associated with abnormal amygdala dopamine D2 gene expression in the human fetus. Biol Psychiatry. (2004)
  166. Martinez D1, et al. Alcohol dependence is associated with blunted dopamine transmission in the ventral striatum. Biol Psychiatry. (2005)
  167. Martinez D1, et al. Amphetamine-induced dopamine release: markedly blunted in cocaine dependence and predictive of the choice to self-administer cocaine. Am J Psychiatry. (2007)
  168. Volkow ND1, et al. Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects. Nature. (1997)
  169. Sevy S1, et al. Cerebral glucose metabolism and D2/D3 receptor availability in young adults with cannabis dependence measured with positron emission tomography. Psychopharmacology (Berl). (2008)
  170. Stokes PR1, et al. History of cannabis use is not associated with alterations in striatal dopamine D2/D3 receptor availability. J Psychopharmacol. (2012)
  171. Urban NBL, et al. Dopamine Release in Chronic Cannabis Users: A {11C}Raclopride Positron Emission Tomography Study. Biol Psychiatry. (2012)
  172. Albrecht DS1, et al. Striatal D(2)/D(3) receptor availability is inversely correlated with cannabis consumption in chronic marijuana users. Drug Alcohol Depend. (2013)
  173. Kawamura Y1, et al. The CB1 cannabinoid receptor is the major cannabinoid receptor at excitatory presynaptic sites in the hippocampus and cerebellum. J Neurosci. (2006)
  174. Bodor AL1, et al. Endocannabinoid signaling in rat somatosensory cortex: laminar differences and involvement of specific interneuron types. J Neurosci. (2005)
  175. Freund TF1, Buzsáki G. Interneurons of the hippocampus. Hippocampus. (1996)
  176. Katona I1, et al. GABAergic interneurons are the targets of cannabinoid actions in the human hippocampus. Neuroscience. (2000)
  177. Laaris N1, Good CH, Lupica CR. Delta9-tetrahydrocannabinol is a full agonist at CB1 receptors on GABA neuron axon terminals in the hippocampus. Neuropharmacology. (2010)
  178. Ali AB1, Todorova M. Asynchronous release of GABA via tonic cannabinoid receptor activation at identified interneuron synapses in rat CA1. Eur J Neurosci. (2010)
  179. Sigel E1, et al. The major central endocannabinoid directly acts at GABA(A) receptors. Proc Natl Acad Sci U S A. (2011)
  180. Hoffman AF1, Lupica CR. Mechanisms of cannabinoid inhibition of GABA(A) synaptic transmission in the hippocampus. J Neurosci. (2000)
  181. Deshpande LS1, Blair RE, DeLorenzo RJ. Prolonged cannabinoid exposure alters GABA(A) receptor mediated synaptic function in cultured hippocampal neurons. Exp Neurol. (2011)
  182. Blair RE1, et al. Prolonged exposure to WIN55,212-2 causes downregulation of the CB1 receptor and the development of tolerance to its anticonvulsant effects in the hippocampal neuronal culture model of acquired epilepsy. Neuropharmacology. (2009)
  183. Han J1, et al. Acute cannabinoids impair working memory through astroglial CB1 receptor modulation of hippocampal LTD. Cell. (2012)
  184. Navarrete M1, Araque A. Endocannabinoids mediate neuron-astrocyte communication. Neuron. (2008)
  185. Lu W1, et al. Subunit composition of synaptic AMPA receptors revealed by a single-cell genetic approach. Neuron. (2009)
  186. Fan N1, et al. Reduced expression of glutamate receptors and phosphorylation of CREB are responsible for in vivo Delta9-THC exposure-impaired hippocampal synaptic plasticity. J Neurochem. (2010)
  187. Hampson RE1, et al. Cannabinoid receptor activation modifies NMDA receptor mediated release of intracellular calcium: implications for endocannabinoid control of hippocampal neural plasticity. Neuropharmacology. (2011)
  188. Chen R1, et al. Δ9-THC-caused synaptic and memory impairments are mediated through COX-2 signaling. Cell. (2013)
  189. Barco A1, Pittenger C, Kandel ER. CREB, memory enhancement and the treatment of memory disorders: promises, pitfalls and prospects. Expert Opin Ther Targets. (2003)
  190. Sánchez-Blázquez P, Rodríguez-Muñoz M, Garzón J. The cannabinoid receptor 1 associates with NMDA receptors to produce glutamatergic hypofunction: implications in psychosis and schizophrenia. Front Pharmacol. (2014)
  191. Sánchez-Blázquez P1, et al. Cannabinoid receptors couple to NMDA receptors to reduce the production of NO and the mobilization of zinc induced by glutamate. Antioxid Redox Signal. (2013)
  192. Garzón J1, et al. Gz mediates the long-lasting desensitization of brain CB1 receptors and is essential for cross-tolerance with morphine. Mol Pain. (2009)
  193. Hoffman AF1, et al. Opposing actions of chronic Delta9-tetrahydrocannabinol and cannabinoid antagonists on hippocampal long-term potentiation. Learn Mem. (2007)
  194. Melis M1, et al. Endocannabinoids mediate presynaptic inhibition of glutamatergic transmission in rat ventral tegmental area dopamine neurons through activation of CB1 receptors. J Neurosci. (2004)
  195. Domenici MR1, et al. Cannabinoid receptor type 1 located on presynaptic terminals of principal neurons in the forebrain controls glutamatergic synaptic transmission. J Neurosci. (2006)
  196. Vicente-Sánchez A1, et al. HINT1 protein cooperates with cannabinoid 1 receptor to negatively regulate glutamate NMDA receptor activity. Mol Brain. (2013)
  197. Palazzo E1, et al. Metabotropic and NMDA glutamate receptors participate in the cannabinoid-induced antinociception. Neuropharmacology. (2001)
  198. Glycine Receptors in CNS Neurons as a Target for Nonretrograde Action of Cannabinoids
  199. Mukhtarov M1, Ragozzino D, Bregestovski P. Dual Ca2+ modulation of glycinergic synaptic currents in rodent hypoglossal motoneurones. J Physiol. (2005)
  200. Hejazi N1, et al. Delta9-tetrahydrocannabinol and endogenous cannabinoid anandamide directly potentiate the function of glycine receptors. Mol Pharmacol. (2006)
  201. Pearlman RJ1, Aubrey KR, Vandenberg RJ. Arachidonic acid and anandamide have opposite modulatory actions at the glycine transporter, GLYT1a. J Neurochem. (2003)
  202. Xiong W1, et al. Cannabinoid potentiation of glycine receptors contributes to cannabis-induced analgesia. Nat Chem Biol. (2011)
  203. Xiong W1, et al. A common molecular basis for exogenous and endogenous cannabinoid potentiation of glycine receptors. J Neurosci. (2012)
  204. Spano MS1, et al. CB1 receptor agonist and heroin, but not cocaine, reinstate cannabinoid-seeking behaviour in the rat. Br J Pharmacol. (2004)
  205. Justinova Z1, et al. Blockade of THC-seeking behavior and relapse in monkeys by the cannabinoid CB(1)-receptor antagonist rimonabant. Neuropsychopharmacology. (2008)
  206. Navarro M1, et al. Functional interaction between opioid and cannabinoid receptors in drug self-administration. J Neurosci. (2001)
  207. Braida D1, et al. Conditioned place preference induced by the cannabinoid agonist CP 55,940: interaction with the opioid system. Neuroscience. (2001)
  208. Justinova Z1, et al. The opioid antagonist naltrexone reduces the reinforcing effects of Delta 9 tetrahydrocannabinol (THC) in squirrel monkeys. Psychopharmacology (Berl). (2004)
  209. Yao L1, et al. Adenosine A2a blockade prevents synergy between mu-opiate and cannabinoid CB1 receptors and eliminates heroin-seeking behavior in addicted rats. Proc Natl Acad Sci U S A. (2006)
  210. Navarro M1, et al. CB1 cannabinoid receptor antagonist-induced opiate withdrawal in morphine-dependent rats. Neuroreport. (1998)
  211. Beardsley PM, Balster RL, Harris LS. Dependence on tetrahydrocannabinol in rhesus monkeys. J Pharmacol Exp Ther. (1986)
  212. Haney M1, Bisaga A, Foltin RW. Interaction between naltrexone and oral THC in heavy marijuana smokers. Psychopharmacology (Berl). (2003)
  213. Cooper ZD1, Haney M. Opioid antagonism enhances marijuana's effects in heavy marijuana smokers. Psychopharmacology (Berl). (2010)
  214. Riering K1, Rewerts C, Zieglgänsberger W. Analgesic effects of 5-HT3 receptor antagonists. Scand J Rheumatol Suppl. (2004)
  215. Engleman EA1, et al. The role of 5-HT3 receptors in drug abuse and as a target for pharmacotherapy. CNS Neurol Disord Drug Targets. (2008)
  216. Yang KH, et al. The effect of Δ9-tetrahydrocannabinol on 5-HT3 receptors depends on the current density. Neuroscience. (2010)
  217. Xiong W1, et al. Anandamide inhibition of 5-HT3A receptors varies with receptor density and desensitization. Mol Pharmacol. (2008)
  218. Oz M1, Zhang L, Morales M. Endogenous cannabinoid, anandamide, acts as a noncompetitive inhibitor on 5-HT3 receptor-mediated responses in Xenopus oocytes. Synapse. (2002)
  219. Morales M1, Bäckman C. Coexistence of serotonin 3 (5-HT3) and CB1 cannabinoid receptors in interneurons of hippocampus and dentate gyrus. Hippocampus. (2002)
  220. Franklin JM1, et al. Cannabinoid 2 receptor- and beta Arrestin 2-dependent upregulation of serotonin 2A receptors. Eur Neuropsychopharmacol. (2013)
  221. Franklin JM1, Carrasco GA. Cannabinoid receptor agonists upregulate and enhance serotonin 2A (5-HT(2A)) receptor activity via ERK1/2 signaling. Synapse. (2013)
  222. Van de Kar LD1, et al. 5-HT2A receptors stimulate ACTH, corticosterone, oxytocin, renin, and prolactin release and activate hypothalamic CRF and oxytocin-expressing cells. J Neurosci. (2001)
  223. Hill MN1, et al. Altered responsiveness of serotonin receptor subtypes following long-term cannabinoid treatment. Int J Neuropsychopharmacol. (2006)
  224. Berghuis P1, et al. Endocannabinoids regulate interneuron migration and morphogenesis by transactivating the TrkB receptor. Proc Natl Acad Sci U S A. (2005)
  225. Butovsky E1, et al. In vivo up-regulation of brain-derived neurotrophic factor in specific brain areas by chronic exposure to Delta-tetrahydrocannabinol. J Neurochem. (2005)
  226. Maj PF1, et al. Long-term reduction of brain-derived neurotrophic factor levels and signaling impairment following prenatal treatment with the cannabinoid receptor 1 receptor agonist (R)-(+)-{2,3-dihydro-5-methyl-3-(4-morpholinyl-methyl) pyrrolo{1,2,3-de}-1,4-benzoxazin-6-yl}-1- naphthalenylmethanone. Eur J Neurosci. (2007)
  227. Rubino T1, et al. Changes in the expression of G protein-coupled receptor kinases and beta-arrestins in mouse brain during cannabinoid tolerance: a role for RAS-ERK cascade. Mol Neurobiol. (2006)
  228. Derkinderen P1, et al. Regulation of extracellular signal-regulated kinase by cannabinoids in hippocampus. J Neurosci. (2003)
  229. Valjent E1, et al. Delta 9-tetrahydrocannabinol-induced MAPK/ERK and Elk-1 activation in vivo depends on dopaminergic transmission. Eur J Neurosci. (2001)
  230. Derkinderen P1, et al. Cannabinoids activate p38 mitogen-activated protein kinases through CB1 receptors in hippocampus. J Neurochem. (2001)
  231. Alonso M1, Medina JH, Pozzo-Miller L. ERK1/2 activation is necessary for BDNF to increase dendritic spine density in hippocampal CA1 pyramidal neurons. Learn Mem. (2004)
  232. Tyler WJ1, et al. From acquisition to consolidation: on the role of brain-derived neurotrophic factor signaling in hippocampal-dependent learning. Learn Mem. (2002)
  233. D'Souza DC1, et al. Preliminary evidence of cannabinoid effects on brain-derived neurotrophic factor (BDNF) levels in humans. Psychopharmacology (Berl). (2009)
  234. Graeber MB1, Streit WJ. Microglia: biology and pathology. Acta Neuropathol. (2010)
  235. Saijo K1, Glass CK. Microglial cell origin and phenotypes in health and disease. Nat Rev Immunol. (2011)
  236. Kreutz S1, et al. Cannabinoids and neuronal damage: differential effects of THC, AEA and 2-AG on activated microglial cells and degenerating neurons in excitotoxically lesioned rat organotypic hippocampal slice cultures. Exp Neurol. (2007)
  237. Juknat A1, et al. Microarray and pathway analysis reveal distinct mechanisms underlying cannabinoid-mediated modulation of LPS-induced activation of BV-2 microglial cells. PLoS One. (2013)
  238. Esposito G1, et al. Cannabidiol reduces Aβ-induced neuroinflammation and promotes hippocampal neurogenesis through PPARγ involvement. PLoS One. (2011)
  239. O'Sullivan SE. Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors. Br J Pharmacol. (2007)
  240. Benowitz NL, Jones RT. Cardiovascular effects of prolonged delta-9-tetrahydrocannabinol ingestion. Clin Pharmacol Ther. (1975)
  241. Benowitz NL, et al. Cardiovascular effects of intravenous delta-9-tetrahydrocannabinol: autonomic nervous mechanisms. Clin Pharmacol Ther. (1979)
  242. Kanakis C Jr, Pouget JM, Rosen KM. The effects of delta-9-tetrahydrocannabinol (cannabis) on cardiac performance with and without beta blockade. Circulation. (1976)
  243. Mathew RJ1, Wilson WH, Davis R. Postural syncope after marijuana: a transcranial Doppler study of the hemodynamics. Pharmacol Biochem Behav. (2003)
  244. Mathew RJ1, et al. Middle cerebral artery velocity during upright posture after marijuana smoking. Acta Psychiatr Scand. (1992)
  245. Mathew RJ1, et al. Time course of tetrahydrocannabinol-induced changes in regional cerebral blood flow measured with positron emission tomography. Psychiatry Res. (2002)
  246. Mathew RJ1, et al. Regional cerebral blood flow after marijuana smoking. J Cereb Blood Flow Metab. (1992)
  247. Iring A1, et al. Role of endocannabinoids and cannabinoid-1 receptors in cerebrocortical blood flow regulation. PLoS One. (2013)
  248. Wagner JA1, et al. Hemodynamic effects of cannabinoids: coronary and cerebral vasodilation mediated by cannabinoid CB(1) receptors. Eur J Pharmacol. (2001)
  249. Mathew RJ1, et al. Regional cerebral blood flow and depersonalization after tetrahydrocannabinol administration. Acta Psychiatr Scand. (1999)
  250. Lee MC1, et al. Amygdala activity contributes to the dissociative effect of cannabis on pain perception. Pain. (2013)
  251. Wallace M1, et al. Dose-dependent effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers. Anesthesiology. (2007)
  252. Li J1, et al. The cannabinoid receptor agonist WIN 55,212-2 mesylate blocks the development of hyperalgesia produced by capsaicin in rats. Pain. (1999)
  253. Kraft B1, et al. Lack of analgesia by oral standardized cannabis extract on acute inflammatory pain and hyperalgesia in volunteers. Anesthesiology. (2008)
  254. Cahill L1, et al. Sex-related hemispheric lateralization of amygdala function in emotionally influenced memory: an FMRI investigation. Learn Mem. (2004)
  255. Ji G1, Neugebauer V. Hemispheric lateralization of pain processing by amygdala neurons. J Neurophysiol. (2009)
  256. Carrasquillo Y1, Gereau RW 4th. Hemispheric lateralization of a molecular signal for pain modulation in the amygdala. Mol Pain. (2008)
  257. Rukwied R1, et al. Cannabinoid agonists attenuate capsaicin-induced responses in human skin. Pain. (2003)
  258. Ware MA1, et al. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ. (2010)
  259. Wilsey B1, et al. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. J Pain. (2008)
  260. Wilsey B1, et al. Low-dose vaporized cannabis significantly improves neuropathic pain. J Pain. (2013)
  261. Ellis RJ1, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology. (2009)
  262. Aggarwal SK1, et al. Medicinal use of cannabis in the United States: historical perspectives, current trends, and future directions. J Opioid Manag. (2009)
  263. Higgins SC1, Gueorguiev M, Korbonits M. Ghrelin, the peripheral hunger hormone. Ann Med. (2007)
  264. Schneeberger M1, Claret M. Recent Insights into the Role of Hypothalamic AMPK Signaling Cascade upon Metabolic Control. Front Neurosci. (2012)
  265. Andersson U1, et al. AMP-activated protein kinase plays a role in the control of food intake. J Biol Chem. (2004)
  266. Kola B1, et al. The orexigenic effect of ghrelin is mediated through central activation of the endogenous cannabinoid system. PLoS One. (2008)
  267. Lim CT1, et al. Ghrelin and cannabinoids require the ghrelin receptor to affect cellular energy metabolism. Mol Cell Endocrinol. (2013)
  268. Alen F1, et al. Ghrelin-induced orexigenic effect in rats depends on the metabolic status and is counteracted by peripheral CB1 receptor antagonism. PLoS One. (2013)
  269. Pavon FJ1, et al. Antiobesity effects of the novel in vivo neutral cannabinoid receptor antagonist 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole--LH 21. Neuropharmacology. (2006)
  270. Alonso M1, et al. Anti-obesity efficacy of LH-21, a cannabinoid CB(1) receptor antagonist with poor brain penetration, in diet-induced obese rats. Br J Pharmacol. (2012)
  271. Riggs PK1, et al. A pilot study of the effects of cannabis on appetite hormones in HIV-infected adult men. Brain Res. (2012)
  272. Ramesh D1, Haney M, Cooper ZD. Marijuana's dose-dependent effects in daily marijuana smokers. Exp Clin Psychopharmacol. (2013)
  273. Bloomfield MA1, et al. The link between dopamine function and apathy in cannabis users: an {18F}-DOPA PET imaging study. Psychopharmacology (Berl). (2014)
  274. Wallace MJ1, et al. The endogenous cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy. J Pharmacol Exp Ther. (2003)
  275. Wallace MJ1, Martin BR, DeLorenzo RJ. Evidence for a physiological role of endocannabinoids in the modulation of seizure threshold and severity. Eur J Pharmacol. (2002)
  276. Blair RE1, et al. Activation of the cannabinoid type-1 receptor mediates the anticonvulsant properties of cannabinoids in the hippocampal neuronal culture models of acquired epilepsy and status epilepticus. J Pharmacol Exp Ther. (2006)
  277. Deshpande LS1, et al. Endocannabinoids block status epilepticus in cultured hippocampal neurons. Eur J Pharmacol. (2007)
  278. Sensi SL1, Jeng JM. Rethinking the excitotoxic ionic milieu: the emerging role of Zn(2+) in ischemic neuronal injury. Curr Mol Med. (2004)
  279. Ghasemi M1, Schachter SC. The NMDA receptor complex as a therapeutic target in epilepsy: a review. Epilepsy Behav. (2011)
  280. Liu Q1, et al. Signaling pathways from cannabinoid receptor-1 activation to inhibition of N-methyl-D-aspartic acid mediated calcium influx and neurotoxicity in dorsal root ganglion neurons. J Pharmacol Exp Ther. (2009)
  281. Kedzior KK1, Laeber LT. A positive association between anxiety disorders and cannabis use or cannabis use disorders in the general population- a meta-analysis of 31 studies. BMC Psychiatry. (2014)
  282. Chabrol H1, Chauchard E, Girabet J. Cannabis use and suicidal behaviours in high-school students. Addict Behav. (2008)
  283. Chabrol H1, et al. Relations between cannabis use and dependence, motives for cannabis use and anxious, depressive and borderline symptomatology. Addict Behav. (2005)
  284. Cannabis dependence in Swiss adolescents: Exploration of the role of anxiety, coping styles, and psychosocial difficulties
  285. Agosti V1, Nunes E, Levin F. Rates of psychiatric comorbidity among U.S. residents with lifetime cannabis dependence. Am J Drug Alcohol Abuse. (2002)
  286. Brook JS1, Cohen P, Brook DW. Longitudinal study of co-occurring psychiatric disorders and substance use. J Am Acad Child Adolesc Psychiatry. (1998)
  287. Buckner JD1, et al. Specificity of social anxiety disorder as a risk factor for alcohol and cannabis dependence. J Psychiatr Res. (2008)
  288. Buckner JD1, et al. Daily marijuana use and suicidality: the unique impact of social anxiety. Addict Behav. (2012)
  289. Buckner JD1, Schmidt NB. Marijuana effect expectancies: relations to social anxiety and marijuana use problems. Addict Behav. (2008)
  290. Degenhardt L1, Hall W, Lynskey M. The relationship between cannabis use, depression and anxiety among Australian adults: findings from the National Survey of Mental Health and Well-Being. Soc Psychiatry Psychiatr Epidemiol. (2001)
  291. Degenhardt L1, et al. The persistence of the association between adolescent cannabis use and common mental disorders into young adulthood. Addiction. (2013)
  292. Fergusson DM1, Lynskey MT, Horwood LJ. The short-term consequences of early onset cannabis use. J Abnorm Child Psychol. (1996)
  293. Low NC1, et al. The association between anxiety and alcohol versus cannabis abuse disorders among adolescents in primary care settings. Fam Pract. (2008)
  294. Martins SS1, Gorelick DA. Conditional substance abuse and dependence by diagnosis of mood or anxiety disorder or schizophrenia in the U.S. population. Drug Alcohol Depend. (2011)
  295. Roberts RE1, Roberts CR, Xing Y. Comorbidity of substance use disorders and other psychiatric disorders among adolescents: evidence from an epidemiologic survey. Drug Alcohol Depend. (2007)
  296. van der Pol P1, et al. Mental health differences between frequent cannabis users with and without dependence and the general population. Addiction. (2013)
  297. van Laar M1, et al. Does cannabis use predict the first incidence of mood and anxiety disorders in the adult population. Addiction. (2007)
  298. Wittchen HU1, et al. Cannabis use and cannabis use disorders and their relationship to mental disorders: a 10-year prospective-longitudinal community study in adolescents. Drug Alcohol Depend. (2007)
  299. Cheung JT1, et al. Anxiety and mood disorders and cannabis use. Am J Drug Alcohol Abuse. (2010)
  300. Degenhardt L1, et al. Outcomes of occasional cannabis use in adolescence: 10-year follow-up study in Victoria, Australia. Br J Psychiatry. (2010)
  301. Lamers CT1, et al. Cognitive function and mood in MDMA/THC users, THC users and non-drug using controls. J Psychopharmacol. (2006)
  302. Hayatbakhsh MR1, et al. Cannabis and anxiety and depression in young adults: a large prospective study. J Am Acad Child Adolesc Psychiatry. (2007)
  303. McGee R1, et al. A longitudinal study of cannabis use and mental health from adolescence to early adulthood. Addiction. (2000)
  304. Patton GC1, et al. Cannabis use and mental health in young people: cohort study. BMJ. (2002)
  305. Swift W1, et al. Adolescent cannabis users at 24 years: trajectories to regular weekly use and dependence in young adulthood. Addiction. (2008)
  306. Zvolensky MJ1, et al. Lifetime associations between cannabis, use, abuse, and dependence and panic attacks in a representative sample. J Psychiatr Res. (2006)
  307. Zvolensky MJ1, et al. Marijuana use and panic psychopathology among a representative sample of adults. Exp Clin Psychopharmacol. (2010)
  308. Cougle JR1, et al. Posttraumatic stress disorder and cannabis use in a nationally representative sample. Psychol Addict Behav. (2011)
  309. Crum RM1, Anthony JC. Cocaine use and other suspected risk factors for obsessive-compulsive disorder: a prospective study with data from the Epidemiologic Catchment Area surveys. Drug Alcohol Depend. (1993)
  310. Beard JR1, et al. Incidence and outcomes of mental disorders in a regional population: the Northern Rivers Mental Health Study. Aust N Z J Psychiatry. (2006)
  311. Moylan S1, et al. Cigarette smoking, nicotine dependence and anxiety disorders: a systematic review of population-based, epidemiological studies. BMC Med. (2012)
  312. Harder VS1, Morral AR, Arkes J. Marijuana use and depression among adults: Testing for causal associations. Addiction. (2006)
  313. Degenhardt L1, Hall W, Lynskey M. Exploring the association between cannabis use and depression. Addiction. (2003)
  314. Association between Severity of Cannabis Dependence and Depression
  315. Manrique-Garcia E1, et al. Cannabis use and depression: a longitudinal study of a national cohort of Swedish conscripts. BMC Psychiatry. (2012)
  316. Leweke FM1, Koethe D. Cannabis and psychiatric disorders: it is not only addiction. Addict Biol. (2008)
  317. Denson TF1, Earleywine M. Decreased depression in marijuana users. Addict Behav. (2006)
  318. Gonzalez R1, Carey C, Grant I. Nonacute (residual) neuropsychological effects of cannabis use: a qualitative analysis and systematic review. J Clin Pharmacol. (2002)
  319. Lundqvist T. Cognitive consequences of cannabis use: comparison with abuse of stimulants and heroin with regard to attention, memory and executive functions. Pharmacol Biochem Behav. (2005)
  320. Vadhan NP1, Serper MR, Haney M. Effects of Δ-THC on Working Memory: Implications for Schizophrenia. Prim psychiatry. (2009)
  321. Bolla KI1, et al. Dose-related neurocognitive effects of marijuana use. Neurology. (2002)
  322. Verdejo-Garcia A1, et al. The differential relationship between cocaine use and marijuana use on decision-making performance over repeat testing with the Iowa Gambling Task. Drug Alcohol Depend. (2007)
  323. Verrico CD, et al. Repeated Δ9-tetrahydrocannabinol exposure in adolescent monkeys: persistent effects selective for spatial working memory. Am J Psychiatry. (2014)
  324. Lichtman AH1, Martin BR. Delta 9-tetrahydrocannabinol impairs spatial memory through a cannabinoid receptor mechanism. Psychopharmacology (Berl). (1996)
  325. Baddeley A. Working memory: looking back and looking forward. Nat Rev Neurosci. (2003)
  326. Pope HG Jr1, Yurgelun-Todd D. The residual cognitive effects of heavy marijuana use in college students. JAMA. (1996)
  327. Block RI1, Ghoneim MM. Effects of chronic marijuana use on human cognition. Psychopharmacology (Berl). (1993)
  328. Lyons MJ, et al. Neuropsychological consequences of regular marijuana use: a twin study. Psychol Med. (2004)
  329. Schreiner AM, Dunn ME. Residual effects of cannabis use on neurocognitive performance after prolonged abstinence: a meta-analysis. Exp Clin Psychopharmacol. (2012)
  330. Renaud AM, Cormier Y. Acute effects of marihuana smoking on maximal exercise performance. Med Sci Sports Exerc. (1986)
  331. Steadward RD, Singh M. The effects of smoking marihuana on physical performance. Med Sci Sports. (1975)
  332. Jones RT. Cardiovascular system effects of marijuana. J Clin Pharmacol. (2002)
  333. Gorelick DA1, et al. Tolerance to effects of high-dose oral δ9-tetrahydrocannabinol and plasma cannabinoid concentrations in male daily cannabis smokers. J Anal Toxicol. (2013)
  334. Kanakis C, Pouget M, Rosen KM. Lack of cardiovascular effects of delta-9-tetrahydrocannabinol in chemically denervated men. Ann Intern Med. (1979)
  335. Pavisian B1, et al. Effects of cannabis on cognition in patients with MS: A psychometric and MRI study. Neurology. (2014)
  336. Panitz C1, et al. Brain-heart coupling at the P300 latency is linked to anterior cingulate cortex and insula--a cardio-electroencephalographic covariance tracing study. Biol Psychol. (2013)
  337. de Morree HM1, et al. Central nervous system involvement in the autonomic responses to psychological distress. Neth Heart J. (2013)
  338. Hester R1, Nestor L, Garavan H. Impaired error awareness and anterior cingulate cortex hypoactivity in chronic cannabis users. Neuropsychopharmacology. (2009)
  339. Szeszko PR1, et al. Anterior cingulate grey-matter deficits and cannabis use in first-episode schizophrenia. Br J Psychiatry. (2007)
  340. Liu J1, et al. Functional CB1 cannabinoid receptors in human vascular endothelial cells. Biochem J. (2000)
  341. Rajesh M1, et al. Cannabinoid-1 receptor activation induces reactive oxygen species-dependent and -independent mitogen-activated protein kinase activation and cell death in human coronary artery endothelial cells. Br J Pharmacol. (2010)
  342. Rajesh M1, et al. CB2-receptor stimulation attenuates TNF-alpha-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion. Am J Physiol Heart Circ Physiol. (2007)
  343. Zhao Y1, et al. Activation of cannabinoid CB2 receptor ameliorates atherosclerosis associated with suppression of adhesion molecules. J Cardiovasc Pharmacol. (2010)
  344. Srivastava MD1, Srivastava BI, Brouhard B. Delta9 tetrahydrocannabinol and cannabidiol alter cytokine production by human immune cells. Immunopharmacology. (1998)
  345. Zhu LX1, et al. Delta-9-tetrahydrocannabinol inhibits antitumor immunity by a CB2 receptor-mediated, cytokine-dependent pathway. J Immunol. (2000)
  346. Yuan M1, et al. Delta 9-Tetrahydrocannabinol regulates Th1/Th2 cytokine balance in activated human T cells. J Neuroimmunol. (2002)
  347. Steffens S1, et al. Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. Nature. (2005)
  348. Dushkin MI. Macrophage/foam cell is an attribute of inflammation: mechanisms of formation and functional role. Biochemistry (Mosc). (2012)
  349. Chiurchiù V1, et al. Detailed characterization of the endocannabinoid system in human macrophages and foam cells, and anti-inflammatory role of type-2 cannabinoid receptor. Atherosclerosis. (2014)
  350. Mach F1, Steffens S. The role of the endocannabinoid system in atherosclerosis. J Neuroendocrinol. (2008)
  351. Greaves DR1, Gordon S. The macrophage scavenger receptor at 30 years of age: current knowledge and future challenges. J Lipid Res. (2009)
  352. Collot-Teixeira S1, et al. CD36 and macrophages in atherosclerosis. Cardiovasc Res. (2007)
  353. Engel T1, et al. Expression and functional characterization of ABCG1 splice variant ABCG1(666). FEBS Lett. (2006)
  354. Wittwer J1, Hersberger M. The two faces of the 15-lipoxygenase in atherosclerosis. Prostaglandins Leukot Essent Fatty Acids. (2007)
  355. Kuhn H1, Walther M, Kuban RJ. Mammalian arachidonate 15-lipoxygenases structure, function, and biological implications. Prostaglandins Other Lipid Mediat. (2002)
  356. Han KH1, et al. CB1 and CB2 cannabinoid receptors differentially regulate the production of reactive oxygen species by macrophages. Cardiovasc Res. (2009)
  357. Molica F1, et al. Endogenous cannabinoid receptor CB1 activation promotes vascular smooth-muscle cell proliferation and neointima formation. J Lipid Res. (2013)
  358. Netherland C1, Thewke DP. Rimonabant is a dual inhibitor of acyl CoA:cholesterol acyltransferases 1 and 2. Biochem Biophys Res Commun. (2010)
  359. Thewke D1, et al. AM-251 and SR144528 are acyl CoA:cholesterol acyltransferase inhibitors. Biochem Biophys Res Commun. (2009)
  360. Jiang LS1, et al. Role of activated endocannabinoid system in regulation of cellular cholesterol metabolism in macrophages. Cardiovasc Res. (2009)
  361. Dol-Gleizes F1, et al. Rimonabant, a selective cannabinoid CB1 receptor antagonist, inhibits atherosclerosis in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol. (2009)
  362. Faggiotto A, Ross R, Harker L. Studies of hypercholesterolemia in the nonhuman primate. I. Changes that lead to fatty streak formation. Arteriosclerosis. (1984)
  363. Glukhova MA1, et al. Identification of smooth muscle-derived foam cells in the atherosclerotic plaque of human aorta with monoclonal antibody IIG10. Tissue Cell. (1987)
  364. Ma L1, et al. Activation of TRPV1 reduces vascular lipid accumulation and attenuates atherosclerosis. Cardiovasc Res. (2011)
  365. Arnold JC1, et al. CB2 and TRPV1 receptors mediate cannabinoid actions on MDR1 expression in multidrug resistant cells. Pharmacol Rep. (2012)
  366. Costa B1, et al. Vanilloid TRPV1 receptor mediates the antihyperalgesic effect of the nonpsychoactive cannabinoid, cannabidiol, in a rat model of acute inflammation. Br J Pharmacol. (2004)
  367. Li BH, et al. TRPV1 activation impedes foam cell formation by inducing autophagy in oxLDL-treated vascular smooth muscle cells. Cell Death Dis. (2014)
  368. Roth MD. Pharmacology: marijuana and your heart. Nature. (2005)
  369. Vandrey R1, Umbricht A, Strain EC. Increased blood pressure after abrupt cessation of daily cannabis use. J Addict Med. (2011)
  370. Nathan I, et al. Specific impairment of ADP-induced platelet aggregation by cannabinoids. Int J Tissue React. (1986)
  371. Formukong EA1, Evans AT, Evans FJ. The inhibitory effects of cannabinoids, the active constituents of Cannabis sativa L. on human and rabbit platelet aggregation. J Pharm Pharmacol. (1989)
  372. Levy R, et al. Impairment of ADP-induced platelet aggregation by hashish components. Thromb Haemost. (1976)
  373. Jedlitschky G1, Greinacher A, Kroemer HK. Transporters in human platelets: physiologic function and impact for pharmacotherapy. Blood. (2012)
  374. Velenovská M1, Fisar Z. Effect of cannabinoids on platelet serotonin uptake. Addict Biol. (2007)
  375. Volfe Z, Dvilansky A, Nathan I. Cannabinoids block release of serotonin from platelets induced by plasma from migraine patients. Int J Clin Pharmacol Res. (1985)
  376. El Amrani L1, et al. Changes on metabolic parameters induced by acute cannabinoid administration (CBD, THC) in a rat experimental model of nutritional vitamin A deficiency. Nutr Hosp. (2013)
  377. Rodondi N1, et al. Marijuana use, diet, body mass index, and cardiovascular risk factors (from the CARDIA study). Am J Cardiol. (2006)
  378. Muniyappa R1, et al. Metabolic effects of chronic cannabis smoking. Diabetes Care. (2013)
  379. Penner EA1, Buettner H, Mittleman MA. The impact of marijuana use on glucose, insulin, and insulin resistance among US adults. Am J Med. (2013)
  380. Rajavashisth TB1, et al. Decreased prevalence of diabetes in marijuana users: cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) III. BMJ Open. (2012)
  381. Migrenne S1, et al. Adiponectin is required to mediate rimonabant-induced improvement of insulin sensitivity but not body weight loss in diet-induced obese mice. Am J Physiol Regul Integr Comp Physiol. (2009)
  382. Sowers JR. Endocrine functions of adipose tissue: focus on adiponectin. Clin Cornerstone. (2008)
  383. Ravinet Trillou C1, et al. CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity. Int J Obes Relat Metab Disord. (2004)
  384. Permutt MA, et al. The effect of marijuana on carbohydrate metabolism. Am J Psychiatry. (1976)
  385. Sanz P, Rodríguez-Vicente C, Repetto M. Alteration of glucose metabolism in liver by acute administration of cannabis. Bull Narc. (1985)
  386. Chakravarty I, Ghosh JJ. Effect of cannabis extract on uterine glycogen metabolism in prepubertal rats under normal and estradiol-treated conditions. Biochem Pharmacol. (1977)
  387. Jørgensen SB1, Richter EA, Wojtaszewski JF. Role of AMPK in skeletal muscle metabolic regulation and adaptation in relation to exercise. J Physiol. (2006)
  388. Cavuoto P1, et al. The expression of receptors for endocannabinoids in human and rodent skeletal muscle. Biochem Biophys Res Commun. (2007)
  389. Cavuoto P1, et al. Effects of cannabinoid receptors on skeletal muscle oxidative pathways. Mol Cell Endocrinol. (2007)
  390. Kola B1, et al. Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase. J Biol Chem. (2005)
  391. Hennessy A. Cannabis masks diabetic ketoacidosis. BMJ Case Rep. (2011)
  392. Levendal RA1, et al. Cannabis exposure associated with weight reduction and β-cell protection in an obese rat model. Phytomedicine. (2012)
  393. Mechoulam R1, Hanus L, Fride E. Towards cannabinoid drugs--revisited. Prog Med Chem. (1998)
  394. Williams CM1, Kirkham TC. Anandamide induces overeating: mediation by central cannabinoid (CB1) receptors. Psychopharmacology (Berl). (1999)
  395. Hao S1, et al. Low dose anandamide affects food intake, cognitive function, neurotransmitter and corticosterone levels in diet-restricted mice. Eur J Pharmacol. (2000)
  396. Tucci SA1, et al. The cannabinoid CB1 receptor antagonist SR141716 blocks the orexigenic effects of intrahypothalamic ghrelin. Br J Pharmacol. (2004)
  397. Senin LL1, et al. The gastric CB1 receptor modulates ghrelin production through the mTOR pathway to regulate food intake. PLoS One. (2013)
  398. González S1, et al. Identification of endocannabinoids and cannabinoid CB(1) receptor mRNA in the pituitary gland. Neuroendocrinology. (1999)
  399. Schwartz MW1, et al. Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus. Diabetes. (1997)
  400. Seeley RJ, et al. Melanocortin receptors in leptin effects. Nature. (1997)
  401. Stephens TW1, et al. The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature. (1995)
  402. Chin-Chance C1, Polonsky KS, Schoeller DA. Twenty-four-hour leptin levels respond to cumulative short-term energy imbalance and predict subsequent intake. J Clin Endocrinol Metab. (2000)
  403. Valassi E1, Scacchi M, Cavagnini F. Neuroendocrine control of food intake. Nutr Metab Cardiovasc Dis. (2008)
  404. Tschöp M1, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature. (2000)
  405. Thompson NM1, et al. Ghrelin and des-octanoyl ghrelin promote adipogenesis directly in vivo by a mechanism independent of the type 1a growth hormone secretagogue receptor. Endocrinology. (2004)
  406. Wortley KE1, et al. Genetic deletion of ghrelin does not decrease food intake but influences metabolic fuel preference. Proc Natl Acad Sci U S A. (2004)
  407. Motaghedi R1, McGraw TE. The CB1 endocannabinoid system modulates adipocyte insulin sensitivity. Obesity (Silver Spring). (2008)
  408. Gallant M1, et al. Biological effects of THC and a lipophilic cannabis extract on normal and insulin resistant 3T3-L1 adipocytes. Phytomedicine. (2009)
  409. Pagano C1, et al. The endogenous cannabinoid system stimulates glucose uptake in human fat cells via phosphatidylinositol 3-kinase and calcium-dependent mechanisms. J Clin Endocrinol Metab. (2007)
  410. Gasperi V1, et al. Endocannabinoids in adipocytes during differentiation and their role in glucose uptake. Cell Mol Life Sci. (2007)
  411. Purohit V, Rapaka R, Shurtleff D. Role of cannabinoids in the development of fatty liver (steatosis). AAPS J. (2010)
  412. Teixeira D, et al. Modulation of adipocyte biology by δ(9)-tetrahydrocannabinol. Obesity (Silver Spring). (2010)
  413. Blázquez C, et al. The stimulation of ketogenesis by cannabinoids in cultured astrocytes defines carnitine palmitoyltransferase I as a new ceramide-activated enzyme. J Neurochem. (1999)
  414. Osei-Hyiaman D, et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest. (2005)
  415. Lichtman AH, Cravatt BF. Food for thought: endocannabinoid modulation of lipogenesis. J Clin Invest. (2005)
  416. Cota D1, et al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest. (2003)
  417. Matias I1, et al. Regulation, function, and dysregulation of endocannabinoids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia. J Clin Endocrinol Metab. (2006)
  418. Gary-Bobo M1, et al. The cannabinoid CB1 receptor antagonist rimonabant (SR141716) inhibits cell proliferation and increases markers of adipocyte maturation in cultured mouse 3T3 F442A preadipocytes. Mol Pharmacol. (2006)
  419. Di Marzo V1, et al. Changes in plasma endocannabinoid levels in viscerally obese men following a 1 year lifestyle modification programme and waist circumference reduction: associations with changes in metabolic risk factors. Diabetologia. (2009)
  420. Blüher M1, et al. Dysregulation of the peripheral and adipose tissue endocannabinoid system in human abdominal obesity. Diabetes. (2006)
  421. Côté M1, et al. Circulating endocannabinoid levels, abdominal adiposity and related cardiometabolic risk factors in obese men. Int J Obes (Lond). (2007)
  422. Annuzzi G1, et al. Differential alterations of the concentrations of endocannabinoids and related lipids in the subcutaneous adipose tissue of obese diabetic patients. Lipids Health Dis. (2010)
  423. Bennetzen MF1, et al. Investigations of the human endocannabinoid system in two subcutaneous adipose tissue depots in lean subjects and in obese subjects before and after weight loss. Int J Obes (Lond). (2011)
  424. Di Marzo V. The endocannabinoid system in obesity and type 2 diabetes. Diabetologia. (2008)
  425. Le Strat Y1, Le Foll B. Obesity and cannabis use: results from 2 representative national surveys. Am J Epidemiol. (2011)
  426. Smit E1, Crespo CJ. Dietary intake and nutritional status of US adult marijuana users: results from the Third National Health and Nutrition Examination Survey. Public Health Nutr. (2001)
  427. Jones RT, Benowitz NL, Herning RI. Clinical relevance of cannabis tolerance and dependence. J Clin Pharmacol. (1981)
  428. Saugy M1, et al. Cannabis and sport. Br J Sports Med. (2006)
  429. Lutz B. The endocannabinoid system and extinction learning. Mol Neurobiol. (2007)
  430. Marsicano G1, et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature. (2002)
  431. Wagner JC. Abuse of drugs used to enhance athletic performance. Am J Hosp Pharm. (1989)
  432. Wei J1, et al. Increase of plasma IL-6 concentration with age in healthy subjects. Life Sci. (1992)
  433. Keen L 2nd1, Pereira D2, Latimer W3. Self-reported lifetime marijuana use and interleukin-6 levels in middle-aged African Americans. Drug Alcohol Depend. (2014)
  434. Charles BA1, et al. The roles of IL-6, IL-10, and IL-1RA in obesity and insulin resistance in African-Americans. J Clin Endocrinol Metab. (2011)
  435. Sugiura T1, et al. New perspectives in the studies on endocannabinoid and cannabis: 2-arachidonoylglycerol as a possible novel mediator of inflammation. J Pharmacol Sci. (2004)
  436. Kishimoto S1, et al. Endogenous cannabinoid receptor ligand induces the migration of human natural killer cells. J Biochem. (2005)
  437. Sugiura T1, et al. Evidence that 2-arachidonoylglycerol but not N-palmitoylethanolamine or anandamide is the physiological ligand for the cannabinoid CB2 receptor. Comparison of the agonistic activities of various cannabinoid receptor ligands in HL-60 cells. J Biol Chem. (2000)
  438. Ignatowska-Jankowska B1, et al. Cannabidiol-induced lymphopenia does not involve NKT and NK cells. J Physiol Pharmacol. (2009)
  439. El-Gohary M1, Eid MA. Effect of cannabinoid ingestion (in the form of bhang) on the immune system of high school and university students. Hum Exp Toxicol. (2004)
  440. Galiègue S1, et al. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem. (1995)
  441. Lee SF1, et al. Differential expression of cannabinoid CB(2) receptor mRNA in mouse immune cell subpopulations and following B cell stimulation. Eur J Pharmacol. (2001)
  442. Lee SF1, et al. Downregulation of cannabinoid receptor 2 (CB2) messenger RNA expression during in vitro stimulation of murine splenocytes with lipopolysaccharide. Adv Exp Med Biol. (2001)
  443. Schroder AJ1, et al. Cutting edge: STAT6 serves as a positive and negative regulator of gene expression in IL-4-stimulated B lymphocytes. J Immunol. (2002)
  444. Carayon P1, et al. Modulation and functional involvement of CB2 peripheral cannabinoid receptors during B-cell differentiation. Blood. (1998)
  445. Tanikawa T1, Kurohane K, Imai Y. Induction of preferential chemotaxis of unstimulated B-lymphocytes by 2-arachidonoylglycerol in immunized mice. Microbiol Immunol. (2007)
  446. Rayman N1, et al. Distinct expression profiles of the peripheral cannabinoid receptor in lymphoid tissues depending on receptor activation status. J Immunol. (2004)
  447. Agudelo M1, et al. Cannabinoid receptor 2 (CB2) mediates immunoglobulin class switching from IgM to IgE in cultures of murine-purified B lymphocytes. J Neuroimmune Pharmacol. (2008)
  448. Rachelefsky GS, et al. Intact humoral and cell-mediated immunity in chronic marijuana smoking. J Allergy Clin Immunol. (1976)
  449. Derocq JM1, et al. Cannabinoids enhance human B-cell growth at low nanomolar concentrations. FEBS Lett. (1995)
  450. Harmon J, Aliapoulios MA. Gynecomastia in marihuana users. N Engl J Med. (1972)
  451. Harmon JW, Aliapoulios MA. Marijuana-induced gynecomastia: clinical and laboratory experience. Surg Forum. (1974)
  452. Sauer MA, et al. Marijuana: interaction with the estrogen receptor. J Pharmacol Exp Ther. (1983)
  453. Ruh MF1, et al. Failure of cannabinoid compounds to stimulate estrogen receptors. Biochem Pharmacol. (1997)
  454. Lee SY1, Oh SM, Chung KH. Estrogenic effects of marijuana smoke condensate and cannabinoid compounds. Toxicol Appl Pharmacol. (2006)
  455. Wirth PW, et al. Constituents of Cannabis sativa L. XXI: Estrogenic activity of a non-cannabinoid constituent. Experientia. (1981)
  456. Dalterio S, Bartke A, Burstein S. Cannabinoids inhibit testosterone secretion by mouse testes in vitro. Science. (1977)
  457. Burstein S, Hunter SA, Shoupe TS. Cannabinoid inhibition of rat luteal cell progesterone synthesis. Res Commun Chem Pathol Pharmacol. (1979)
  458. Jakubovic A, McGeer EG, McGeer PL. Effects of cannabinoids on testosterone and protein synthesis in rat testis Leydig cells in vitro. Mol Cell Endocrinol. (1979)
  459. Barnett G, Chiang CW, Licko V. Effects of marijuana on testosterone in male subjects. J Theor Biol. (1983)
  460. Cone EJ, et al. Acute effects of smoking marijuana on hormones, subjective effects and performance in male human subjects. Pharmacol Biochem Behav. (1986)
  461. Schaefer CF, Gunn CG, Dubowski KM. Letter: Normal plasma testosterone concentrations after marihuana smoking. N Engl J Med. (1975)
  462. Dax EM, et al. The effects of 9-ene-tetrahydrocannabinol on hormone release and immune function. J Steroid Biochem. (1989)
  463. Cushman P Jr. Plasma testosterone levels in healthy male marijuana smokers. Am J Drug Alcohol Abuse. (1975)
  464. Block RI, Farinpour R, Schlechte JA. Effects of chronic marijuana use on testosterone, luteinizing hormone, follicle stimulating hormone, prolactin and cortisol in men and women. Drug Alcohol Depend. (1991)
  465. Kolodny RC, et al. Depression of plasma testosterone levels after chronic intensive marihuana use. N Engl J Med. (1974)
  466. Gorzalka BB, Hill MN, Chang SC. Male-female differences in the effects of cannabinoids on sexual behavior and gonadal hormone function. Horm Behav. (2010)
  467. List A, et al. The effects of delta9-tetrahydrocannabinol and cannabidiol on the metabolism of gonadal steroids in the rat. Drug Metab Dispos. (1977)
  468. Dixit VP, Lohiya NK. Effects of Cannabis extract on the response of accessory sex organs of adult male mice to testosterone. Indian J Physiol Pharmacol. (1975)
  469. Ghosh SP, Chatterjee TK, Ghosh JJ. Antiandrogenic effect of delta-9-tetrahydrocannabinol in adult castrated rats. J Reprod Fertil. (1981)
  470. Purohit V, Ahluwahlia BS, Vigersky RA. Marihuana inhibits dihydrotestosterone binding to the androgen receptor. Endocrinology. (1980)
  471. Wenger T, et al. The central cannabinoid receptor inactivation suppresses endocrine reproductive functions. Biochem Biophys Res Commun. (2001)
  472. Benowitz NL, Jones RT, Lerner CB. Depression of growth hormone and cortisol response to insulin-induced hypoglycemia after prolonged oral delta-9-tetrahydrocannabinol administration in man. J Clin Endocrinol Metab. (1976)
  473. Ranganathan M1, et al. The effects of cannabinoids on serum cortisol and prolactin in humans. Psychopharmacology (Berl). (2009)
  474. Brown TT1, Dobs AS. Endocrine effects of marijuana. J Clin Pharmacol. (2002)
  475. Martín-Calderón JL1, et al. Characterization of the acute endocrine actions of (-)-11-hydroxy-delta8-tetrahydrocannabinol-dimethylheptyl (HU-210), a potent synthetic cannabinoid in rats. Eur J Pharmacol. (1998)
  476. Tanasescu R, Constantinescu CS. Cannabinoids and the immune system: an overview. Immunobiology. (2010)
  477. Izzo AA, Camilleri M. Emerging role of cannabinoids in gastrointestinal and liver diseases: basic and clinical aspects. Gut. (2008)
  478. Mendez-Sanchez N1, et al. Endocannabinoid receptor CB2 in nonalcoholic fatty liver disease. Liver Int. (2007)
  479. Howaizi M1, et al. Cannabis-induced recurrent acute pancreatitis. Acta Gastroenterol Belg. (2012)
  480. Matsuda K1, et al. The cannabinoid 1 receptor antagonist, AM251, prolongs the survival of rats with severe acute pancreatitis. Tohoku J Exp Med. (2005)
  481. Weiss L1, et al. Cannabidiol lowers incidence of diabetes in non-obese diabetic mice. Autoimmunity. (2006)
  482. Li X, Kaminski NE, Fischer LJ. Examination of the immunosuppressive effect of delta9-tetrahydrocannabinol in streptozotocin-induced autoimmune diabetes. Int Immunopharmacol. (2001)
  483. Taylor DR1, Hall W; Thoracic Society of Australia and New Zealand. Respiratory health effects of cannabis: position statement of the Thoracic Society of Australia and New Zealand. Intern Med J. (2003)
  484. Tashkin DP, et al. Subacute effects of heavy marihuana smoking on pulmonary function in healthy men. N Engl J Med. (1976)
  485. Taylor DR1, et al. The respiratory effects of cannabis dependence in young adults. Addiction. (2000)
  486. Tashkin DP, Shapiro BJ, Frank IM. Acute pulmonary physiologic effects of smoked marijuana and oral 9 -tetrahydrocannabinol in healthy young men. N Engl J Med. (1973)
  487. Osborne NN1, et al. Retinal ischemia: mechanisms of damage and potential therapeutic strategies. Prog Retin Eye Res. (2004)
  488. El-Remessy AB1, et al. Neuroprotective effect of (-)Delta9-tetrahydrocannabinol and cannabidiol in N-methyl-D-aspartate-induced retinal neurotoxicity: involvement of peroxynitrite. Am J Pathol. (2003)
  489. Opere CA1, et al. Inhibition of potassium- and ischemia-evoked {3H} D-aspartate release from isolated bovine retina by cannabinoids. Curr Eye Res. (2006)
  490. Tomida I1, et al. Effect of sublingual application of cannabinoids on intraocular pressure: a pilot study. J Glaucoma. (2006)
  491. Cooler P, Gregg JM. Effect of delta-9-tetrahydrocannabinol on intraocular pressure in humans. South Med J. (1977)
  492. Merritt JC, et al. Effect of marihuana on intraocular and blood pressure in glaucoma. Ophthalmology. (1980)
  493. Flom MC, Adams AJ, Jones RT. Marijuana smoking and reduced pressure in human eyes: drug action or epiphenomenon. Invest Ophthalmol. (1975)
  494. Zhang LR1, et al. Cannabis smoking and lung cancer risk: Pooled analysis in the International Lung Cancer Consortium. Int J Cancer. (2014)
  495. Tetrault JM1, et al. Effects of marijuana smoking on pulmonary function and respiratory complications: a systematic review. Arch Intern Med. (2007)
  496. Mehra R1, et al. The association between marijuana smoking and lung cancer: a systematic review. Arch Intern Med. (2006)
  497. De Petrocellis L1, et al. Non-THC cannabinoids inhibit prostate carcinoma growth in vitro and in vivo: pro-apoptotic effects and underlying mechanisms. Br J Pharmacol. (2013)
  498. Díaz-Laviada I. The endocannabinoid system in prostate cancer. Nat Rev Urol. (2011)
  499. Sarfaraz S1, et al. Cannabinoid receptor as a novel target for the treatment of prostate cancer. Cancer Res. (2005)
  500. Chung SC1, et al. A high cannabinoid CB(1) receptor immunoreactivity is associated with disease severity and outcome in prostate cancer. Eur J Cancer. (2009)
  501. Ramos JA1, Bianco FJ. The role of cannabinoids in prostate cancer: Basic science perspective and potential clinical applications. Indian J Urol. (2012)
  502. Lamb DJ1, Weigel NL, Marcelli M. Androgen receptors and their biology. Vitam Horm. (2001)
  503. Pacher P. Towards the use of non-psychoactive cannabinoids for prostate cancer. Br J Pharmacol. (2013)
  504. Bar-Sela G, et al. Is the clinical use of cannabis by oncology patients advisable. Curr Med Chem. (2014)
  505. Martín-Sánchez E1, et al. Systematic review and meta-analysis of cannabis treatment for chronic pain. Pain Med. (2009)
  506. Bao Y1, et al. Complementary and alternative medicine for cancer pain: an overview of systematic reviews. Evid Based Complement Alternat Med. (2014)
  507. Robson PJ. Therapeutic potential of cannabinoid medicines. Drug Test Anal. (2014)
  508. Di Marzo V, Matias I. Endocannabinoid control of food intake and energy balance. Nat Neurosci. (2005)
  509. Lucanic M, et al. N-acylethanolamine signalling mediates the effect of diet on lifespan in Caenorhabditis elegans. Nature. (2011)
  510. Bilsland LG, et al. Increasing cannabinoid levels by pharmacological and genetic manipulation delay disease progression in SOD1 mice. FASEB J. (2006)
  511. Bloom GS. Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol. (2014)
  512. Morales I1, et al. Neuroinflammation in the pathogenesis of Alzheimer's disease. A rational framework for the search of novel therapeutic approaches. Front Cell Neurosci. (2014)
  513. Streit WJ1, Mrak RE, Griffin WS. Microglia and neuroinflammation: a pathological perspective. J Neuroinflammation. (2004)
  514. Solito E1, Sastre M. Microglia function in Alzheimer's disease. Front Pharmacol. (2012)
  515. Koppel J1, et al. CB2 Receptor Deficiency Increases Amyloid Pathology and Alters Tau Processing in a Transgenic Mouse Model of Alzheimer's Disease. Mol Med. (2014)
  516. Wu J1, et al. Activation of the CB2 receptor system reverses amyloid-induced memory deficiency. Neurobiol Aging. (2013)
  517. Lunn CA1, Reich EP, Bober L. Targeting the CB2 receptor for immune modulation. Expert Opin Ther Targets. (2006)
  518. Walter L1, et al. Nonpsychotropic cannabinoid receptors regulate microglial cell migration. J Neurosci. (2003)
  519. Grünblatt E1, et al. Comparison analysis of gene expression patterns between sporadic Alzheimer's and Parkinson's disease. J Alzheimers Dis. (2007)
  520. Grünblatt E1, et al. Gene expression as peripheral biomarkers for sporadic Alzheimer's disease. J Alzheimers Dis. (2009)
  521. Solas M1, et al. CB2 receptor and amyloid pathology in frontal cortex of Alzheimer's disease patients. Neurobiol Aging. (2013)
  522. D'Addario C1, et al. Epigenetic regulation of fatty acid amide hydrolase in Alzheimer disease. PLoS One. (2012)
  523. Cameron B1, Landreth GE. Inflammation, microglia, and Alzheimer's disease. Neurobiol Dis. (2010)
  524. Colton C1, Wilcock DM. Assessing activation states in microglia. CNS Neurol Disord Drug Targets. (2010)
  525. Bamberger ME1, et al. A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation. J Neurosci. (2003)
  526. Reed-Geaghan EG1, et al. CD14 and toll-like receptors 2 and 4 are required for fibrillar A{beta}-stimulated microglial activation. J Neurosci. (2009)
  527. Ramírez BG1, et al. Prevention of Alzheimer's disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J Neurosci. (2005)
  528. Diaz P1, et al. 2,3-Dihydro-1-benzofuran derivatives as a series of potent selective cannabinoid receptor 2 agonists: design, synthesis, and binding mode prediction through ligand-steered modeling. ChemMedChem. (2009)
  529. Consroe P1, et al. The perceived effects of smoked cannabis on patients with multiple sclerosis. Eur Neurol. (1997)
  530. Brunt TM1, et al. Therapeutic satisfaction and subjective effects of different strains of pharmaceutical-grade cannabis. J Clin Psychopharmacol. (2014)
  531. Kozela E1, et al. Cannabinoids decrease the th17 inflammatory autoimmune phenotype. J Neuroimmune Pharmacol. (2013)
  532. Koppel BS1, et al. Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. (2014)
  533. Zajicek J1, et al. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet. (2003)
  534. Zajicek JP1, et al. Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up. J Neurol Neurosurg Psychiatry. (2005)
  535. Zajicek JP1, et al. Multiple sclerosis and extract of cannabis: results of the MUSEC trial. J Neurol Neurosurg Psychiatry. (2012)
  536. Ghaffar O1, Feinstein A. Multiple sclerosis and cannabis: a cognitive and psychiatric study. Neurology. (2008)
  537. Honarmand K1, et al. Effects of cannabis on cognitive function in patients with multiple sclerosis. Neurology. (2011)
  538. Aragona M1, et al. Psychopathological and cognitive effects of therapeutic cannabinoids in multiple sclerosis: a double-blind, placebo controlled, crossover study. Clin Neuropharmacol. (2009)
  539. Freeman RM1, et al. The effect of cannabis on urge incontinence in patients with multiple sclerosis: a multicentre, randomised placebo-controlled trial (CAMS-LUTS). Int Urogynecol J Pelvic Floor Dysfunct. (2006)
  540. Andersson KE. Current and future drugs for treatment of MS-associated bladder dysfunction. Ann Phys Rehabil Med. (2014)
  541. Yiangou Y1, et al. COX-2, CB2 and P2X7-immunoreactivities are increased in activated microglial cells/macrophages of multiple sclerosis and amyotrophic lateral sclerosis spinal cord. BMC Neurol. (2006)
  542. Raman C1, et al. Amyotrophic lateral sclerosis: delayed disease progression in mice by treatment with a cannabinoid. Amyotroph Lateral Scler Other Motor Neuron Disord. (2004)
  543. Carter GT1, Rosen BS. Marijuana in the management of amyotrophic lateral sclerosis. Am J Hosp Palliat Care. (2001)
  544. Amtmann D1, et al. Survey of cannabis use in patients with amyotrophic lateral sclerosis. Am J Hosp Palliat Care. (2004)
  545. Frankel JP, et al. Marijuana for parkinsonian tremor. J Neurol Neurosurg Psychiatry. (1990)
  546. Carroll CB1, et al. Cannabis for dyskinesia in Parkinson disease: a randomized double-blind crossover study. Neurology. (2004)
  547. Lotan I1, et al. Cannabis (medical marijuana) treatment for motor and non-motor symptoms of Parkinson disease: an open-label observational study. Clin Neuropharmacol. (2014)
  548. Venderová K1, et al. Survey on cannabis use in Parkinson's disease: subjective improvement of motor symptoms. Mov Disord. (2004)
  549. Moore TH1, et al. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet. (2007)
  550. Hall W1, Degenhardt L. Cannabis use and psychosis: a review of clinical and epidemiological evidence. Aust N Z J Psychiatry. (2000)
  551. Arseneault L1, et al. Causal association between cannabis and psychosis: examination of the evidence. Br J Psychiatry. (2004)
  552. Degenhardt L1, Hall W. Is cannabis use a contributory cause of psychosis. Can J Psychiatry. (2006)
  553. Smit F1, Bolier L, Cuijpers P. Cannabis use and the risk of later schizophrenia: a review. Addiction. (2004)
  554. Power RA1, et al. Genetic predisposition to schizophrenia associated with increased use of cannabis. Mol Psychiatry. (2014)
  555. Metcalfe C1, et al. The scope for biased recall of risk-factor exposure in case-control studies: evidence from a cohort study of Scottish men. Scand J Public Health. (2008)
  556. Zammit S1, et al. Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: historical cohort study. BMJ. (2002)
  557. van Os J1, et al. Cannabis use and psychosis: a longitudinal population-based study. Am J Epidemiol. (2002)
  558. Fergusson DM1, Horwood LJ, Ridder EM. Tests of causal linkages between cannabis use and psychotic symptoms. Addiction. (2005)
  559. Arseneault L1, et al. Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study. BMJ. (2002)
  560. Kuepper R1, et al. Continued cannabis use and risk of incidence and persistence of psychotic symptoms: 10 year follow-up cohort study. BMJ. (2011)
  561. D'Souza DC1, et al. Effects of haloperidol on the behavioral, subjective, cognitive, motor, and neuroendocrine effects of Delta-9-tetrahydrocannabinol in humans. Psychopharmacology (Berl). (2008)
  562. D'Souza DC1, et al. Delta-9-tetrahydrocannabinol effects in schizophrenia: implications for cognition, psychosis, and addiction. Biol Psychiatry. (2005)
  563. Freeman D1, et al. How Cannabis Causes Paranoia: Using the Intravenous Administration of ∆9-Tetrahydrocannabinol (THC) to Identify Key Cognitive Mechanisms Leading to Paranoia. Schizophr Bull. (2014)
  564. Radhakrishnan R1, Wilkinson ST1, D'Souza DC2. Gone to Pot - A Review of the Association between Cannabis and Psychosis. Front Psychiatry. (2014)
  565. Shrivastava A1, et al. Cannabis and psychosis: Neurobiology. Indian J Psychiatry. (2014)
  566. The Emerging Role of Glutamate in the Pathophysiology and Treatment of Schizophrenia
  567. NMDA Receptor and Schizophrenia: A Brief History
  568. Storr M1, et al. Cannabis use provides symptom relief in patients with inflammatory bowel disease but is associated with worse disease prognosis in patients with Crohn's disease. Inflamm Bowel Dis. (2014)
  569. Naftali T1, et al. Treatment of Crohn's disease with cannabis: an observational study. Isr Med Assoc J. (2011)
  570. Lahat A1, Lang A, Ben-Horin S. Impact of cannabis treatment on the quality of life, weight and clinical disease activity in inflammatory bowel disease patients: a pilot prospective study. Digestion. (2012)
  571. Naftali T1, et al. Cannabis induces a clinical response in patients with Crohn's disease: a prospective placebo-controlled study. Clin Gastroenterol Hepatol. (2013)
  572. Cohen C1, et al. SR141716, a central cannabinoid (CB(1)) receptor antagonist, blocks the motivational and dopamine-releasing effects of nicotine in rats. Behav Pharmacol. (2002)
  573. Rodríguez de Fonseca F1, et al. Cannabinoid receptor antagonist SR141716A decreases operant ethanol self administration in rats exposed to ethanol-vapor chambers. Zhongguo Yao Li Xue Bao. (1999)
  574. Freedland CS1, et al. Effects of SR141716A on ethanol and sucrose self-administration. Alcohol Clin Exp Res. (2001)
  575. Colombo G1, et al. Reduction of voluntary ethanol intake in ethanol-preferring sP rats by the cannabinoid antagonist SR-141716. Alcohol Alcohol. (1998)
  576. Arnone M1, et al. Selective inhibition of sucrose and ethanol intake by SR 141716, an antagonist of central cannabinoid (CB1) receptors. Psychopharmacology (Berl). (1997)
  577. Gonzales RA1, Job MO, Doyon WM. The role of mesolimbic dopamine in the development and maintenance of ethanol reinforcement. Pharmacol Ther. (2004)
  578. Straiker AJ1, Borden CR, Sullivan JM. G-protein alpha subunit isoforms couple differentially to receptors that mediate presynaptic inhibition at rat hippocampal synapses. J Neurosci. (2002)
  579. Navarrete M1, Araque A. Endocannabinoids potentiate synaptic transmission through stimulation of astrocytes. Neuron. (2010)
  580. Perez-Reyes M1, et al. Antagonism of marihuana effects by indomethacin in humans. Life Sci. (1991)
  581. Păunescu H, et al. Cannabinoid system and cyclooxygenases inhibitors. J Med Life. (2011)
  582. Gamaleddin I1, et al. Cannabinoid receptor stimulation increases motivation for nicotine and nicotine seeking. Addict Biol. (2012)
  583. Cohen C1, et al. Nicotine-associated cues maintain nicotine-seeking behavior in rats several weeks after nicotine withdrawal: reversal by the cannabinoid (CB1) receptor antagonist, rimonabant (SR141716). Neuropsychopharmacology. (2005)
  584. Forget B1, Hamon M, Thiébot MH. Cannabinoid CB1 receptors are involved in motivational effects of nicotine in rats. Psychopharmacology (Berl). (2005)
  585. Valjent E1, et al. Behavioural and biochemical evidence for interactions between Delta 9-tetrahydrocannabinol and nicotine. Br J Pharmacol. (2002)
  586. Wiley JL, Jones AR, Wright MJ Jr. Exposure to a high-fat diet decreases sensitivity to Δ9-tetrahydrocannabinol-induced motor effects in female rats. Neuropharmacology. (2011)
  587. Carlini EA. Tolerance to chronic administration of Cannabis sativa (marihuana) in rats. Pharmacology. (1968)
  589. Sim-Selley LJ1, Martin BR. Effect of chronic administration of R-(+)-{2,3-Dihydro-5-methyl-3-{(morpholinyl)methyl}pyrrolo{1,2,3-de}-1,4-benzoxazinyl}-(1-naphthalenyl)methanone mesylate (WIN55,212-2) or delta(9)-tetrahydrocannabinol on cannabinoid receptor adaptation in mice. J Pharmacol Exp Ther. (2002)
  590. Jin W1, et al. Distinct domains of the CB1 cannabinoid receptor mediate desensitization and internalization. J Neurosci. (1999)
  591. Hirvonen J1, et al. Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers. Mol Psychiatry. (2012)
  592. Sim-Selley LJ. Regulation of cannabinoid CB1 receptors in the central nervous system by chronic cannabinoids. Crit Rev Neurobiol. (2003)
  593. Sim-Selley LJ1, et al. Prolonged recovery rate of CB1 receptor adaptation after cessation of long-term cannabinoid administration. Mol Pharmacol. (2006)
  594. Budney AJ1, Hughes JR. The cannabis withdrawal syndrome. Curr Opin Psychiatry. (2006)
  595. Vandrey RG1, et al. A within-subject comparison of withdrawal symptoms during abstinence from cannabis, tobacco, and both substances. Drug Alcohol Depend. (2008)
  596. Budney AJ1, et al. Comparison of cannabis and tobacco withdrawal: severity and contribution to relapse. J Subst Abuse Treat. (2008)
  597. Budney AJ1, et al. The time course and significance of cannabis withdrawal. J Abnorm Psychol. (2003)
  598. Allsop DJ1, et al. The Cannabis Withdrawal Scale development: patterns and predictors of cannabis withdrawal and distress. Drug Alcohol Depend. (2011)
  599. Levin FR1, et al. Dronabinol for the treatment of cannabis dependence: a randomized, double-blind, placebo-controlled trial. Drug Alcohol Depend. (2011)
  600. Budney AJ1, et al. Oral delta-9-tetrahydrocannabinol suppresses cannabis withdrawal symptoms. Drug Alcohol Depend. (2007)
  601. Vandrey R1, et al. The dose effects of short-term dronabinol (oral THC) maintenance in daily cannabis users. Drug Alcohol Depend. (2013)
  602. Gorelick DA1, et al. Diagnostic criteria for cannabis withdrawal syndrome. Drug Alcohol Depend. (2012)
  603. Levin KH1, et al. Cannabis withdrawal symptoms in non-treatment-seeking adult cannabis smokers. Drug Alcohol Depend. (2010)
  604. Budney AJ1, et al. Marijuana abstinence effects in marijuana smokers maintained in their home environment. Arch Gen Psychiatry. (2001)
  605. Hesse M1, Thylstrup B. Time-course of the DSM-5 cannabis withdrawal symptoms in poly-substance abusers. BMC Psychiatry. (2013)
  606. Cornelius JR1, et al. Cannabis withdrawal is common among treatment-seeking adolescents with cannabis dependence and major depression, and is associated with rapid relapse to dependence. Addict Behav. (2008)
  607. Chung T1, et al. Cannabis withdrawal predicts severity of cannabis involvement at 1-year follow-up among treated adolescents. Addiction. (2008)
  608. Arendt M1, et al. Withdrawal symptoms do not predict relapse among subjects treated for cannabis dependence. Am J Addict. (2007)
  609. Mennes CE1, Ben Abdallah A, Cottler LB. The reliability of self-reported cannabis abuse, dependence and withdrawal symptoms: multisite study of differences between general population and treatment groups. Addict Behav. (2009)
  610. Milin R1, et al. Prospective assessment of cannabis withdrawal in adolescents with cannabis dependence: a pilot study. J Am Acad Child Adolesc Psychiatry. (2008)
  611. Bolla KI1, et al. Polysomnogram changes in marijuana users who report sleep disturbances during prior abstinence. Sleep Med. (2010)
  612. Kouri EM1, Pope HG Jr. Abstinence symptoms during withdrawal from chronic marijuana use. Exp Clin Psychopharmacol. (2000)
  613. Andoh T1, et al. Protective effect of IL-18 on kainate- and IL-1 beta-induced cerebellar ataxia in mice. J Immunol. (2008)
  614. Motoki K1, et al. The direct excitatory effect of IL-1beta on cerebellar Purkinje cell. Biochem Biophys Res Commun. (2009)
  615. Stella N. Chronic THC intake modifies fundamental cerebellar functions. J Clin Invest. (2013)
  616. Compton WM1, et al. Crosswalk between DSM-IV dependence and DSM-5 substance use disorders for opioids, cannabis, cocaine and alcohol. Drug Alcohol Depend. (2013)
  617. Budney AJ1, et al. Marijuana dependence and its treatment. Addict Sci Clin Pract. (2007)
  618. Richter KP1, Levy S. Big Marijuana - Lessons from Big Tobacco. N Engl J Med. (2014)
  619. Martinez D1, et al. Deficits in dopamine D(2) receptors and presynaptic dopamine in heroin dependence: commonalities and differences with other types of addiction. Biol Psychiatry. (2012)
  620. Wang GJ1, et al. Dopamine D2 receptor availability in opiate-dependent subjects before and after naloxone-precipitated withdrawal. Neuropsychopharmacology. (1997)
  621. Fatma H1, et al. Cannabis: a rare cause of acute pancreatitis. Clin Res Hepatol Gastroenterol. (2013)
  622. Grant P1, Gandhi P. A case of cannabis-induced pancreatitis. JOP. (2004)
  623. Rawal SY1, Tatakis DN, Tipton DA. Periodontal and oral manifestations of marijuana use. J Tenn Dent Assoc. (2012)
  624. Price SL1, et al. Cannabinoid hyperemesis syndrome as the underlying cause of intractable nausea and vomiting. J Am Osteopath Assoc. (2011)
  625. Haubrich C, et al. Recurrent transient ischemic attacks in a cannabis smoker. J Neurol. (2005)
  626. Mouzak A1, et al. Transient ischemic attack in heavy cannabis smokers--how 'safe' is it. Eur Neurol. (2000)
  627. Kosior DA, et al. Paroxysmal atrial fibrillation following marijuana intoxication: a two-case report of possible association. Int J Cardiol. (2001)
  628. Tatli E, et al. Cannabis-induced coronary artery thrombosis and acute anterior myocardial infarction in a young man. Int J Cardiol. (2007)
  629. Hartung B1, et al. Sudden unexpected death under acute influence of cannabis. Forensic Sci Int. (2014)
  630. Dahdouh Z, et al. Cannabis and coronary thrombosis: What is the role of platelets. Platelets. (2012)
  631. Dwivedi S, Kumar V, Aggarwal A. Cannabis smoking and acute coronary syndrome: two illustrative cases. Int J Cardiol. (2008)
  632. Bailly C, et al. Cannabis induced acute coronary syndrome in a young female. Int J Cardiol. (2010)
  633. Duchene C1, et al. Cannabis-induced cerebral and myocardial infarction in a young woman. Rev Neurol (Paris). (2010)
  634. Cappelli F1, et al. Cannabis: a trigger for acute myocardial infarction? A case report. J Cardiovasc Med (Hagerstown). (2008)
  635. Lindsay AC, et al. Cannabis as a precipitant of cardiovascular emergencies. Int J Cardiol. (2005)
  636. Casier I, et al. Is recent cannabis use associated with acute coronary syndromes? An illustrative case series. Acta Cardiol. (2014)

(Common misspellings for Marijuana include mariwana, mariwhana, mariwanna, mariwhanna, canabis, cannibis, canibis)

(Common phrases used by users for this page include reverse marijuana effects with supplements, marijuana obesonogen, lipids in cannabis, hydro marijuana supplements harmful, cannbis effect on the fat cells, 129591)

(Users who contributed to this page include ttarrier, , jaxgaret, , alexh934, GregoryLopez, , BillWillis)