Research analysis lead by Kamal Patel
Last Updated: Apr 21, 2019
Why is CBD such a big deal? Two reasons. First, isolated CBD won’t get you “high”, unlike THC (the other main cannabinoid in cannabis). Second, isolated CBD has shown a ton of promise in animal research (anxiety, pain, inflammation, cancer, etc). Unfortunately, there are relatively few human trials as of 2019. And unregulated CBD often contains way lower or higher doses than the label states, sometimes even containing unlisted THC. Things are heating up though: in 2018, the FDA approved the first CBD pharmaceutical – Epidiolex, for two rare types of epilepsy. Stay tuned to this page, as nearly 190 trials are ongoing!
Our evidence-based analysis on CBD features 119 unique references to scientific papers.
Summary of CBD
Primary Information, Benefits, Effects and Important Facts
What is CBD?
CBD (cannabidiol) is the second most abundant cannabinoid in cannabis, after THC (Delta-9 Tetrahydrocannabinol). Isolated CBD is typically used medicinally, not recreationally, with the four most commonly targeted conditions being pain, anxiety, depression and sleep disorders.
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 history: The Farm Act was passed in December of 2018 and it legalized hemp (the source of CBD). CBD advocates rejoiced – CBD supplements were already commonplace in 2018, but now in 2019 they’re pretty much everywhere. 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. 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. 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.
What are CBD’s potential benefits?
The main studied benefit to CBD is on two rare forms of epilepsy (Lennox-Gastaut and Dravet syndrome), but potential benefits stretch from common maladies (anxiety, chronic pain) to reduction in inflammation, even to potential benefits for cancer.
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 bio-available in the mouse, leading to larger effects. 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.
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. Side effects of CBD are typically relatively minor, including fatigue, decreased appetite and diarrhea.
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, yet certain cancer types could theoretically worsen from CBD-induced receptor activation (in this study, colon cancer). 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”.
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, and increasingly found to be important to human health and well-being through maintaining homeostasis (balance) in various aspects of physiology. 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. 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.
Anyhow, 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. Other receptors that CBD impacts include GPR55, 5HTI-alpha and adenosine A2A, which variously can help with inflammation, pain, anxiety and even potentially cancer.
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. 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.
The vast majority of CBD extracts are not regulated, so different batches may contain more or less CBD than the labels claim. Always start with a low dose.
How to Take CBD
Recommended dosage, active amounts, other details
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. 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. High-fat and high-calorie meals lead to much higher CBD concentrations, 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.
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!
Human Effect Matrix
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]|
|LEVEL OF EVIDENCE
|OUTCOME||MAGNITUDE OF EFFECT
|CONSISTENCY OF RESEARCH RESULTS
|Seizure Frequency||Strong||Very High||These studies only looked at disorders with severe epilepsy, including Dravet and Lennox-Gastaut Syndromes and Tuberous sclerosis complex (TSC).|
|Anxiety||Notable||Very HighSee all 5 studies||No long term anxiety trials exist and very few types of anxiety have been researched thus far.|
|Pain||Minor||Very HighSee all 3 studies||Studies are very preliminary, with only one being randomized and all being small with short treatment durations.|
|Symptoms of Schizophrenia||Minor||ModerateSee 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.|
1. Background Information
CBD popularity exploded in the 2000s, especially after parents started experimenting with CBD for their children, as a treatment option for drug-resistant seizures in the rare and severe epilepsy condition called Dravet Syndrome.
The cannabinoids in cannabis have been studied since the 1940s,, with the structures of THC and CBD discovered in the 1960s. Research really heated up in the 1990s, as cannabinoid receptors in the body were found, and were later found to also be activated by endogenous compounds (which we make in our own bodies) in 1992.
CBD products that maintain a low-to-zero percentage of THC (below 0.3%) are currently in legal gray area in the US, with legality bolstered after the Farm Act was passed in December of 2018, yet the FDA still technically requiring marketed supplements to be approved by the FDA first. The FDA sent warning letters in April of 2019 to three companies who they deemed to be making egregious health claims, including:
- “CBD successfully stopped cancer cells in multiple different cervical cancer varieties.”
- “CBD also decreased human glioma cell growth and invasion, thus suggesting a possible role of CBD as an antitumor agent.”
- “For Alzheimer’s patients, CBD is one treatment option that is slowing the progression of that disease.”
- “Fibromyalgia is conceived as a central sensitization state with secondary hyperalgesia. CBD has demonstrated the ability to block spinal, peripheral and gastrointestinal mechanisms responsible for the pain associated with migraines, fibromyalgia, IBS and other related disorders.”
- “Cannabidiol May be Effective for Treating Substance Use Disorders.”
- “CBD reduced the rewarding effects of morphine and reduced drug seeking of heroin.”
- “CBD may be used to avoid or reduce withdrawal symptoms.”
Presumably, this is because evidence is scant right now for most conditions outside of severe epilepsy and since these statements don’t include that disclaimer, patients could presume that the evidence level is stronger than it actually is. Thus the FDA states “we won’t tolerate this kind of deceptive marketing to vulnerable patients”. The interaction between FDA regulation of food, drugs and supplements (all of which may apply to cannabis), along with different regulations around cannabis in different states, makes legal issues regarding CBD and other cannabinoid products complex.
CBD is typically extracted from the hemp plant. Here’s a quick overview of terms: Cannabis is a plant genus, that comes in two main botanical types — Cannabis indica and Cannabis sativa. Marijuana (which contains both CBD and THC) can be of either type, while hemp is only of the sativa type.
Note that these both belong to the same genus and species and are rather distinguished by their THC level. Hemp contains a maximum of 0.3% THC content, while marijuana typically ranges between 5-20% THC. Marijuana is often grown for recreational use, or mixed recreational/medicinal use, whereas hemp is grown for a wider variety of uses (hemp clothing, hemp oil, hemp fiber, isolated CBD and dozens more).
CBD and THC are not the only cannabinoids found on the market. For example, CBG (cannabigerol) is found in lesser amounts in cannabis, but has been studied for inflammatory disease in an animal model.
1.3 Biological Activity
Because the endocannabinoid system impacts so many facets of basic life (e.g. appetite, immune function, reproduction and pain management), there’s a bevy of possibilities for CBD (and other cannabinoids) impacting health. CBD may prevent the CB1 and CB2 receptor from being overly activated, reducing the effects of stress mediated by those receptors. Additional roles include anti-oxidation – CBD as well as THC have both been shown to act as neuroprotective antioxidants in rats.
While THC acts mainly on the CB1 and CB2 receptors, CBD acts on other receptors including the TRPV1 calcium channel, activating and rapidly desensitizing it, ultimately resulting in less potential for hyperexcitation.
2.1 Side Effects and Adverse Events
In order to find adverse events and side effects, which may be rare, you need a relatively big sample size. So the main studies to assess these were the larger trials in young patients with severe seizure disorders, namely Dravet syndrome and Lennox-Gastaut Syndrome.
The effects that happened more frequently with CBD than with placebo include: sleepiness, diarrhea, fatigue, vomiting, fever and lethary. Some patients also had increased levels of liver aminotransferase.
A comprehensive review found that doses of up to 1,500 mg/d seem to be fairly well tolerated, although it’s not at all safe to presume that dose will be safe for a given individual (due to the relative lack of long-term safety information and variety of conditions/drugs/etc that could theoretically interact with CBD).
CBD has also has promise as a method of reducing side effects when other medications are taken, such as in a trial of CBD for patients with schizophrenia taking amisulpride.
Contaminants from cannabis plants grown, harvested and packaged with less-controlled practices could theoretically also show up in CBD products, including pesticides, metal particles, synthetic cannabinoids, heavy metals, molds and bacteria and aflatoxins.Residual solvents from the production process can also show up in cannabis extracts, namely hexane, ethanol, isopropyl alcohol, toluene, benzene, xylene and acetone. This research is all on general cannabis extracts though; research into contaminants specifically in isolated CBD products is still to be done.
CBD taken by an oral route (specifically the liquid medication Epidiolex) takes between 2.5 and 5 hours to reach maximal concentration in the blood. The half life is between 56-61 hours. In both humans and rats, being in a fed state appears to increase plasma levels of CBD.
CBD pharmacokinetics can vary fairly widely among different people, which may be compounded by batch-to-batch variation and labeling inaccuracies in certain CBD products.
Right now, there’s just a hint of promise for CBD improving skin conditions, none based on randomized trial research. For example, CBD was found in a preclinical in vitro study to display antiinflammatory, antiproliferative and lipostatic effects that suggest it may potentially have some efficacy in treatments of skin conditions such as acne vulgaris.
A case study reported that a daily dose of 2×300 mg of CBD was associated with improvement of dysphagia from ALS. While eighteen months after onset, dysphagia progress and speech was almost competely lose, limb weakness, fasciculation and atrophy worsened relatively less. The authors theorize that progression of some but not all symptoms of motor neuron disease may be able to be slowed using CBD.
Autism spectrum disorder (ASD) likely involves alterations in certain neurological chemical pathways, such as with glutamate and GABA. It is with this idea that a study tested whether CBD altered these pathways in a way that might help with autism, using magnetic resonance spectroscopy. The researchers found that CBD was not effective in this manner. However, a retrospective case series showed improved behavior in 61% of a sample of children with ASD. There was no control group, however.
5.3 Parkinson’s Disease
CBD doesn’t appear to improve movement-related symptoms in Parkinson’s, although it may improve sleep problems stemming from the condition, notably parasomnia with nightmares and loss of muscle atonia during REM sleep.
In an exploratory trial, 2000 mg/d of CBD reduced psychotic symptoms of schizophrenia and patients on CBD were more likely to be rated as improved by the treating clinician.. A randomized trial of CBD found that both it and amisulpride improved symptoms, but CBD had a better side-effect profile.
However, in a randomized trial of 600 mg/d of CBD, no improvements in symptoms were noted. A non-controlled study found no benefit of CBD in doses increasing from 40 mg/d up to 1280 mg/d over 35 days in patients with treatment-resistent schizophrenia.
In six randomized trials with over 500 patients having severe seizures (typically young children), CBD significantly improves seizure symptoms. Notably, the percentage of patients who had an over 50% reduction in seizeures went down, as did the number who stopped having seizures altogether. While randomized studies typically looked at Dravet and Lennox-Gastaut syndrome patients, extended nonrandomized trials (“compassionate use” studies) also showed efficacy in CDKL5 deficiency disorder as well as Aicardi, Doose and Dup15q syndromes. A case series of three patients also suggested that CBD can help with brain-tumor related epilepsy.
Longer term followups confirm that CBD continues to be effective and relatively safe in these patients, although initially common side effects such as reduced appetite and diarrhea persisted in one study. CBD appears to have a similarly-sized effect on severe pediatric epilepsy as do other antiepileptic drugs. A small cohort study suggests that caregivers also felt that the overall health of their children with severe epilepsy was improved.
The reason that CBD can help with seizures has to do with endocannabinoid signaling pathways. These are altered in seizure disorder and THC and CBD act in different ways to potentially help. THC likely helps through activating the CB1 receptor, while CBD’s mechanisms are less well understood and may include a variety of other receptors, such as GPR55 and TRPV1.
6. Effects on Pain
While the potential for CBD helping certain types of chronic pain is high, the evidence base is surprisingly tiny, with only one randomized trial and two nonrandomized trials.
One randomized looked at pain and spasticity in patients with multiple sclerosis, spinal cord injury and other conditions with these symptoms. Although several patients didn’t complete the trial, pain control improved in the CBD group (while spasm and other symptoms did not).
Two non-randomized, uncontrolled trials looked at CBD for pain relief. One looked at pain in young girls with chronic pain from the HPV vaccine. It found reduced body pain and better functioning from CBD. A very very small study looked at pain in kidney transplant patients and found that two out of seven patients had total relief of pain, while four had some relief.
7. Effects on Mood
Whereas a single dose of THC appears to increase anxiety relative to placebo, a single dose of CBD was found to be similar to placebo. Long term randomized trials are lacking, but short term randomized trials and longer-term case series studies have explored CBD’s potential beneficial impacts on anxiety.
In a case series of 72 psychiatric outpatients, CBD (with most patients taking 25 mg/d) improved anxiety scores rapidly in around 80% of patients, with the effect typically sustaining over the course of three months.
Three trials have looked at the effects of CBD on anxiety experimentally induced by public speaking (shudder!). An early nonrandomized trial in 1993 showed that 300 mg of CBD helped anxiety after the public speaking test, but not before it. A randomized 2017 study by the same author also showed anxiety reduction from the same 300 mg dose, after the speaking test, with 100 mg and 900 mg showing no effect. A different group studied 600 mg of CBD and found significant anxiety reduction during the public speaking test.
Non-controlled trials provide weaker evidence, but extend the evidence to other populations. One retrospective case series showed that nearly 80% of patients that CBD was used for at a psychiatric clinic for anxiety had improved anxiety, with most of them maintaining benefits past the first month.
7.2 Cannabis withdrawal
A case study suggested that CBD dosed for 10 days reduced symptoms of cannabis withdrawal in a heavy user, such as anxiety, loss of appetite and irritability.
7.3 Nicotine withdrawal
Preliminary evidence suggested that CBD reduced cigarette smoking (despite not impacting craving for cigarettes), and reduced the pleasantness of cigarette-related cues after a night of abstinence.
Alas, in cigarette smokers aiming for abstinence, CBD did not improve verbal or spatial working memory, or impulsivity.
7.4 Opioid Withdrawal
A small pilot study in individuals addicted to opioids showed that CBD in doses of 400 or 800 mg reduced craving after subjects were abstinent from opioids for seven days (after a video session to induce craving). However, most evidence for potential CBD benefits on opioid withdrawal are preclinical and based on very small studies.
A case series reported PTSD symptom reduction in 10 out of 11 patients CBD was tried on, after eight weeks of treatment, with the CBD being well tolerated.
8. Effects on Sleep
A case series of 72 psychiatric outpatients found that CBD (with most patients taking 25 mg/d) did not improve sleep scores over the course of three months.
On the flip side, double-blinded crossover study found that CBD did not disrupt the sleep-wake cycle of patients taking a relatively high dose intended to clinically reduce anxiety (300 mg).
9. Effects on Cancer
Human CBD trials are lacking when it comes to cancer treatment.
One case study reported on a lung cancer patient who had a “striking response” with apparent tumour reduction after self-administering CBD. Of course, this is a case report and it’s anyone’s guess if CBD was the causative element. But it is food for thought, nonetheless.
Speaking of case reports, another suggested that CBD may have improved chemoradiation in two cases of high-grade gliomas. A retrospective case series reported that 92% of the 119 cancer cases looked at had a reduction in circulating tumor cells and sometimes a reduction in tumor size, when pharmaceutical-grade CBD was taken. Again, this is low-level evidence, but something to chew on.
10. Effects on Gastrointestinal Disorders
10.1 Crohn’s Disease
A trial of 10 mg of CBD, twice a day, found no beneficial effects. The authors hypothesize that this may have been influenced by the low dose or small number of patients in the study, or by the lack of other synergistic cannabinoids (i.e. the entourage effect).
10.2 Ulcerative Colitis
A proof-of-concept study (randomized, with a placebo group) tested a CBD-rich botanical extract and found no difference remission rates compared to placebo, but improvement in some symptoms.
11. Drug and Nutrient Interactions
11.1 Drug Interactions
CBD appears to interact with commonly used antiepleptic drugs, changing their serum levels significantly. These include clobazam, rufinamide, topiramate, zonisamide and eslicarbazepine.
CBD also can inhibit an enzyme called CYP2D6, which is targeted by common drugs including omeprazole and risperidone. It may also inhibit the enzyme CYP2C9, which would reduce the metabolization of warfarin and diclofenac. It’s not known whether in vitroinhibitions will translate to actual inhibitions in living humans and further study on this is needed. In a study of 6×100 mg/d of CBD, it increased the bioavailability and elimination half-life of hexobarbital.
On the flip side, it’s also possible for other drugs to impact the metabolization of CBD. For example, the antibiotic rifampicin reduces peak CBD concentrations in the blood due to inducing the enzyme CYP3A4, while the CYP3A4 inhibitor ketoconazole nearly doubles peak CBD concentration.
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