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Abuse potential assessment of cannabidiol (CBD) in recreational polydrug users: A randomized, double-blind, controlled trial

Published on Nov 1, 2018in Epilepsy & Behavior2.378
· DOI :10.1016/j.yebeh.2018.07.027
Kerri A. Schoedel12
Estimated H-index: 12
,
Isabella Szeto3
Estimated H-index: 3
+ 5 AuthorsKenneth W. Sommerville14
Estimated H-index: 14
Source
Abstract
Abstract Rationale Treatment with a highly purified oral solution of cannabidiol (CBD), derived from the plant Cannabis sativa L., demonstrated some evidence of central nervous system (CNS)-related adverse events in patients enrolled in phase 3 trials for treatment of childhood-onset epilepsy. Cannabidiol was categorized as a Schedule 1 substance by the United States Drug Enforcement Administration; therefore, it was important to test CBD for human abuse potential. Methods This was a single-dose, randomized, double-blind, double-dummy, placebo- and active-controlled crossover trial. The abuse potential of single oral doses of plant-derived pharmaceutical formulations of highly purified CBD (Epidiolex®; 750 mg, 1500 mg, and 4500 mg) was compared with that of single oral doses of alprazolam (2 mg), dronabinol (10 mg and 30 mg), and placebo in healthy recreational polydrug users. The primary endpoint to assess abuse potential was the maximum effect (E max ) on Drug-Liking visual analog scale (VAS). Other measurements included E max on Overall Drug-Liking VAS, Take Drug Again VAS, positive and negative effects, other subjective effects, and Drug Similarity VAS. Cognitive and psychomotor functions were assessed using the Divided Attention Test, the Hopkins Verbal Learning Test—Revised, and the Digit–Symbol Substitution Task. Pharmacokinetic parameters were determined for CBD and its major metabolites. Standard safety measures and adverse events were assessed. Principal results Of 95 eligible subjects, 43 qualified for the treatment phase, received at least 1 dose of investigational medicinal product, and were included in safety assessments; 35 subjects were included in the pharmacodynamic analysis. Subjects receiving alprazolam and dronabinol had significantly higher Drug-Liking E max ( P P  = 0.51). Drug-Liking E max values for 1500-mg and 4500-mg CBD were significantly different from placebo ( P  = 0.04 and 0.002, respectively); however, the mean differences were  18-point differences between positive controls and placebo. Alprazolam and dronabinol had significantly higher Drug-Liking, Overall-Liking, and Take Drug Again VAS E max values compared with all doses of CBD ( P  ≤ 0.004). In contrast to alprazolam, CBD administration had no observable effect on cognitive/psychomotor tests. Pharmacokinetic parameters for CBD in this trial were consistent with previous studies. The majority of adverse events reported during the trial were of mild or moderate severity; no serious adverse events or deaths were reported. Conclusion Administration of a therapeutic dose of CBD (750 mg) showed significantly low abuse potential in a highly sensitive population of polydrug users. Although high and supratherapeutic doses of CBD (1500 mg and 4500 mg, respectively) had detectable subjective effects compared with placebo; the effects were significantly lower than those observed with alprazolam and dronabinol.
  • References (25)
  • Citations (6)
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References25
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#1Orrin DevinskyH-Index: 82
#2Anup D. PatelH-Index: 13
Last. Sameer M. ZuberiH-Index: 37
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Abstract Background Cannabidiol has been used for treatment-resistant seizures in patients with severe early-onset epilepsy. We investigated the efficacy and safety of cannabidiol added to a regimen of conventional antiepileptic medication to treat drop seizures in patients with the Lennox–Gastaut syndrome, a severe developmental epileptic encephalopathy. Methods In this double-blind, placebo-controlled trial conducted at 30 clinical centers, we randomly assigned patients with the Lennox–Gastaut...
90 CitationsSource
#1Ian Miller (Boston Children's Hospital)H-Index: 17
#2Orrin Devinsky (Comprehensive Epilepsy Center)H-Index: 82
Last. Claire RobertsH-Index: 5
view all 7 authors...
Objective: Assess long-term safety and efficacy of CBD as add-on to existing antiepileptic drug (AED) treatment in patients with treatment-resistant DS. Background: The safety and efficacy of CBD for the treatment of seizures associated with DS has been demonstrated in controlled trials. We present a prespecified interim analysis of an OLE study (GWPCARE5; NCT02224573). Design/Methods: Children and adults who participated in a 14-week, double-blind, randomized, controlled DS trial (GWPCARE1 [NCT...
3 Citations
#2Eric D. Marsh (Children's Hospital of Philadelphia)H-Index: 25
#3J. French (NYU: New York University)H-Index: 3
Last. Angus A. WilfongH-Index: 19
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Summary Background Patients with Lennox-Gastaut syndrome, a rare, severe form of epileptic encephalopathy, are frequently treatment resistant to available medications. No controlled studies have investigated the use of cannabidiol for patients with seizures associated with Lennox-Gastaut syndrome. We therefore assessed the efficacy and safety of cannabidiol as an add-on anticonvulsant therapy in this population of patients. Methods In this randomised, double-blind, placebo-controlled trial done ...
119 CitationsSource
#1Kerri A. SchoedelH-Index: 12
#2Armel Stockis (UCB)H-Index: 26
Last. Edward M. SellersH-Index: 68
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1 CitationsSource
2 CitationsSource
#1Joshua S. Kaplan (UW: University of Washington)H-Index: 2
#2Nephi Stella (UW: University of Washington)H-Index: 34
Last. Ruth E. Westenbroek (UW: University of Washington)H-Index: 56
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Worldwide medicinal use of cannabis is rapidly escalating, despite limited evidence of its efficacy from preclinical and clinical studies. Here we show that cannabidiol (CBD) effectively reduced seizures and autistic-like social deficits in a well-validated mouse genetic model of Dravet syndrome (DS), a severe childhood epilepsy disorder caused by loss-of-function mutations in the brain voltage-gated sodium channel Na V 1.1. The duration and severity of thermally induced seizures and the frequen...
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#1Orrin Devinsky (NYU: New York University)H-Index: 82
#2Jh Cross (UCL: University College London)H-Index: 46
Last. Stephen Wright (GW Pharmaceuticals)H-Index: 11
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BackgroundThe Dravet syndrome is a complex childhood epilepsy disorder that is associated with drug-resistant seizures and a high mortality rate. We studied cannabidiol for the treatment of drug-resistant seizures in the Dravet syndrome. MethodsIn this double-blind, placebo-controlled trial, we randomly assigned 120 children and young adults with the Dravet syndrome and drug-resistant seizures to receive either cannabidiol oral solution at a dose of 20 mg per kilogram of body weight per day or p...
261 CitationsSource
#1Shanna Babalonis (UK: University of Kentucky)H-Index: 8
#2Margaret Haney (CUMC: Columbia University Medical Center)H-Index: 50
Last. Sharon L. Walsh (UK: University of Kentucky)H-Index: 21
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Abstract Background Cannabidiol (CBD) is a naturally occurring constituent of the marijuana plant. In the past few years, there has been great interest in the therapeutic effects of isolated CBD and it is currently being explored for numerous disease conditions (e.g., pain, epilepsy, cancer, various drug dependencies). However, CBD remains a Schedule I drug on the U.S. Controlled Substances Act (CSA). Despite its status, there are no well-controlled data available regarding its abuse liability. ...
27 CitationsSource
#2Kerri A. SchoedelH-Index: 12
Last. Hailong Cheng (Sunovion)H-Index: 6
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#1Lance R. McMahon (University of Texas Health Science Center at San Antonio)H-Index: 22
Abstract Background Cannabidiol, a therapeutic with potential serotonin (5-hydroxytryptamine; 5-HT) 5-HT 1A receptor agonist activity, is the second most prevalent cannabinoid in Cannabis after Δ 9 -THC. The extent to which cannabidiol modifies the effects of Δ 9 -THC has not been firmly established, especially with respect to abuse-related effects in rhesus monkeys where previously antagonistic interactions have been reported for some behavioral outcomes. Methods Cannabidiol and the 5-HT 1A rec...
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#2Guo-Hua Bi (NIDA: National Institute on Drug Abuse)H-Index: 4
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Abstract Cocaine abuse continues to be a serious health problem worldwide. Despite intense research there is currently no FDA-approved medication to treat cocaine use disorder. The recent search has been focused on agents targeting primarily the dopamine system, while limited success has been achieved at the clinical level. Cannabidiol (CBD) is a U.S. FDA-approved cannabinoid for the treatment of epilepsy and recently was reported to have therapeutic potential for other disorders. Here we system...
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#1Edward Chesney ('KCL': King's College London)H-Index: 3
#2Dominic Oliver ('KCL': King's College London)H-Index: 8
Last. Philip McGuire (NIHR: National Institute for Health Research)H-Index: 110
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Cannabidiol (CBD) is being investigated as a treatment for several medical disorders but there is uncertainty about its safety. We conducted the first systematic review and meta-analysis of the adverse effects of CBD across all medical indications. Double-blind randomized placebo-controlled clinical trials lasting >/=7 days were included. Twelve trials contributed data from 803 participants to the meta-analysis. Compared with placebo, CBD was associated with an increased likelihood of withdrawal...
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#1Tory R. Spindle (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 10
#2Edward J. Cone (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 67
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INTRODUCTION: The use and availability of oral and inhalable products containing cannabidiol (CBD) as the principal constituent has increased with expanded cannabis/hemp legalization. However, few controlled clinical laboratory studies have evaluated the pharmacodynamic effects of oral or vaporized CBD or CBD-dominant cannabis. METHODS: Eighteen healthy adults (9 men; 9 women) completed four, double-blind, double-dummy, drug administration sessions. Sessions were separated by >/=1 week and inclu...
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This review aims to present completed clinical trial data surrounding the medicinal benefits and potential side effects of the increasingly popular cannabidiol (CBD)-based drug products, specifically Epidiolex. The article is divided into two sections based on if the ailment being treated by this cannabinoid is classified as either physiological or neurological conditions. In addition to describing the current status, we also examined the different primary and secondary outcomes recorded for eac...
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#1Meghann Wheeler (UNF: University of North Florida)
#2Julie Williams Merten (UNF: University of North Florida)H-Index: 5
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AbstractBackground: Cannabidiol (CBD), a non-psychoactive component of cannabis is marketed as a potential treatment for many conditions and widely available to purchase as a dietary supplement. In...
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#1Sin Yin Lim (University of Oklahoma Health Sciences Center)H-Index: 1
#1Sin Yin Lim (University of Oklahoma Health Sciences Center)
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INTRODUCTION: There is a large variation in cannabidiol (CBD) pharmacokinetics and little information on its bioavailability. This study aims to establish the CBD dose-exposure relationship and to evaluate the effects of dosage forms, food, and doses on CBD absorption. METHODS: Single-dose (range: 5-6000 mg) CBD plasma concentration-time profiles administered as oral solution (OS), oral capsule (OC), or oromucosal spray/drop (OM) from healthy volunteers were extracted from 15 published clinical ...
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#1Bola TayoH-Index: 1
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