Cannabidiol (CBD)

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.^[4]

The cannabinoids in cannabis have been studied since the 1940s,^[5], 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,^[6], and were later found to also be activated by endogenous compounds (which we make in our own bodies) in 1992.^[7]

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.^[8] The FDA sent warning letters in April of 2019 to three companies who they deemed to be making egregious health claims, including:^[9]

• “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.^[10]

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.^[11] 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.^[12]

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.^[13] CBD may prevent the CB1 and CB2 receptor from being overly activated, reducing the effects of stress mediated by those receptors.^[14] Additional roles include anti-oxidation - CBD as well as THC have both been shown to act as neuroprotective antioxidants in rats.^[15]

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.^[16]

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.^[17][4]

Two trials looked at potential hemodynamic side effects (such as changes in heart rate, respiratory rate, or blood pressure), and did not find significant effects when CBD was taken.^[18][19]

A comprehensive review found that doses of up to 1,500 mg/d seem to be fairly well tolerated,^[20] 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).

Animal studies have reported some theoretical side effects not seen in existing human studies, such as reduced fertilization capacity and inhibited drug metabolism in the liver.^[21][22]

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.^[23]

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.^[24][25] Residual solvents from the production process can also show up in cannabis extracts, namely hexane, ethanol, isopropyl alcohol, toluene, benzene, xylene and acetone.^[26] 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.^[27] In both humans and rats, being in a fed state appears to increase plasma levels of CBD.^[3][28]

CBD pharmacokinetics can vary fairly widely among different people,^[29] 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.^[30] 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.^[31]

A case study reported that a daily dose of 2x300 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.^[32]

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.^[33] However, a retrospective case series showed improved behavior in 61% of a sample of children with ASD. There was no control group, however.^[34]

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.^[35][36]

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.^[37]. A randomized trial of CBD found that both it and amisulpride improved symptoms, but CBD had a better side-effect profile.^[23]

However, in a randomized trial of 600 mg/d of CBD, no improvements in symptoms were noted.^[38] 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.^[39]

In six randomized trials with over 500 patients having severe seizures (typically young children), CBD significantly improves seizure symptoms.^[40] 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.^[41] A case series of three patients also suggested that CBD can help with brain-tumor related epilepsy.^[42]

Longer term followups confirm that CBD continues to be effective and relatively safe in these patients,^[43][44][45] although initially common side effects such as reduced appetite and diarrhea persisted in one study.^[46] CBD appears to have a similarly-sized effect on severe pediatric epilepsy as do other antiepileptic drugs.^[47] A small cohort study suggests that caregivers also felt that the overall health of their children with severe epilepsy was improved.^[48]

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,^[49] while CBD's mechanisms are less well understood and may include a variety of other receptors, such as GPR55 and TRPV1.^[50][51][52]

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.^[56] 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.^[57]

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.^[58] 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.^[59] A different group studied 600 mg of CBD, and found significant anxiety reduction during the public speaking test.^[60]

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.^[57]

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.^[61]

Preliminary evidence suggested that CBD reduced cigarette smoking (despite not impacting craving for cigarettes),^[62] and reduced the pleasantness of cigarette-related cues after a night of abstinence.^[63]

Alas, in cigarette smokers aiming for abstinence, CBD did not improve verbal or spatial working memory, or impulsivity.^[64]

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).^[65] However, most evidence for potential CBD benefits on opioid withdrawal are preclinical and based on very small studies.^[66]

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.^[67]

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).^[72]

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.^[73]

CBD appears to interact with commonly used antiepleptic drugs, changing their serum levels significantly. These include clobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine.^[74]

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.^[75] It's not known whether in vitro inhibitions will translate to actual inhibitions in living humans, and further study on this is needed.^[76] In a study of 6x100 mg/d of CBD, it increased the bioavailability and elimination half-life of hexobarbital.^[77]

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.^[78]