CBD

What is CBD?

CBD (cannabidiol) is the second most abundant cannabinoid in cannabis, after THC (tetrahydrocannabinol).^[5] Isolated CBD is typically used medicinally, not recreationally, with the four most commonly targeted conditions being pain, anxiety, depression, and sleep disorders.^[6]

Is CBD legal?

Let's just say ... it's complicated. CBD products that are derived from hemp, with a low-to-zero percentage of THC (below 0.3%), are currently in a legal gray area in the US.

A quick bit of history: The Farm Act was passed in December of 2018, and it legalized hemp (the source of CBD).^[7] CBD advocates rejoiced – CBD supplements were already commonplace in 2018, but now in 2019 they're pretty much everwhere. Some estimates suggest up to 7% of adults have used CBD, and there were up to $2 billion in sales in 2018 (projected to rise dramatically in the next couple years).

In December of 2018 though, the FDA stated that CBD cannot be marketed as a supplement without FDA approval, but in April of 2019, the FDA was taking public comments to formulate a revised position.^[8] Currently, non-pharmaceutical CBD is technically only legal under very specific conditions, such as when the source hemp was produced in a manner consistent with the Farm Bill, and by a licensed grower. Complicating matters further: the DEA and individual states can have different legal perspectives on CBD. Clarification on CBD legality should come within the first half of 2019.

As far as 100% unquestionably legal CBD goes, the liquid CBD medication Epidiolex was recently FDA-approved in 2018. Note that it's not the first cannabis extract drug. Nabiximols (brand name Sativex) is a cannabis extract spray with a nearly 1:1 ratio of THC:CBD, and it was approved as a drug in the UK in 2010 (but has not been approved in the US). Due to the THC content, it has a different side effect profile than Epidiolex, such as dizziness and disorientation.^[9] However, due to the THC, it may have benefits for a wider variety of conditions than CBD alone (due to the "entourage effect"), such as for spasticity from multiple sclerosis.^[10]

What are CBD's potential benefits?

The main studied benefit to CBD is on two rare forms of epilepsy (Lennox-Gastaut and Dravet syndrome),^[11] but potential benefits stretch from common maladies (anxiety,^[12] chronic pain^[13]) to reduction in inflammation^[14], even to potential benefits for cancer.^[15] Human randomized trials are quite scarce, though.

Before protesting, "Hey, why doesn't your Scientific Research section cover XYZ mouse study showing CBD benefits?", take note that mice are not human. In fact, the same exact dose of CBD in a mouse versus a human will be more bioavailable in the mouse, leading to larger effects.^[16] That's besides the bevy of other reasons that animal studies often don't translate to humans, such as different metabolic pathways in animals, lab conditions differing from free-living human conditions, etc.^[17] 

Is CBD dangerous?

In small amounts, probably not for most people. In large amounts over time ... well, read on to get a gist of the risks.

The most notable (acute) drawbacks of cannabis consumption don't apply to isolated CBD: a possible mind-altered state involving one or more of impaired memory, altered judgment, and impaired coordination.^[18] Side effects of CBD are typically relatively minor, including fatigue, decreased appetite, and diarrhea.^[19]

Yet CBD is not without potential detriment. The long-term use of isolated CBD isn't well researched in humans, so potential harms may be possible. For example, CBD and cannabis in general has been touted as a potential cancer treatment,^[20] yet certain cancer types could theoretically worsen from CBD-induced receptor activation (in this study, colon cancer).^[21] CBD studies are typically very short term, and side effects are captured as part of studies exploring potential benefits. It would take months- or years-long studies to assess long-term risk of chronic ingestion on specific body systems.

Despite this, CBD appears to be much safer than many other treatments aimed at chronic pain and anxiety, as well as drugs used for recreational use. In fact, the World Health Organization concluded in a review: "to date, there is no evidence of recreational use of CBD or any public health-related problems associated with the use of pure CBD".^[22]

How exactly does CBD work?

The myriad ways in which it works are not fully understood, but do not appear to center on the CB1 and CB2 receptors that THC acts on. Those receptors are part of the relatively newly-discovered endocannabinoid system, first described in 1992,^[23] and increasingly found to be important to human health and well-being through maintaining homeostasis (balance) in various aspects of physiology.^{[24][25][26][27]} CBD actually opposes the action of THC at the CB1 receptor (and certain other receptors as well), which can help counter THC's (potential) worsening of cognition, memory, psychosis, and other effects.^[28][29] Most notably, you won't get "high" (at least in the conventional sense of the word) from CBD, due to its differential impact on CB1 compared to THC.^[30]

Anywho, back to CBD's main effects. It appears to impact a variety of other receptors in the body, including an important receptor involved in pain and stress response, called TRPV1.^[31][32][33] Other receptors that CBD impacts include GPR55, 5HTI-alpha, and adenosine A2A, which variously can help with inflammation, pain, anxiety, and even potentially cancer.^{[34][35][36][37]} 

There's a big catch though! CBD often seems to work better with THC (basically, in the typically consumed or inhaled form of medical cannabis, rather than as isolated CBD). This is often referred to as the "entourage effect" – that a single ingredient might, maybe do a little something, but you need the whole crew of compounds in the plant to have full efficacy.^[38] The problem here is that the whole crew can make you high, which is not typically desired in continuously-taken medications, and may even increase the risk of psychosis with longer term use.^[39]

CBD dosage recommendations? That opens up a huge can of worms.

CBD products, save for the pharmaceutical Epidiolex, are not regulated. So batches often vary in potency.^[1] Not only that, but some products have pretty much only CBD in them, and others have various other cannabinoids (you'll see "whole plant extract" and "single compound extracts" on shelves). Yet others have more than the allowed percentage of THC included.^[2] High-fat and high-calorie meals lead to much higher CBD concentrations,^[3] which adds another wrinkle.

Oh, and yet another wrinkle: CBD is vastly understudied at the moment, so different doses are rarely compared against each other and against a placebo. Long-term safety is essentially unstudied, and even several month long trials are rare.^[4]

So as far as recommendations go ... we're not giving any at the moment (we shall assess more evidence, and think it through in our typical thorough fashion), but always talk to your doctor before taking CBD, and start with as low of a dose as you can. Study dosages vary widely by clinical indication, from less than 5 mg/d to well over 100 mg/d. To repeat: talk to your doctor!

The Human Effect Matrix looks at human studies (it excludes animal and in vitro studies) to tell you what effects cbd has on your body, and how strong these effects are.

Grade	Level of Evidence [show legend]
	Robust research conducted with repeated double-blind clinical trials
	Multiple studies where at least two are double-blind and placebo controlled
	Single double-blind study or multiple cohort studies
	Uncontrolled or observational studies only

Level of Evidence ? The amount of high quality evidence. The more evidence, the more we can trust the results.	Outcome	Magnitude of effect ? The direction and size of the supplement's impact on each outcome. Some supplements can have an increasing effect, others have a decreasing effect, and others have no effect.	Consistency of research results ? Scientific research does not always agree. HIGH or VERY HIGH means that most of the scientific research agrees.	Notes
	Seizure Frequency	Strong	Very High See all 3 studies	These studies only looked at disorders with severe epilepsy, including Dravet and Lennox-Gastaut Syndromes, and Tuberous sclerosis complex (TSC).
	Anxiety	Notable	Very High See all 5 studies	No long term anxiety trials exist, and very few types of anxiety have been researched thus far.
	Pain	Minor	Very High See all 3 studies	Studies are very preliminary, with only one being randomized, and all being small with short treatment durations.
	Symptoms of Schizophrenia	Minor	Moderate See 2 studies	These trials don't look at impact on development of schizophrenia, but of symptom reduction in those with schizophrenia.
	Symptoms of Ulcerative Colitis	Minor	- See study	Remission rates, however, were not impacted at all.
	Symptoms of Crohn's Disease	-	- See study	Used a relatively low dose of 10 mg, twice a day.

• ERD Mini: The Arthritis Foundation’s recommendations concerning CBD for arthritis

Click here to subscribe to Examine.com Research Digest to stay on top of the latest research.