Cannabidiol Adverse Effects and Toxicity
Marilyn A. Huestis, Renata Solimini, Simona Pichini, Roberta Pacifici, Jeremy Carlier and Francesco Paolo Busardò
Current Neuropharmacology, 2019, 17, 974-989
Doi : 10.2174/1570159XI7666190603171901
Background : Currently, there is a great interest in the potential medical use of cannabidiol (CBD), a non-intoxicating cannabinoid. Productive pharmacological research on CBD occurred in the 1970s and intensified recently with many discoveries about the endocannabinoid system. Multiple preclinical and clinical studies led to FDA-approval of Epidiolex®, a purified CBD medicine formulated for oral administration for the treatment of infantile refractory epileptic syndromes, by the US Food and Drug Administration in 2018. The World Health Organization considers rescheduling cannabis and cannabinoids. CBD use around the world is expanding for diseases that lack scientific evidence of the drug’s efficacy. Preclinical and clinical studies also report adverse effects (AEs) and toxicity following CBD intake.
Methods : Relevant studies reporting CBD’s AEs or toxicity were identified from PubMed, Cochrane Central, and EMBASE through January 2019. Studies defining CBD’s beneficial effects were included to provide balance in estimating risk/benefit.
Results : CBD is not risk-free. In animals, CBD AEs included developmental toxicity, embryo-fetal mortality, central nervous system inhibition and neurotoxicity, hepatocellular injuries, spermatogenesis reduction, organ weight alterations, male reproductive system alterations, and hypotension, although at doses higher than recommended for human pharmacotherapies. Human CBD studies for epilepsy and psychiatric disorders reported CBD-induced drug-drug interactions, hepatic abnormalities, diarrhea, fatigue, vomiting, and somnolence.
Conclusion : CBD has proven therapeutic efficacy for serious conditions such as Dravet and Lennox-Gastaut syndromes and is likely to be recommended off label by physicians for other conditions. However, AEs and potential drug-drug interactions must be taken into consideration by clinicians prior to recommending off-label CBD.
Keywords : Cannabidiol, adverse effects, toxicity, animal studies, in vitro studies, in vivo studies, studies in humans.
1.1. Cannabinoid Pharmacology
Δ9-tetrahydrocannabinol (THC) was shown to be the primary psychoactive compound in cannabis (marijuana) in 1964 by Gaoni and Mechoulam . There were few advances in cannabinoid pharmacology until 1988, when Devane et al. identified the first CB1 cannabinoid receptor , quickly followed by the discovery of the CB2 peripheral receptor by Munro et al. in 1990 . The CB1 and CB2 cannabinoid receptors were cloned by Matsuda et al. in 1992  and Munro et al. in 1993 , respectively. However, the endogenous cannabinoid system may include additional cannabinoid G protein-coupled receptors (GPCR) GPR55, GPR18, and GPR119, transient receptor potential cation channels (TRP) TRPV, TRPA, TRPM, and TRPC and nuclear peroxisome proliferator-activated receptors (PPAR) . Anandamide was the first identified endogenous cannabinoid ligand , but there are many other endocannabinoids including 2-arachidonylglycerol, N-palmitoyl ethanolamide, and N-oleoyl ethanolamide.
Cannabidiol (CBD or 2-[(6R)-6-isopropenyl-3-methyl-2- cyclohexen-1-yl]-5-pentyl-1,3-benzene-diol) was identified in an extract of Minnesota wild hemp by Adams et al. at the University of Illinois in 1940 , but its structure was not fully elucidated until 1963 . To date, CBD’s mechanisms of action are not fully elucidated . CBD modulates central nervous system (CNS) receptors such as CB1, CB2, serotonin 1A receptor (5-HT1A), TRPV1, and PPARγ, although it binds poorly to the THC-binding site on CB1 and CB2 cannabinoid receptors . CBD may antagonize CB1 receptor function by negative allosteric modulation of the orthosteric receptor site [11-14]. CBD may be an inverse agonist at the CB2 receptor, partially explaining its antiinflammatory properties , which also are supported by CBD PPARɤ activation . High CBD doses activate TRPV1 receptors promoting anxiolytic effects . CBD also increases serotoninergic and glutamatergic transmission through a positive allosteric modulation of 5-HT1A serotonin receptors . 5-HT1A receptor activation is also involved in CBD neuroprotection in in vitro adult and rat newborn models of the acute hypoxic-ischemic brain .
CBD is metabolized in the liver and the intestine by cytochrome P450 (CYP) CYP2C19 and CYP3A4, and 5′- diphospho-glucuronosyltransferase (UGT) UGT1A7, UGT1A9, and UGT2B7 isoforms, mainly producing hydroxylated and carboxylated metabolites . CBD inhibited barbiturate metabolism, increasing barbiturate-induced sleep duration in mice, and also phenazone hepatic metabolism  due to the inhibition of CYP3A and CYP2C microsomal enzymes . Other research suggested that CBD also induced hepatic CYP3A, CYP2B, and CYP2C . Later, CBD was shown to inhibit THC metabolic hydroxylation in humans. The pharmacokinetic interaction between THC and CBD may explain why CBD administration prior to THC potentiates THC effects .
The complexity of CBD pharmacology offers tremendous therapeutic potential but also the potential for AEs and drug-drug interactions.
1.2. 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 . 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.