Severe AEs occurred in 20 (23%) of 86 patients in the CBD group including sleep apnea. Twelve (14%) patients treated with CBD and one (1%) treated with placebo withdrew from the study. Human CBD studies for epilepsy and psychiatric disorders reported CBD-induced drug-drug interactions, hepatic abnormal-ities, diarrhea, fatigue, vomiting, and somnolence. From the list of identified reports, clinical studies with a title and abstract mentioning CBD use were eligible for full-text reading. If a title/abstract was insufficient to understand whether the corresponding report should be included, the report was eligible for full-text reading.
Acute Clinical Data
The aim of the present study was to address this issue by conducting a systematic review and meta-analysis of the adverse effects of CBD across a range of indications. Since cannabidiol is typically added to existing medicine treatments, interactions can occur between CBD and other co-administered medications. Pharmacokinetic drug-drug interactions can occur at the absorption, distribution, is cannabidiol addictive and elimination stages, resulting in changes in drug plasma concentrations. When cannabidiol is used with another medication, the pharmacokinetics of the CBD or the other drug may change [23]. CYP2C19 and, to a lesser extent, CYP3A4 are the main cytochrome P450 (CYP) enzymes that metabolize CBD, converting it to its primary active metabolite 7-hydroxy CBD [24,25].
Cannabinoid Poisoning
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].
CBD-drug interactions
- The results of the evaluation of pharmacokinetics, to see if interaction between the drugs occurred, were as follows.
- Nonetheless, we also included these studies with repeated CBD treatment, because we think that compared to a one-time dose of CBD, repeated CBD regimens add value and knowledge to the field and therefore should be mentioned here.
- Children were concomitantly taking clobazam, valproate, levetiracetam, topiramate, and stiripentol.
- An RCT, double-blind, placebo-controlled trial was carried out for two weeks.
- CBD affected the exposure of caffeine, a CYP1A2 substrate, leading to an elevation of 15% for Cmax, 88% for AUC0-t, and 95% for AUC0-∞, and showed a good safety profile with no unexpected AEs.
- Interestingly, an open-label trial was conducted to assess the pharmacokinetics and safety of CBD in subjects with mild to severe hepatic impairment.
Moreover, clinical studies have focused on CBD antiseizure properties in other forms of refractory childhood epilepsy, expanding its therapeutic application. Considering the recent approval by the FDA and EMA for childhood epilepsy syndrome and the wide range of pharmacological effects with a broad spectrum of potential clinical use, CBD safety needs to be investigated. In 2019, we reviewed the scientific evidence on CBD-related toxicity and adverse events (AEs) [28]. However, most clinical studies involving CBD were published in recent years, providing essential data on CBD safety at specific controlled doses in humans. The aim of the present review was to provide an update on CBD toxicity and AEs, specifically focusing on clinical trials. However, its ability to inhibit the hepatic metabolism of other medications (such as clobazam and sodium valproate) has the potential to cause adverse effects.
In 2017, Garberg et al. administered 50 mg/kg IV CBD to four piglets to evaluate drug safety and potential neuroprotective effects. CBD significantly reduced brain-derived neurotrophic factor (BDNF) expression and other signaling proteins in the hippocampus and frontal cortex with no effect in the striatum. It was concluded that CBD did not provide neuroprotection during early global hypoxia-ischemia [63]. In 1981, Rosenkrantz and Hayden investigated acute cannabinoid toxicity in rhesus monkeys following 150, 200, 225, 250, or 300 mg/kg intravenous (IV) CBD for 9 days [61]. Tremors were observed at all doses and CNS inhibition (depression, sedation, and prostration) was evident within 30 min.
- The highest densities are found in the frontal cerebral cortex (higher functioning), hippocampus (memory, cognition), basal ganglion and cerebellum (movement), and striatum (brain reward).
- Even if the targets, to which CBD binds, are the same in both studied animals and humans, for example, the affinity or duration of CBD binding to its targets might differ and consequently alter its effects.
- 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.
- Of the 953 remaining records, 707 were removed as they included preclinical studies, inappropriate study design/population, and THC co-administration.
- Duration of toxicity secondary to inhalation and ingestion lasts approximately 2 to 6 hours and 8 to 12 hours, respectively.
Data extraction
- Furthermore, the disruption of mitochondrial membrane potential (MMP), and ROS production were reduced.
- Given the recent approval of CBD by the FDA and EMA for childhood epilepsy syndromes, and the wide range of other indications for which it is being marketed, a quantitative assessment of its safety and tolerability is timely.
- The authors thank Michal Carus, Executive Director of the EIHA, for making this review possible, for his encouragement, and helpful hints.
- If there was no extracellular Ca2+, CBD-induced cell death was reduced at 1 µM by 50.4%±18%.
- 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].
