The present paper is an updated systematic review of the adverse effects of orally administered purified cannabidiol for different clinical conditions published in the last three years. The previous review [8] reported data from 18 RCTs published between 1980 and early 2020, involving 1127 subjects from clinical samples and healthy volunteers, with daily CBD treatment at doses ranging from 20 to 1500 mg/day and a duration ranging from one to 18 weeks. The results showed that CBD had mild and moderate adverse effects in most studies, the most common being drowsiness, sedation, fatigue, dizziness, headache, diarrhea, nausea, decreased appetite, and abdominal discomfort. Regarding SAEs, the highest incidence was reported in RCTs on epilepsy. Some of the most relevant effects were severe drowsiness, lethargy, hypertransaminasemia, rash, and pneumonia with or without respiratory failure. In the present review, we identified 12 trials with a total of 745 participants. In most studies, CBD showed mild and moderate adverse effects. The most common adverse effects were gastrointestinal symptoms (59.5%), which are probably related to the endocannabinoid system’s role in regulating gastrointestinal motility [22] and or by the product formulations (drug vehicle); other common AEs were somnolence (16.7%), loss of appetite (16.5%), increased ALT/AST (12.8%), and fatigue (11.4%). Although CBD was associated with a probability of SAEs, these events only occurred in epilepsy studies that used CBD as an add-on anticonvulsant treatment. SAEs with an incidence ≥1% were hypertransaminasemia (6.4%), seizures (1.3%), and rash (1.1%). Statistical analysis revealed a significant effect of CBD treatment for the increase in gastrointestinal symptoms, ALT/AST, rash, as well as change in appetite (both increasing and decreasing). In contrast, there was statistical significance for fever, with fewer cases for subjects who used CBD in the trials, possibly reflecting its anti-inflammatory effects. With the increase in the use of CBD in several countries and several RCTs being carried out, the strengths of our study included updating the evaluation of the most recent published studies and assessing their methodological qualities, resulting in a trend towards a low level of bias between the RCTs included. However, our analysis and conclusions are limited by the small sample size of the RCTs and the absence of studies with low doses of purified CBD.

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, 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]. These hepatic enzymes are also involved in the metabolism of several other drugs, including the anticonvulsants clobazam and valproate. CBD has been reported to inhibit CYP2C19 at doses as low as 5 mg/kg [26]. CYP2C19 inhibition increases the levels of N-desmethylclobazam, the main active metabolite in clobazam [26], and has the potential to interact with a broad range of other generally prescribed medications. The clinical impact of these interactions, particularly at the usual therapeutic doses of CBD, must be carefully investigated. Hypertransaminasemia has also been reported after CBD’s clinical use. Even if most cases occurred in epileptic patients using valproate, increases in hepatic transaminases were reported in open-label studies employing 300 mg/day CBD as a single medication [27]. The precise mechanism of valproate-CBD interaction is not fully understood. The co-administration of CBD and valproate does not significantly alter their plasma levels or metabolites [28]. However, 7-COOH-CBD, valproate and its metabolite 4-ene-valproic acid may affect hepatic mitochondrial function [26].

As SAEs, in addition to hypertransaminasemia, seizures and rash have also been reported, resulting in treatment discontinuation. The three studies reporting severe seizures were in the context of patients diagnosed with epilepsy, and it is not simple to differentiate the worsening of the baseline pathology (epilepsy) from an adverse effect of the treatment. Rash is one of the most common adverse drug reactions. It can present in a variety of ways, from mild rashes to extensive lesions with epidermal detachment associated with severe systemic involvement, as seen, for example, in Stevens-Johnson syndrome and toxic epidermal necrolysis. However, the rash is very non-specific and can often be found in other conditions, such as viral infections; in isolated CBD oil, the rash may be related to the medication vehicle, for example. Thus, rash diagnosis secondary to medication requires extensive laboratory investigation and histopathological confirmation. A case series [29] from an open-label clinical trial [30] involving CBD and rash were reported in four participants who were not using other medications. An extensive laboratory investigation, including histopathological analysis, was performed, in addition to re-exposure to the medication vehicle only, showing no new reactions, suggesting that the skin reactions were related to CBD.

While numerous countries have a growing demand for legal cannabidiol use to treat various mental and physical health problems, determining the best regulatory response to these requests is a substantial challenge. CBD products can come in a variety of formulations (e.g., purified CBD, CBD:THC ratios, CBD enriched products), routes of administration (e.g., oral [oil, tablets, capsules], sublingual spray, inhaled, topical) [2], and many are prepared without adequate manufacturing quality control, pharmaceutical grade production and labeling. There is a common perception that CBD is a “natural medicine”, even though its derivatives are commonly extracted from cannabis and synthetically modified. Furthermore, to date, there needs to be more robust data to support the indications of its therapeutic use for many of these conditions required by global demand. In some countries, CBD is marketed as a supplement, food, or pet product, which becomes a problem as no robust regulatory standards are required. Recently, the Science Advisory Committee of Health Canada reported some recommendations on Health Products Containing Cannabis—products containing cannabidiol can be purchased without needing a prescription from a medical professional, similar to other over-the-counter products [31]; At the same time, the European Food Safety Authority made a statement on the safety of cannabidiol as a novel food and, considering the significant uncertainties and data gaps, concluded that the safety of CBD as a novel food cannot currently be established [32].

With the increase in demand for the medicinal use of CBD, new high-quality studies are essential, with dose variations, particularly smaller doses, contemplating real-world studies with larger samples, and reporting adverse events, to better assess the effectiveness, safety, and tolerability of CBD. The clinical use of CBD must be aligned with many other pharmaceutical products, ensuring its effectiveness and safety for patients, and informing them of its potential adverse effects and interactions with other drugs. As new research emerges, it may become evident that there is a range of CBD doses at which clinically relevant adverse effects and drug interactions are likely to occur [23]. Therefore, as quality data is built, it is urgently necessary to inform and protect consumers, ensuring the quality and safety of CBD products.