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Cannabidiol

Common Name(s): Cannabidiol, Cannabidiol oil, CBD, Epidiolex

Medically reviewed by Drugs.com. Last updated on Sep 1, 2018.

Clinical Overview

Use

Note: This monograph specifically discusses cannabidiol (CBD), a chemical constituent of the cannabis plant (Cannabis sativa L.). For more information regarding clinical uses (including those for CBD in combination with tetrahydrocannabinol [THC]), interactions, adverse reactions, and toxicology associated with C. sativa plant, see the Cannabis monograph.

CBD has been evaluated for use in epilepsy, particularly as an adjuvant to standard therapy in resistant forms. Use in the management of various CNS disorders, as well as other conditions (eg, diabetes, graft-vs-host disease [GVHD], inflammatory bowel disease) has also been investigated. Clinical trials are ongoing.

Dosing

Epilepsy (treatment-resistant forms): CBD dosages of 10 mg/kg/day and 20 mg/kg/day for 14 days have been used in clinical trials. Systematic reviews of randomized controlled trials report a variety of CBD dosages and treatment durations. Graft-vs-host disease: CBD 300 mg/day orally starting 7 days before transplantation until day 30 was used in a phase 2 clinical study. Schizophrenia: CBD dosages have ranged from 600 mg/day to 1,000 mg/day orally for up to 6 weeks in randomized controlled trials.

Contraindications

Contraindications have not been identified.

Pregnancy/Lactation

Avoid use. Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

Few case reports exist of interactions in which CBD is solely implicated.

Adverse Reactions

Information regarding adverse effects specifically attributed to CBD is limited. Seizure aggravation, leading to treatment withdrawal, has been reported. Information regarding cardiovascular effects is unclear.

Toxicology

Information specific to CBD is limited. Most data are derived from studies related to preparations from whole cannabis plant material.

Scientific Family

  • Cannabaceae

Source

CBD is a chemical constituent of the cannabis plant Cannabis sativa L. Species ascribed to the Cannabis genus include C. sativa, Cannabis indica, and Cannabis ruderalis; however, disagreement exists regarding distinct classification of these species.Gloss 2015 Variants of C. sativa such as Charlotte's Web cannabis, cultivated specifically to be low in THC and high in CBD content, have been described.Jikomes 2018

History

The chemical structure of CBD and other major phytocannabinoids was elucidated in the 1960s, with the first clinical use of cannabidiol in epilepsy reported in the literature in 1974.Friedman 2017, Russo 2017

Federal and state laws in the United States are not synchronized with respect to the medical use of cannabis or cannabinoid medicines.Mead 2017 CBD as monotherapy is being evaluated for applications in seizures and other disorders. CBD/THC ("nabiximols" [ie, Sativex]) as an orobuccal spray is approved for multiple sclerosis spasticity in more than 20 countries, including Canada and the United Kingdom, and is being studied in phase 3 clinical trials in the United States.NIH 2018, O'Connell 2017

Chemistry

CBD is a chemical constituent of C. sativa L. Cannabidiol (2-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol) is distinct from the more than 100 other cannabinoid compounds, such as cannabinol, cannabigerol, and cannabivarin, found in lower concentrations in the plant.Morales 2017, NCBI 2018

Uses and Pharmacology

The uses described in the following sections focus on CBD specifically. See also Cannabis monograph for further information regarding potential uses of other cannabinoids.

CBD acts as an antagonist or partial antagonist at endogenous cannabinoid receptors (both CB1 and CB2 receptor types as well as other G-protein-coupled receptors [GPCRs]) by inhibiting full binding of direct ligands, and may act primarily at allosteric receptor sites. CBD acts as a modulator of receptor activation, influencing the endogenous cannabinoid system by potentiating intrinsic anandamide-mediated neurotransmission and regulating other cerebral neurotransmitters and receptors. It also modulates activity of various transient receptor potential channels and glycine receptors involved within and without the endocannabinoid system. Anti-inflammatory and antioxidant properties have been described.Gaston 2017, Grant 2018, Martinez-Pinilla 2017, Pertwee 2008, Tzadok 2016

CNS effects

Antinociceptive effects

Animal data

Results from experiments conducted in animals and reviews of animal data suggest anti-inflammatory and antinociceptive effects of CBD in conditions such as arthritis,Hammell 2016 chronic neuropathic pain,Lötsch 2018, Mücke 2018 and osteoarthritis pain.O'Brien 2018

Clinical data

Few studies have investigated, or are currently investigating, the effect of CBD alone on pain; most rely on CBD/THC combination preparations.Mücke 2018, NIH 2018 High-quality clinical evidence for the use of CBD in neuropathic pain is lacking,Mücke 2018 with one clinical study suggesting improvement in quality-of-life scores, including a physical discomfort measure as part of the Parkinson Disease Questionnaire (PDQ-39), in patients with Parkinson disease.Chagas 2014

A bias towards reporting positive findings exists both within individual clinical studies, as well as within systematic reviews of CBD use for pain management.Häuser 2018, Lötsch 2018

Parkinson disease

Clinical data

Clinical trials evaluating CBD alone in the management of motor symptoms in Parkinson disease are being conducted.NIH 2018 In a small study, patients with Parkinson disease (N=21) received CBD 75 mg/day, CBD 300 mg/day, or placebo for 6 weeks. There were no significant differences concerning motor and general symptoms; however, in Parkinson disease patients without psychiatric comorbidities, significant improvement in measures related to quality of life were observed with the higher CBD dosage compared to placebo.Chagas 2014

In a case series of Parkinson disease patients with rapid eye movement (REM) sleep behavior disorder, CBD 75 mg/day and 300 mg/day for 6 weeks resulted in a reduction in the frequency of REM sleep behavior disorder–related events. Further research is needed.Chagas 2014

Schizophrenia

Clinical data

Several phase 1 and phase 2 clinical trials have evaluated CBD as an antipsychotic intervention, with no net effects reported in some, and publication of results pending for others.Boggs 2018, NIH 2018

In one phase 2 trial, men and women 18 to 50 years of age with schizophrenia (N=42) were randomized to receive CBD or amisulpride, each starting at 200 mg/day and increased to 200 mg 4 times per day (800 mg/day) within the first week. After 4 weeks of treatment, both CBD and amisulpride treatment resulted in significant clinical improvement in psychotic symptoms, as evidenced by a reduction in Positive and Negative Syndrome Scale (PANSS) total score (P<0.001), among other measures. Compared to amisulpride, CBD was well tolerated and was associated with fewer extrapyramidal symptoms, less weight gain, and a lower incidence of sexual dysfunction.Leweke 2012

A study of 36 stable antipsychotic-treated patients with schizophrenia showed no improvement in PANSS or MATRICS Consensus Cognitive Battery scores with CBD 600 mg/day for 2 weeks compared to placebo.Boggs 2018

In another multicenter, randomized, controlled trial, patients with schizophrenia (N=43) received CBD 1,000 mg/day or placebo in addition to their existing antipsychotic medication. After 6 weeks, the CBD group had lower levels of positive psychotic symptoms (treatment difference in PANSS positive score, −1.4). Patients receiving CBD also showed greater improvements in cognitive performance and overall functioning, but differences between groups were not statistically significant.McGuire 2018

Seizures

The exact mechanism by which CBD exerts its anticonvulsant activity is unknown. The antiseizure activity of THC seems to be mediated to an important extent by its partial agonist action on the CB1 receptor, whereas CBD has very weak affinity for the CB1 and CB2 receptors, indicating its antiseizure activity is mediated by other mechanisms; various targets have been investigated to explain CBD's anticonvulsant properties, including transient receptor potential channels, voltage-gated potassium and sodium channels, and certain GPCRs (such as GPR55), among others.Gaston 2017, Perucca 2017

Clinical data

Few moderate- or high-quality clinical trials (randomized controlled trials with a low risk of bias) have been conducted.Perucca 2017, Stockings 2018, Wong 2017 A number of open-label studies conducted by the manufacturers of the CBD preparation Epidiolex have contributed to knowledge surrounding the safety profile of CBD for treatment-resistant epilepsy.Neale 2017, O'Connell 2017, Wong 2017 Retrospective analyses of case reports or clinical data, generally supportive of efficacy of CBD alone or in combination with THC in treatment-resistant seizures, have also been reviewed in the literature.Neale 2017, O'Connell 2017, Perucca 2017, Stockings 2018, Wong 2017

A meta-analysis of data from 2 prospective clinical trials (N=291) (Devinsky et al and Thiele et al) reported CBD 20 mg/kg/day as adjunctive therapy is more likely than placebo to produce a greater than 50% reduction in seizures (relative risk [RR], 1.74; 95% CI, 1.24 to 2.43); number needed to treat (NNT) was 8 for one person to achieve a 50% reduction in seizures.Stockings 2018 A further clinical study by the same group of researchers reports significant findings for both 10 mg/kg/day and 20 mg/kg/day dosages evaluating the same outcome measure (odds ratio for a greater than 50% reduction in seizures in the CBD 20 mg/kg/day group vs placebo was 3.85 [95% CI, 1.75 to 8.47; P<0.001]; and odds ratio for the CBD 10 mg/kg/day group vs placebo was 3.27 [95% CI, 1.47 to 7.26; P=0.003]).Devinsky 2018 These studies included both pediatric and adult patients with Dravet and Lennox-Gastaut syndromes. Seizure aggravation, leading to treatment withdrawal of some participants, was reported.Perucca 2017

It should be noted that studies report a high placebo effect, and findings from open-label design studies must be interpreted with caution. Seizures were reduced in 63% of participants in the placebo arm in one trial of predominantly pediatric Lennox-Gastaut syndrome patients; a meta-analysis of studies in patients with treatment-resistant focal epilepsy found a placebo response of almost 20% in children and 10% in adults.Rosenberg 2015 Further clinical studies are being conducted, with publication of trial findings pending.NIH 2018

Other

Clinical data

Limited studies have evaluated the efficacy of CBD alone in generalized social anxiety disorder (1 study) and psychosis (2 studies). A review deemed the studies to be of lower quality or with potential for bias.Whiting 2015 Clinical trials evaluating CBD alone in the management of Prader-Willi Syndrome are being conducted.NIH 2018

Studies are lacking regarding use of CBD alone in Tourette syndrome or tics.NIH 2018

Diabetes

The role of the endocannabinoid system in energy metabolism has been investigated, with emerging evidence showing CBD may slow beta-cell damage in type 1 diabetes mellitus.Di Marzo 2011, Mastinu 2018

Animal data

Limited experiments in nonobese diabetic mice treated with CBD demonstrated reductions in incidence and manifestations of type 1 diabetes.Di Marzo 2011, Zuardi 2008

Clinical data

The CB1 receptor antagonist rimonabant has been evaluated in clinical trials of obese patients with and without comorbidities (dyslipidemia and/or type 2 diabetes) and has demonstrated reductions in hemoglobin A1c (HbA1c) levels; however, use was suspended in 2008 by the European Medicines Agency when documentation of psychiatric adverse effects (worsening anxiety and depression) showed that the benefits no longer outweighed the risks.Di Marzo 2011 Focus is now on other cannabinoid CB1 antagonists, including the less well studied tetrahydrocannabivarin (THCV), the propyl homologue of THC.

In one small randomized, double-blind, placebo-controlled study (N=62), patents with noninsulin–treated type 2 diabetes received CBD, THCV, a combination of CBD and THCV, or placebo for 13 weeks. CBD and THCV were well tolerated. THCV decreased fasting plasma glucose and improved pancreatic beta cell function, adiponectin, and apolipoprotein A. CBD decreased resistin and increased glucose-dependent insulinotropic peptide. However, the primary end point (change in HDL cholesterol) was not affected by treatment with CBD, THCV, or combination treatment.Jadoon 2016 More research is needed.

Graft-vs-host disease

Animal and in vitro data

Effects of CBD on T cells, cytokines, and other modulators of inflammation have been demonstrated in vitro and in animal models. Insufficient data exist.NIH 2018, Yeshurun 2015

Clinical data

Limited clinical studies evaluating use of CBD alone have been conducted. A small phase 2 study of 48 transplant patients examined effects of CBD on development of GVHD. In addition to GVHD standard prophylaxis (cyclosporine and methotrexate), CBD 300 mg/day was given orally, starting 7 days before transplantation until day 30. No patients developed GVHD during treatment with CBD. Following discontinuation of treatment, 8 patients developed GVHD. It was determined that addition of CBD to GVHD prophylaxis resulted in low cumulative incidence rates of GVHD by day 100.NIH 2018, Yeshurun 2015 Further studies are needed.

Inflammatory bowel disease

Animal and in vitro data

Cannabinoids have been shown to decrease macroscopic inflammation, myeloperoxidase activity, and peristalsis, and to ameliorate inflammation in rodent studies.Naftali 2013, Wallace 2013 CBD demonstrated anti-inflammatory activity in inflamed colonic tissue of inflammatory bowel disease explants.Couch 2017

Clinical data

A small clinical study (N= 20) evaluating CBD 10 mg orally or placebo twice daily in patients with moderately active Crohn disease reported no effect, possibly due to a lack of effect by CBD, the low CBD dose used, and/or the small number of participants.Naftali 2017 Further clinical studies in Crohn disease and inflammatory bowel disease are being conducted, with publication of results pending.NIH 2018

Multiple sclerosis:

Clinical data

Clinical studies evaluating CBD alone in the management of multiple sclerosis are limited, with most studies using commercially available CBD/THC combination preparations.NIH 2018, Nielsen 2018

Dosing

A phase 1 clinical study is being conducted by Johns Hopkins University to describe the pharmacokinetics of oral and vaporized CBD.Johns Hopkins University 2018

Epilepsy (treatment-resistant forms)

CBD dosages of 10 mg/kg/day and 20 mg/kg/day for 14 days have been used in clinical trials.Devinsky 2018 Systematic reviews of randomized controlled trials report a wide variety of CBD dosages and treatment durations.Stockings 2018, Wong 2017

Graft-vs-host disease

CBD 300 mg/day orally starting 7 days before transplantation until day 30 was used in a phase 2 clinical study.Yeshurun 2015

Schizophrenia

CBD dosages have ranged from 600 mg/day to 1,000 mg/day orally for up to 6 weeks in randomized controlled trials.Boggs 2018, Leweke 2012, McGuire 2018

Pregnancy / Lactation

Avoid use. Information regarding safety and efficacy of CBD in pregnancy and lactation is limited. The endocannabinoid system plays an role in regulation of fertility; cannabis use and/or disruptions to the endocannabinoid system have demonstrated negative effects on reproduction.Dekker 2012, Karasu 2011, Lewis 2012

Interactions

The cannabinoids THC and CBD are both metabolized by the cytochrome P450 (CYP-450) enzyme system.Gaston 2017, Tran 2017 CBD has been shown to both inhibit (CYP2C19, CYP2D6, CYP2C9, and CYP3 enzymes), and induce members of the CYP2B family in animal models.Gaston 2017 CBD may also be an inhibitor of certain transporter systems.Perucca 2017 Case reports are minimal.

Cilostazol: CYP2C19 inhibitors may increase the serum concentration of cilostazol. Consider therapy modification.Pletal January 2015, Suri 1999

Citalopram: CYP2C19 inhibitors (moderate) may increase the serum concentration of citalopram. Consider therapy modification.Bondolfi 1996, Celexa August 2011, Mailling 2005, Priskorn 1997, Rocha 2010, Rochat 1997

Clobazam: Cannabidiol may increase serum concentrations of the active metabolite(s) of clobazam. Cannabidiol may increase the serum concentration of clobazam. Monitor therapy. This interaction is only expected with the oral administration of cannabidiol.Epidiolex June 2018, Gaston 2017, Geffrey 2015, Jiang 2013, Onfi December 2016 CBD is well-documented to interact with clobazam, a 2C19 substrate, resulting in increased clobazam levels.Geffrey 2015

Clopidogrel: CYP2C19 inhibitors (moderate) may decrease serum concentrations of the active metabolite(s) of clopidogrel. Consider therapy modification.Brandt 2007, Collet 2009, Fontana 2008, Frere 2008, Gilard 2008, Gilard 2006, Giusti 2009, Hulot 2006, Juurlink 2009, Kim 2008, Mega 2009, Pezalla 2008, Plavix May 2009, Sibbing 2009, Simon 2009, Small 2008, Trenk 2008

CNS depressants: Cannabidiol may enhance the CNS depressant effect of CNS depressants. Monitor therapy.Epidiolex June 2018, Sativex March 2015, Sativex March 2012

CYP2C19 inducers (strong): CYP2C19 inducers (strong) may decrease the serum concentration of cannabidiol. Monitor therapy.Epidiolex June 2018, Jiang 2011, Stott 2013

CYP2C19 inhibitors (moderate): CYP2C19 inhibitors (moderate) may increase the serum concentration of cannabidiol. Monitor therapy.Epidiolex June 2018

CYP2C19 inhibitors (strong): CYP2C19 inhibitors (strong) may increase the serum concentration of cannabidiol. Monitor therapy.Epidiolex June 2018

CYP2C19 substrates (high risk with Inhibitors): CYP2C19 inhibitors (moderate) may decrease the metabolism of CYP2C19 substrates (high risk with inhibitors). Monitor therapy.Bjornsson 2003

CYP3A4 inducers (strong): CYP3A4 inducers (strong) may decrease the serum concentration of cannabidiol. Monitor therapy.Epidiolex June 2018, Jiang 2011, Stott 2013

CYP3A4 inhibitors (moderate): CYP3A4 inhibitors (moderate) may increase the serum concentration of cannabidiol. Monitor therapy.Epidiolex June 2018, Stott 2013, Watanabe 2007

CYP3A4 inhibitors (strong): CYP3A4 inhibitors (strong) may increase the serum concentration of cannabidiol. Monitor therapy.Epidiolex June 2018, Stott 2013, Watanabe 2007

Flibanserin: CYP2C19 Inhibitors (moderate) may increase the serum concentration of flibanserin. Monitor therapy.Addyi August 2015

Tacrolimus: One case report described an interaction with the Epidiolex product and tacrolimus, resulting in tacrolimus toxicity.Leino 2018

Valproate Products: Valproate products may enhance the hepatotoxic effect of cannabidiol. This interaction has only been documented with the oral administration of cannabidiol. Monitor therapy.Epidiolex June 2018, Gaston 2017

Warfarin: Cannabidiol may increase the serum concentration of warfarin. Monitor therapy.Grayson 2017, Yamaori 2012 CBD has been noted to interact with warfarin, resulting in a need for decreased warfarin dosages.Grayson 2017

Adverse Reactions

Seizure aggravation, leading to treatment withdrawal, has been reported in studies of patients with treatment-resistant seizure syndromes. Overall, CBD is generally well tolerated, with mild effects, including drowsiness, reported.Perucca 2017

A systematic review found no effect on blood pressure or heart rate under control conditions, either with acute or chronic CBD administration. However, in models of stress, acute CBD significantly reduced blood pressure and heart rate that had been increased by the stress.Sultan 2017 In animal studies, CBD significantly increased cerebral blood flow.Sultan 2017

Toxicology

Information specific to CBD is limited. Most data are derived from studies related to preparations from whole cannabis plant material.

Index Terms

  • Cannabis indica
  • Cannabis ruderalis
  • Cannabis sativa

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