Results from the first-ever randomised clinical trial of CBD for cannabis use disorder suggests that prescribed doses of the non-intoxicating constituent part of the cannabis plant could help people kick the habit.
In the MRC-funded trial, published in the Lancet Psychiatry, researchers administered CBD or placebo to 82 volunteers who were motivated to quit using cannabis but had previously failed to do so.
They measured the effects of the drug on levels of cannabis use both during a four-week treatment period and up to six months follow-up.
As this was the first clinical trial to assess CBD for reducing cannabis use, they tested three different doses of CBD in an adaptive design to find out which doses might be most effective:
- In the first stage of the trial, 48 volunteers received either placebo or CBD at doses of 200mg, 400mg or 800mg. The researchers found that the lowest dose of 200mg CBD was ineffective and so they dropped it from the trial.
- In the second stage of the trial, the researchers recruited an additional 34 volunteers to receive either placebo, 400mg or 800mg CBD. At the end of the trial, they found consistent evidence that CBD at 400mg or 800mg was more effective than placebo at reducing cannabis use.
Their results showed that participants treated with CBD showed lower levels of cannabis in their urine and an increased number of days abstinent compared to those treated with placebo.
CBD was well tolerated at all doses and there were no increases in side effects compared to placebo. 94% of the volunteers completed treatment. Importantly, the doses of CBD tested were significantly higher than CBD products purchased online or from the High Street (typically 25mg per day).
All participants in the trial met a clinical diagnosis of cannabis use disorder, indicating a problematic pattern of cannabis use which had created significant impairment and distress for the individual.
All participants had previously failed to quit cannabis use at least once and took part in the trial as part of a cessation attempt.
Lead author Dr. Tom Freeman, Director of the Addiction and Mental Health Group within the Department of Psychology at the University of Bath explains: “The results from our trial open up a novel therapeutic strategy for managing problematic cannabis use in clinical settings.
As we highlight, CBD at daily oral doses of 400mg and 800mg has potential to address the substantial and currently unmet clinical need for a pharmacological treatment of cannabis use disorders.
“Whilst it may seem counterintuitive to treat problematic cannabis use with CBD – a constituent part of the cannabis plant – THC and CBD have contrasting effects on our own endogenous cannabinoid system.
Unlike THC, CBD does not produce intoxicating or rewarding effects and it shows potential for a treating several other medical disorders.”
Cannabis is now the primary drug cited by first-time clients presenting at addiction services across Europe, with the number of people entering treatment increasing by 76% over the past decade.
The increase in treatment for cannabis problems has occurred alongside an increase in concentrations of THC, the intoxicating component of cannabis.
Daily use of cannabis with high THC concentrations is associated with a five-times increased risk of psychosis.
At present there are no recommended pharmacotherapies to help people with problematic cannabis use to quit. In demonstrating how CBD could be a promising treatment strategy, this trial adds to existing research on the potential medicinal uses of CBD, including the treatment of severe childhood epilepsy syndromes and psychosis.
Importantly, treatment with CBD does not include any of the intoxicating constituent of cannabis (THC) which might carry a risk of adverse effects.
Professor Valerie Curran, senior author and Director of the Clinical Psychopharmacology Unit at University College London, UK, said: “Our findings indicate that CBD doses ranging from 400mg to 800mg daily have the potential to reduce cannabis use in clinical settings, but higher doses are unlikely to bring any additional benefit.
Larger studies are needed to determine the magnitude of the benefits of daily CBD for reducing cannabis use.”
Potential Therapeutic Effects of CBD
In 2017, the National Academies of Science, Engineering and Medicine evaluated all the published literature through August, 2016 on the potential therapeutic uses of cannabinoids [24].
They determined if there was conclusive evidence, substantial evidence, moderate evidence, limited evidence, or insufficient evidence for cannabinoids being an effective or ineffective therapy to treat chronic pain, cancer, chemotherapy-induced nausea/vomiting, appetite and weight loss, irritable bowel syndrome, epilepsy, spasticity of multiple sclerosis, Tourette syndrome, amyotrophic lateral sclerosis, Huntington’s disease, Parkinson’s disease, dystonia, Alzheimer’s disease/dementia, glaucoma, traumatic brain injury/spinal cord injury, addiction, anxiety, depression, sleep disorders, posttraumatic stress disorder, and schizophrenia.
In addition, they reviewed the knowledge base using the same evidence categories for the health effects of cannabinoids and cancer, cardiometabolic risk, acute myocardial infarction, stroke, metabolic dysregulation, metabolic syndrome, diabetes, respiratory disease, immunity, injury and death, prenatal, perinatal, and postnatal exposure to cannabis, psychosocial, mental health, and problem cannabis use.
This review is not focused on therapeutic indications but rather on potential AEs, toxicities and drug-drug interactions that may accompany CBD therapeutics and that must be considered prior to off-label use of CBD for pathophysiology that has not yet been shown to respond effectively to CBD. However, to enable the reader to independently evaluate CBD’s AEs and toxicity, we briefly highlight some current research supporting CBD therapeutics.
Anti-epileptic
As early as 1980, the potential therapeutic effect of 200-300 mg/day CBD in patients with uncontrolled epilepsy was evaluated [25]. Patients tolerated CBD well, with no signs of toxicity or serious side effects detected. Seven of 8 subjects receiving CBD had fewer convulsive episodes, with 3 only partially improved.
A 2018 meta-analysis concluded that CBD in conjunction with other anti-epileptic drugs decreased seizure frequency in patients with Dravet’s and Lennox-Gastaut syndromes or who experienced intractable seizures, although AEs occurred more frequently than placebo [26]. The US Food and Drug Administration (FDA) approved Epidiolex® for the treatment of refractory epilepsy in 2018 [19, 27].
Anxiolytic
Multiple studies evaluated the potential therapeutic effect of CBD on anxiety, psychotic symptoms, and depression in humans since the 1980s, mostly showing mild AEs [28-35]. CBD effectively treated anxiety by activating limbic and paralimbic regions of the brain [30].
Interestingly, a single acute administration of a low 3 mg/kg CBD dose in mice had an anxiolytic effect, while repeated administration of a 3 or 10 mg/kg dose exerted antidepressant effects by cell proliferation and neurogenesis [36].
Conversely, CBD anxiolytic effects were not observed at higher 10 and 30 mg/kg CBD doses or after 15 days of 30 mg/kg/day dosing. The authors suggest that there is an inverted U-shaped dose-response curve for CBD’s effects on anxiety.
Antipsychotic Properties
CBD is extensively studied for its antipsychotic effects on schizophrenia [35, 37]. Leweke et al. noted that CBD moderately inhibits degradation of the endocannabinoid anandamide [38].
They performed a double-blind, randomized clinical trial of CBD vs. amisulpride, a potent antipsychotic, in acute schizophrenia. Both treatments were safe and significant clinical improvement was achieved, but CBD had a better side effect profile. CBD treatment significantly increased serum anandamide concentrations.
The safety and effectiveness of 1000 mg/day CBD in patients with schizophrenia were assessed [35]. These patients (n=43) with schizophrenia received 1000 mg/day CBD in addition to their existing antipsychotic medications.
After 6 weeks of treatment, the CBD group had lower levels of positive psychotic symptoms (positive and negative syndrome scale (PANSS): treatment difference=21.4, 95% CI=22.5,20.2). CBD was well tolerated, and AEs were similar between the CBD and placebo groups.
Six-hundred mg oral CBD was evaluated for its effects on persecutory ideation and anxiety in a high paranoid trait group (n=32) 130 min before entering a virtual-reality scenario [39].
CBD had no impact on anxiety (Beck’s anxiety inventory), or cortisol concentration, systolic blood pressure, and heart rate. In fact, in this study, a strong trend towards increased anxiety was documented and CBD had no effect on persecutory ideation.
CBD Neuroprotection
CBD’s anti-inflammatory and antioxidant properties may offer a new pharmacological approach for neuroprotection and a reduction in hippocampal volume loss [23, 40, 41]. CBD protects against hippocampal pathology following chronic frequent THC use [42].
This CBD restorative effect on hippocampal substructures suggests a therapeutic potential for other pathologies such as schizophrenia, Alzheimer’s disease, and major depressive disorder [40].
Indeed, in human studies for schizophrenia [35, 38] and Parkinson’s disease [43], and in animal studies for symptoms of Alzheimer’s disease [44], CBD was shown to be an effective treatment.
Spasticity
Many of the double-blinded, placebo-controlled studies for the effects of cannabinoids on spasticity used whole plant cannabis extracts or Sativex® that is a 1:1 THC:CBD extract containing 2.5 to 120 mg THC and CBD/day. Visual Analogue Scale (VAS) scores for each patient’s most troublesome symptom were significantly reduced [45].
Chronic Pain
In adults with chronic pain, patients treated with cannabis or cannabinoids are more likely to experience a clinically significant reduction in pain symptoms [24]. A recent review of specific cannabinoids and cannabinoid extracts on multiple pain types investigates both the preclinical and clinical data supporting cannabinoid pharmacotherapy for pain [46].
Cancer
There is tremendous interest in CBD as an anticancer agent. Aviello et al. showed that CBD had multiple chemopreventive effects in murine colorectal carcinoma cell lines by protecting DNA from oxidative damage, increasing endocannabinoid concentrations and reducing cell proliferation in a CB1-, TRPV1- and PPARγ-antagonists sensitive manner [47].
De Petrocellis et al. found that 1-10 µM CBD significantly inhibited human prostate carcinoma cell viability, inducing apoptosis and elevation of reactive oxygen species (ROS) [48].
Exciting new developments for enhancing CBD effects in inducing cell death and enhancing radiosensitivity of glioblastoma (GBM) cells were recently published [49]. GBM cells treated with CBD, γ-irradiation, and KU60019, an ATM kinase inhibitor, increased apoptosis and with strongly upregulated arrested cells, blockade of cell proliferation, and production of pro-inflammatory cytokines, improving CBD effectiveness.
Addiction Disorders
Recently, Solowij et al. described a 10-week study of daily 200 mg CBD in cannabis dependence to improve psychological symptoms and cognition [41]. CBD was well tolerated with no serious AE, promising therapeutic effects for improving psychological symptoms and cognition in regular cannabis users, and suggested that CBD may be a useful adjunct treatment for cannabis dependence.
CBD improved subicular and CA1 subfields volumes in the brains of chronic cannabis users, suggesting a protective role of CBD against brain structural harms conferred by chronic cannabis use [40]. Moreover, CBD was shown to have low abuse liability [50, 51] and to be effective in decreasing cannabis addiction [52, 53].
The Current Context
In June 2018, the US FDA approved the marketing of Epidiolex®, a CBD-rich whole cannabis plant extract, for the treatment of seizures in patients over age two suffering from Lennox-Gastaut and Dravet syndromes, two drug-resistant forms of epilepsy with a higher early mortality rate [27].
The studies that led to FDA approval of Epidiolex® for the treatment of severe forms of epilepsy, used CBD as an adjunct to clobazam, valproate, levetiracetam, and topiramate, resulting in seizures reduction with few AEs, compared to other drugs.
In January 2019, the World Health Organization (WHO) changed position after 60 years and proposed rescheduling of cannabis and cannabinoids for therapeutic purposes [54, 55]. Three months after FDA Epidiolex® approval, the U.S. Drug Enforcement Administration (DEA) removed Epidiolex® from the most restricted Schedule 1 (no approved medical use and high abuse liability) to Schedule V with low abuse potential [56].
In the wake of growing medical and public interest in medical cannabis and cannabinoids, we aimed to evaluate current knowledge of CBD’s AEs and toxicities by the relevant scientific literature from preclinical and clinical studies. Clinicians should be aware of CBD AEs and potential drug-drug interactions prior to recommending off-label CBD.
RESULTS
CBD clearly has great potential as a new pharmacotherapy based on novel mechanisms of action for currently unmet clinical needs. However, CBD, like almost all medications, also produces AEs and toxicity.
Two previous reviews focused on the therapeutic effects but also included AEs. In 2011, Bergamaschi et al. reviewed CBD AEs in animals and humans, concluding that CBD is generally safe, but further research is needed to investigate in-depth the observed in vitro and in vivo AEs [57].
In 2017, Iffland and Grotenhermen confirmed CBD’s safety profile, especially compared to other antiepileptics and antipsychotics [58]. These authors suggested that research should pursue AEs of chronic administration, hormonal effects, enzyme inhibition or induction, genotoxicity, drug transporters, and interactions with other drugs.
Currently, CBD is the focus of mass marketing campaigns and the subject of anecdotal reports claiming that CBD provides the answer for multiple illnesses from chronic pain to depression. Despite its Schedule I status in the US by the DEA, and lack of control by the FDA, CBD products are sold across the US and the internet.
No medication should be prescribed or recommended until it is proven safe and effective for each indication under consideration. In addition, it is important to reflect whether the medication is safe for each individual based on his or her health, age, genetics, chronic illnesses, and other medications (due to the problem of drug-drug interactions).
Now that Epidiolex® is FDA-approved, off-label prescriptions will increase. The goal of this review is to inform clinicians, pharmacists, nurses, patients, public health authorities, and policymakers about CBD’s AEs, toxicities, and drug-drug interactions that should be evaluated prior to prescribing CBD.
Table 1 lists AEs identified in preclinical research, and Table 2, AEs identified in clinical research. Both Tables 1 and 2 list AEs in chronological order.
Table 1 – CBD adverse effects in preclinical studies.
| Species | CBD Dose | Route | Reported Adverse Effects (AEs) | Refs. |
|---|---|---|---|---|
| Acute AEs | ||||
| Rats | 0.6, 0.8, or 1.2 mg/kg | Inhaled | Organ weight elevation; Seminiferous tubule degeneration, interference in sperm maturation | Rosenkrantz and Hayden, 1979 [100] |
| Rhesus monkeys | 150, 200, 225, 250, or 300 mg/kg/day (9 days) | Intravenous | Tremors, central nervous system inhibition, convulsions, bradycardia, hypopnea, cardiac failure at higher doses; Liver weight increase and testicular weights decrease, inhibition of spermatogenesis | Rosenkrantz and Hayden, 1981 [61] |
| Sea urchin eggs and sperms | 0.1, 0.5, 1.0, or 10 µM | Incubation in CBD-enriched sea water | Dose-dependent decreased fertility of eggs & sperms & fertilization inhibition | Schuel et al., 1987 [101] |
| Rats | 10 mg/kg | Intraperitoneal | Decrease of testosterone metabolism; Decrease of CYP aniline hydroxylation and p-nitroanisole demethylation, alteration of CYP contents | Narimatsu et al., 1990 [86] |
| Sea urchin sperms | 0.1–100 µM | Incubation in CBD-enriched sea water | Dose and time-dependent acrosome reaction inhibition, motility not reduced | Schuel et al., 1991 [102] |
| Piglets | 10, 25, or 50 mg/kg | Intravenous | Hypotension, cardiac arrest | Garberg et al., 2017 [63] |
| Rats | 10 mg/kg + 10 mg/kg THC | Subcutaneous | THC metabolism inhibition with higher THC concentrations & lower CBD concentrations in serum and brain; Hypolocomotion: THC metabolism inhibition shows little to no impact on THC-induced behavior | Hložek et al., 2017 [96] |
| Rats | 10 mg/kg + 10 mg/kg THC | Oral | THC metabolism inhibition with higher THC concentrations & lower CBD concentrations in serum and brain; Almost total immobility (10 mg/kg CBD alone caused mild hyperlocomotion): THC metabolism inhibition shows little to no impact on THC-induced behavior | Hložek et al., 2017 [96] |
| Rats | 10 mg + 10 mg THC (5 min vaporization) | Inhaled | No THC metabolism inhibition | Hložek et al., 2017 [96] |
| Chronic AEs | ||||
| Rhesus monkeys | 30, 100, or 300 mg/kg/day (90 days) | Oral | Liver, heart, kidney, and thyroid weight increase; Decrease in testicular size, spermatogenesis inhibition | Rosenkrantz and Hayden, 1981 [61] |
| Rats | 10 mg/kg (14 days) | Intraperitoneal | Anxiogenic-like effect, decreased brain-derived neurotrophic factor (BDNF) expression & related signaling proteins in the hippocampus and frontal cortex; Protein expression decrease in animals with enhanced protein expression following chronic antidepressant/anxiolytic drug treatment | ElBatsh et al., 2012 [79] |
| Mice | 30 mg/kg (15 days) | Intraperitoneal | Decreased cell proliferation and neurogenesis in the hippocampus and in subgranular zone | Schiavon et al., 2016 [36] |
| Rats (pregnant) | 75, 150, or 250 mg/kg/day (during organogenesis) | Oral | Developmental toxicity, increased embryofetal mortality | Center for Drug Evaluation and Research, 2018 [103] |
| Rats (pregnant) | 75, 150, or 250 mg/kg/day (during pregnancy and lactation) | Oral | Decreased growth, delayed sexual maturation, neurobehavioral changes, alterations of male reproductive organ development & fertility in offspring | Center for Drug Evaluation and Research, 2018 [103] |
| Rabbits (pregnant) | 50, 80, or 125 mg/kg/day (during organogenesis) | Oral | Decreased fetal body weight, increased fetal structural variations | Center for Drug Evaluation and Research, 2018 [103] |
| Mice | 15 or 30 mg/kg (34 days) | Oral | Decreased circulating testosterone, increased frequency of mitotic stages I-VI, decrease in spermiation stages VII-VIII & meiotic stage XII, decrease in number of Sertoli cells at meiotic stage (XII), decrease in number of spermatozoa in the epididymis tail, head abnormalities in sperm, cytoplasmic droplets in the flagella medial region | Carvalho et al., 2018 [104] |
Table 2 –CBD adverse effects in clinical studies.
| Study Characteristic | Patients’ Characteristic | Oral CBD Dose | Simultaneous Drug Administration | Reported Adverse Effects (AEs) | Refs. |
|---|---|---|---|---|---|
| Neurological studies | |||||
| Parental report: online survey | Age 2-16; 18 patients with Dravet syndrome, Lennox-Gastaut syndrome, Doose syndrome, or idiopathic epilepsy | 0.5–28.6 mg/kg/day (2 weeks–12 months) | Not reported | Moderate (defined as: sufficiently discomforting so as to limit or interfere with daily activities and may require interventional treatment): drowsiness (37%), fatigue (16%) | Porter and Jacobson, 2013 [68] |
| Parental report: online survey | Age 3-10; 117 patients with Dravet syndrome, Lennox-Gastaut syndrome, or infantile spasms | Median of 4.3 mg/kg/day (6.8 months) | Clobazam, other not-specified antiepileptics | AEs in 59% patients; Moderate: increased appetite, weight gain, drowsiness | Hussain et al., 2015 [67] |
| Open-label study, expanded-access trial in 11 independent epilepsy centers | Age 1-30; Patients with treatment-resistant epilepsy; 162 patients in safety analysis group (33 with Dravet syndrome, 31 with Lennox-Gastaut syndrome) | 2–5 mg/kg/day increased until intolerance or to a maximum of 25–50 mg/kg/day (12 weeks) | Clobazam, valproate | AEs in 79% safety group patients (128/162); Moderate: somnolence, fatigue, lethargy, sedation, decreased or changes in appetite, diarrhea, transaminases increase, changes of antiepileptics serum concentration; Severe: status epilepticus, convulsions, diarrhea, weight loss, thrombocytopenia, hyperammonaemia, hepatotoxicity | Devinsky et al., 2016 [70] |
| Retrospective study with no control group | Age 1-18; 74 patients with treatment-resistant epilepsy | 1–20 mg/kg/day; 81% patients (60/74) with < 10 mg/kg, 19% (14/74) with >10 mg/kg (> 3 months, average 6 months) | Not reported | AEs reported in 47% patients (34/74); Moderate: seizure aggravation (5 patients stopped CBD treatment due to seizure aggravation), somnolence, fatigue, gastrointestinal disturbances, irritability | Tzadok et al., 2016 [69] |
| Double-blind, randomized, placebo-controlled trial | Age 2-18; 120 patients with Dravet syndrome | 20 mg/kg/day (14 weeks) | Median of 3 antiepileptics (e.g., clobazam, valproate) | AEs in 93% patients; Moderate: diarrhea, loss of appetite, lethargy, fatigue, pyrexia, convulsion, elevated aminotransferase levels, somnolence; Severe (10 patients): elevated levels of liver aminotransferase enzymes (n=3), status epilepticus (n=3) | Devinsky et al., 2017 [71] |
| Double-blind, randomized, placebo-controlled trial | Age 4-10; 34 patients with Dravet syndrome | 5, 10, or 20 mg/kg/day (4-week baseline, 3-week treatment, 10-day taper, and 4-week follow-up) | Clobazam, valproate, levetiracetam, topiramate, stiripentol | Treatment-emergent AEs (TEAEs) reported in 80% patients with 5 mg/kg (8/10), 63% patients with 10 mg/kg (6/8), 78% patients with 20 mg/kg (7/9), 86% patients with placebo (6/7); Moderate: pyrexia, sedation, somnolence, appetite loss, vomiting, ataxia, abnormal behavior, rash; Severe: pyrexia, maculopapular rash, elevated transaminases | Devinsky et al., 2018 [74] |
| Double-blind, randomized, placebo-controlled trial | Age 2-55; 225 patients with Lennox-Gastaut syndrome | 10 or 20/mg/kg/day (28 days) | Not-specified antiepileptics | AEs in 84% patients with 10 mg/kg (56/67), in 94% patients with 20 mg/kg (77/82); Moderate: somnolence, decreased appetite, diarrhea, upper respiratory tract infection, pyrexia, vomiting; Severe: elevated aspartate aminotransferase (AST) concentration, elevated alanine aminotransferase (ALT) concentration, elevated γ-glutamyltransferase concentration, somnolence, increased seizures during weaning, nonconvulsive status epilepticus, lethargy, constipation, worsening chronic cholecystitis | Devinsky et al., 2018 [75] |
| Study Characteristic | Patients’ Characteristic | Oral CBD Dose | Simultaneous Drug Administration | Reported Adverse Effects (AEs) | Refs. |
| Neurological studies | |||||
| Double-blind, randomized, placebo-controlled trial | Age 2-55; 171 patients with Lennox-Gastaut syndrome | 20/mg/kg/day (14 weeks) | Clobazam, valproate, lamotrigine, levetiracetam, rufinamide | AEs in 62% patients (53/86); Moderate: diarrhea, somnolence, pyrexia, decreased appetite, vomiting; Severe: increased ALT concentration, increased AST concentrations, increased γ-glutamyltransferase concentrations | Thiele et al., 2018 [65] |
| Ongoing expanded‐access program (EAP) | Age 0.4-62 (average 13); 607 patients with treatment-resistant epilepsy | 2-10 mg/kg/day increased to a maximum of 25-50 mg/kg/day; median duration 48 weeks | Up to 10, including clobazam, lamotrigine, topiramate, rufinamide, valproate, levetiracetam, stiripentol, felbamate | AEs in 88% patients; Moderate: diarrhea, somnolence, convulsions; Severe (33%): convulsions, status epilepticus, liver abnormalities (10%) | Szaflarski et al., 2018 [66] |
| Psychiatric studies and psychiatric AEs | |||||
| Double-blind, randomized CBD versus amisulpride trial | Age 18-50; 42 patients with acute paranoid schizophrenia or schizophreniform psychosis | 200 mg/day increased to a maximum of 800 mg/day (28 days) | Lorazepam | Fewer motor disturbances, weight gain, and sexual dysfunction than amisulpride | Leweke et al., 2012 [38] |
| Meta-analysis of studies & reviews on CBD efficacy & safety in schizophrenia | 57 patients with schizophrenia | 300–600 mg | Not reported | Does not decrease anxiety; Frequent AEs (not reported) | Guinguis et al., 2017 [62] |
| Double-blind, randomized, placebo-controlled trial | Age 18-50; 32 patients with persecutory ideation and anxiety | 600 mg | Not reported | AEs in 31% patients (5/16); Tiredness/sedation (n=5), lightheaded/dizziness (n=2), nausea (n=2), abdominal discomfort (n=1), increased appetite/hunger (n=2); A strong trend toward increased anxiety was documented; no effect on persecution ideation | Hundal et al., 2018 [39] |
| Double-blind, randomized, placebo-controlled trial | Age 18-65; 88 patients with no treatment-resistant schizophrenia or related psychotic disorder | 1,000 mg/day (43±3 days) | Not-specified antipsychotics | AEs in 35% patients (15/43) (similar as placebo); Moderate: diarrhea (n=4; placebo, n=2), nausea (n=3), headache (n=2, placebo, n=2) | Mc Guire et al., 2018 [35] |
More information:Lancet Psychiatry (2020). DOI: 10.1016/S2215-0366(20)30290-X
