Marijuana

Summary (The Good, The Bad, and all other Essential Benefits/Effects/Facts Information)

Cannabis is a herb with a wide range of uses, but is most notably known currently for its use as a recreational drug (for which it is commonly referred to as marijuana or weed). It is typically smoked, but can also be cooked into foods or inhaled through a vaporiser.

It works on a unique set of receptors known as the 'endocannabinoid' (internal cannabinoid) system, named after the plant name (Cannabis). It is the only known plant that can activate these receptors, although our bodies do regulate them without the plant through dietary fats.

It can benefit health in a myriad of ways through the endocannabinoid system. It does seem to suppress acute changes in the body - and could be potentially be an ultimate long term regulator of many body systems, as it can prevent a fair bit of changes that would result in metabolic abnormalities.

In general, Cannabis stays in the body for a long time after initial ingestion as excretion rates are slow

It is currently illegal to buy on its own in many countries and regions, and can usually be acquired only with a prescription in these areas for medical purposes.

Also Known As

Cannabis Sativa, Weed, Medical Marijuana, Hemp, Marihuana, dope, ganja

Is a Form of

• Health Support
• Nootropic
• Herbal supplement

How to Take (recommended dosage, active amounts, other details)

Any dose which provides a neurological sensation is enough to saturate the body for a prolonged time, an 'ideal' dose has not been established.

Frequent toking is not required due to the ability of the cannabinoids to saturate the body for 1-2 weeks, or possibly more, depending on dose.

Things to Note

Marijuana is highly neuroactive, but is generally classified as an anxiolytic.

Caution Notice (just some FYI - if needed)

Marijuana, without a prescription, is illegal in various countries. Consult your region's legal statutes before attempting to smoke up.

It does seem to suppress acute changes in the body, so during any intense fat loss or muscle building phases it should be avoided for the most part. Over the long-term (of which health is ultimate, rather than ego) then it seems that it can prevent a fair bit of changes that would result in metabolic abnormalities, although it may be classified as a pro-obesogen via its suppression of fat lipolysis and habit of giving some people the munchies.

Detailed Summary

1. History and Usage
2. Marijuana Constituents
3. Pharmacokinetics/Pharmacodynamics of Marijuana from ingestion to assimilation
4. Pharmacokinetics/Pharmacodynamics of Marijuana tissue distribution
5. Metabolism of Cannabinoids
6. Endocannabinoid System - Cannabinoids as Agonists
7. Cannabinoids as modulators
8. Cannabinoids and the Immune System
9. Marijuana and Neurology
10. Other metabolic (health) effects of Marijuana
11. Effects of Marijuana on Exercise and Body Composition
12. Diet Interactions
13. Drug-Drug Interactions

Edit1. History and Usage

The plant Cannabis Sativa or Cannabis Indica (otherwise known as Hemp) is a plant used traditionally for various non-nutritional uses, such as fibers and textile manufacturing. Preparations of any Cannabis_ plant used for pharmacological reasons (smoking, vaporizing, or otherwise ingestion) is typically referred to as Marijuana.

Marijuana is, at the moment, the most widely used illicit substance in the world, according to the UN.^[1] It can legally be given as a medical treatment for various forms of cancer, AIDS/HIV, and neurological impairments.^[2][3]

Edit2. Marijuana Constituents

As a plant, marijuana (or the family of cannabis plants) contains various phytochemicals. The primary active ingredient is seen as Delta-9-TetraHydroCannabinol (THC), others including cannabidiol (CBD) and cannabigerol (CBG).^[4] These phytochemicals are collectively known as 'phytocannabinoids' and act on the endocannabinoid system in the body.^[5][6] They are the only known naturally produced cannabinoids that can be ingested, and the typical agonists for these ubiquitous receptors in the human body are anandamide and 2-arachidonoyl glycerol, both derivatives of the omega-6 fatty acid 'Arachidonic Acid'.^[5]

Edit3. Pharmacokinetics/Pharmacodynamics of Marijuana from ingestion to assimilation

When ingested in a gaseous state (toking) pulmonary (lung) assimilation causes a maximum plasma value and the onset of psychotropic effects in a few minutes, a maximum of said psychotropic effects is noted 15-30 minutes after initial ingestion to taper off 2-3 hours after exposure.^[7] Systemic bioavailability ranges from 10+/-7%^[8] to 27+/-10%^[9], with habitual users absorbing more of the active THC. The reason for the low bioavailability is due to a hypothesized (up to) 30% loss from pyrolysis, poor lung absorption, and losses to sidestream smoke not being ingested.^[7] Toking in the form of a pipe seems to eliminate sidestream losses, and absorption rates of up to 45% have been recorded.^[10]

After oral ingestion (brownies) peak serum levels are achieved at a variable 60-120 minutes after ingestion, due to varying digestive potencies inter-person.^[7][11] Some studies have noted delays of peak values up to 4-6 hours post ingestion^[12] and some showing multiple plasma peaks.^[13] 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^[14]) exceeds 90% in most cases^[11], although after extensive hepatic first-pass metabolism the amount available to systemic circulation varies from 2-14%, with high interindividual differences.^[15][7]

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.^[16]

Edit4. Pharmacokinetics/Pharmacodynamics of Marijuana tissue 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.^[17][7] Approximately 10% of assimilated THC is bound to red blood cells^[18] while the otehr 90% floats freely in the blood. Of this 90%, 95-99% are bound to plasma proteins such as lipoproteins and, to a lesser extent, albumin.^[19][20] 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.^[21] Due to its lipophilicity, it eventually almost exclusively settles into adipose tissue (body fat) and can be stored in the long-term.^[22][23]

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.^[24][25][26] 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.^[27]

Edit5. Metabolism of Cannabinoids

Although metabolism exists in the lungs and heart tissue, Tetrahydrocannabinoids are metabolized primarily in the liver through the P450 enzyme system, via hydroxylation and oxidation reactions.^[28][29] A member of the CYP2C subfamily seems to be the most active in humans.^[30]

Although over 100 separate metabolites of THC have been identified^[31], 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.^[32] All mediated by liver P450 enzymes, the rate limiting step of which seems to be hepatic blood flow.^[7][33]

THC metabolites are commonly excreted in the urine through the acid metabolite 11-nor-9-carboxy-THC glucuronide, a glucuronidated form of THC-COOH.^[34] A proposed mechanism of long-term storage is when 11-OH-THC conjugates with fatty acids in the adipocyte.^[35]

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.^[36] The carboxylated metabolite (THC-COOH) can be detected in the plasma for up to 7 days after both dosages.^[36] This long duration metabolism is partially explained by the slow release of THC conjugates from adipose and other body tissue into the bloodstream^[17] 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.^[37][9] 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.^[11][33] 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)^[11][38] Roughly 65% of THC and THC metabolites are excreted after 72 hours from both routes.^[7][11] Full elimination of THC from the body may take up to two weeks to occur.^[12] 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^[39] although averages were 12.9 days for light users and 31.5 days for chronic users.

Edit6. Endocannabinoid System - Cannabinoids as Agonists

The endocannabinoid system is a regulatory system in the body which comprises of Cannabinoid 1 (CB1) and Cannabinoid 2 (CB2) receptors, of which THC and endocannabinoids (such as anandamide) act as agonists.^[40][41][42] CB1 receptors are prominent in neural tissue but are also found in the pituitary and peripheral tissue such as the thyroid, adrenals, gastrointestinal tract, and reproductive organs.^[43] CB2 receptors are found almost exclusively in immune cells^[44], although some are found in keratinocytes as well.^[45] There is suspected to be a third (or more) class(es) of cannabinoid receptors beyond CB1 and CB2; although they have yet to be identified officially^[46] the receptor GPR55 looks to be a promising addition.^[47]

The endocannabinoid system is a system regulating homeostasis in the body^[43], and has implications in nocioreception^[48], regulation of motor activity^[49], neuroprotection against inflammation^[50] injury^[51] and excitotoxicity^[52], certain phases of memory encoding^[53][54] and general neurohomeostatic mechanisms related to stress prevention.^[55] It can also modulate immune and inflammation responses^[56] and parameters of cardiac health.^[57] Cannabinoid agonists also have benefit in tumor anti-proliferation^[58] as well as alleviating chemotherapy induced nausea.^[59]

Beyond the endocannabinoid system and the cannabinoid receptors, marijuana has been noted to act on Vallinoid Receptor 1 (VR1) as an agonist,^[60] 5-HT type 3 receptors,^[61] and alpha7-nicotinic acetylcholine receptors.^[62]

Edit7. Cannabinoids as modulators

Cannabinoids are known as modulators, or of having the ability to suppress and induce effects that are counter to each other, of which significant is titrated towards homeostasis (ie. will induce effects in those deficient in the effects, will inhibit those with a surplus of the effects).

This is shown through cannabinoid agonism possessing the ability to both inhibit^[63] and induce Adenyl Cyclate (AC) activity,^[64] possessing the ability to promote cellular survival^[65] via Akt/PI3K phosphorylation and also induce cell apoptosis (death) via ceramide synthesis,^[66] and also mediate a balance between neurogenesis and neurodegeneration.^[67][68] Marijuana (as a whole plant) has also been involved in both pro-estrogenic reactions^[69] and anti-estrogenic reactions.^[70]

The agonistic effects of Delta-9-Tetrahydrocannabinoid can also be mediated by the antagonistic effects of another component of marijuana, Delta8 & 9-tetrahydrocannabivarin^[71] and the inverse-agonistic properties of cannabidiol.^[72]

Edit8. Cannabinoids and the Immune System

Cannabinoids can be seen and modulators of the immune system, with both influencing and inhibiting effects on various forms of inflammation via CB2 receptor agonism/antagonism, as well as other mechanisms of action.^[73] This receptor seems to be heavily involved in neuroinflammation, or more specifically immune function mediated by the CNS.^[74]

Edit9. Marijuana and Neurology

The CB1 receptor was initially known as the 'brain-active' receptor as it was initially isolated only in neural tissue, but has since been found systemically as well.^[75]

It is highly expressed on the basal ganglia and the hippocampus in the brain.^[75] In the forebrain, CB1 expression by axons of GABAergic interneurones with cholecystokinin basket cells is dominant.^[76]

Edit10. Other metabolic (health) effects of Marijuana

Marijuana is seen as a treatment for glaucoma via acting on retinal cannabinoid (CB1) receptors, which induced numerous effects in the retina. Of most clinical importance is a reduction in Intra-Ocular pressure (IOP), but also noted are anti-oxidant and anti-inflammatory effects as well as suppression of apoptosis and NMDA-mediated hyperexcitability.^[77][78] There appears to be a nonresponse rate for marijuana usage, indicated that it is not a reliable treatment for all.^[79]

Marijuana may help artherosclerosis and artery plaque formation via CB2 agonism.^[80] Anandamide inhibits inflammatory gene expression while THC can inhibit artherosclerotic plaque formation by inhibiting macrophage recruitment, both of which negatively influence monocyte adhesion.^[81]

Marijuana can also be seen as anti-diabetic by preserving islet integrity (synthesizers of insulin) by downregulating inflammatory signals^[82], and is a diabetic treatment for alleviating nerve pains.^[83]

It can aid gut/intestinal disorders by direct suppression of proinflammatory mediators, inhibition of intestinal motility and diarrhoea, and attenuation of visceral sensitivity.^[73][84]

Opposite of the beneficial effects of Marijuana listed above, marijuana seems to be a contributing factor to the development of non-alcoholic fatty liver disease.^[85] The pro-steatogenic actions of marijuana seem to be via agonism of hepatic CB1 receptors^[86] and perhaps CB2 receptors if non-alcoholic fatty liver disease is present.^[87] Via pro-obesogenic transcription factors such as SREBP-1c, an increase in hepatic de novo fatty acid synthesis also occurs.^[86] These effects are almost exclusively mediated through the CB1 receptor.^[88]

Edit11. Effects of Marijuana on Exercise and Body Composition

A marijuana phytocannabinoid known as 'Cannabigerol' has the properties of being an Alpha-2 Adrenergic agonist (the opposite action of Yohimbine) and thus may preserve fat mass.^[89] Activation of hepatic CB1 receptors can also induce cellular changes which can be seen as 'pro-obesogenic' such as expression of the gene SREBP-1c which mediates downstream fat synthesis, such as the enzyme fatty acid synthase^[86][90]

The enzyme CarnitinePalmitoyltransferase 1_ (COMT1), the rate limiting enzyme of fatty acid Beta-oxidation, is suppressed under the influence of marijuana in the liver^[85] yet seems to be elevated in some brain cells, which results in neuronal ketogenesis.^[91] Adipose (body fat) cells seem to mimic the liver cell's pro-obesogenic actions more than the neurons actions.^[92]

Edit12. Diet Interactions

Those exposed to a high fat diet may be less sensitive to the effects of Delta-9-THC.^[93] Possibly through diet-induced desensitization of the cannabinoid receptors via the fatty acid metabolites of anandamide and 2-arachidonoylglycerol (in vivo agonists).

Edit13. Drug-Drug Interactions

Theoretically, there could be interactions with drugs that are metabolized extensively by the CYP1A2 enzyme that primarily metabolizes marijuana. Interactions could also occur with protein carries as Delta-9-THC and other cannabinoids strongly bind to proteins.^[7][38]

Cessation of marijuana during treatment with anti-psychotics has been shown to increase levels of anti-psychotic medication in the blood due to cessation of induction of the CYP1A2 enzyme which degrades both (ie. its activity was induced during marijuana presence, and was not as active in degrading the medications clozapine, olanzapine without the extra induction)^[94][95]

Marijuana usage can also increase the effects of sedatives such as alcohol or benzodiazepines^[96][97] and can synergistically work with muscle relaxants, bronchodilators, and anti-glaucoma medication.^[98] It can also work with the anti-epileptic effects of benzodiazepines.^[99]flunitrazepam binding and analgesic activity of synthetic cannabimimetics]

NSAIDS such as indomethacin or acetylsalicyclic acid (aspirin) can inhibit some aspects of marijuana such as the perceived 'high' and tachycardia, as some effects of THC are mediated through prostaglandins (of which NSAIDS inhibit synthesis of).^[100][101]

Scientific Support & Reference Citations

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Last Updated: Mar 24, 2012 13:24:37