CBD, side effects, and toxicity

by Duncan Fisher

October 25, 2022 - 3 min read

It’s not for no reason that CBD (cannabidiol) and other cannabinoids are showing themselves to be potent agents for pharmaceutical development. The mammalian system of cannabinoid and G protein-coupled receptors, transient receptor potential cation channels, and nuclear peroxisome proliferator-activated receptors makes humans very sensitive to these compounds. We manufacture endocannabinoid ligands of our own, like anandamide, 2-arachidonylglycerol, N-palmitoyl ethanolamide, and N-oleoyl ethanolamide, all of which perform important functions in our physiology. CBD, or 2-[(6R)-6-isopropenyl-3-methyl-2-cyclohexen-1-yl]-5-pentyl-1,3-benzene-diol, modulates an array of central nervous system receptors, including CB1, CB2, serotonin 1A, TRPV1, and PPARγ. It may antagonize CB1 receptor function by negative allosteric modulation, and it may be an inverse agonist at the CB2 receptor, which, supported by CBD PPARɤ activation, could help explain its anti-inflammatory properties. High CBD doses activate TRPV1 receptors and elicit anxiolytic effects, too. And CBD increases serotoninergic and glutamatergic transmission, by positive allosteric regulation of 5-HT1A serotonin receptors. This same receptor activation is also involved in neuroprotection. CBD is metabolized in the liver and intestine by cytochrome P450 (CYP) CYP2C19 and CYP3A4, and 5'-diphosphoglucuronosyltransferase (UGT) UGT1A7, UGT1A9, and UGT2B7 isoforms, where it probably functions indirectly in sedation, and also interacts pharmacokinetically with THC. CBD’s pharmacology is complex, in other words. This implies enormous therapeutic potential, and we have written in detail in other blog posts about where. But it also suggests the likelihood of side effects, and of interactions with other drugs.

Not surprisingly, at large doses, there have been problems.CBD turns out not to be risk-free. In animal studies, adverse events have included developmental toxicity, embryo-fetal mortality, neurotoxicity, liver injuries, organ weight changes, male reproductive system alterations, and hypotension. All of these, it should be emphasized, occurred at doses several times higher than recommended for human pharmacotherapies. In human CBD studies for epilepsy and psychiatric disorders, at lower doses, there have been reported some drug-drug interactions, however, and hepatic abnormalities, diarrhea, fatigue, vomiting, and somnolence. In the clinical trials to date, however, at suitable dosing, very few of these have occurred.It is clear that dose, and also route, and frequency of administration, matter. 

CBD is often added to other medications, especially other anti-epileptics. In vitro and in vivo data suggests that CBD interacts with most with drugs metabolized by the liver, specifically with CYP1A2 substrates (theophylline, caffeine), CYP2B6 substrates (bupropion, efavirenz), UGT1A9 (diflunisal, propofol, fenofibrate), UGT2B7 (gemfibrozil, lamotrigine, morphine, lorazepam). Clinically significant interactions with CYP2C8 and CYP2C9 (phenytoin) substrates have occurred when CBD is co-administered with Epidiolex® for epileptic seizure control. 

In humans receiving CBD for epilepsies and for psychiatric disorders, the most common adverse events have been fatigue, diarrhea, nausea, and hepatotoxicity. Overall, the incidence of these has been low, however. Compared with other drugs indicated for these syndromes, moreover, CBD has a better side effect profile.

Length of treatment matters in all this. Data on adverse events is still fairly limited after chronic CBD administration. Large-scale research following long-term exposure is lacking on genotoxicity and cytotoxicity, hormonal alterations, and immune system changes in particular. Two common adverse events after long-term CBD treatment are somnolence and sedation. These are dose-related, and potentiated by co-administration of anti-epileptic drugs, and other CNS depressants, including alcohol. 

Research also still needs to evaluate the wide variability in CBD formulations. These range through tablets, oromucosal spray, oral capsules, vaporized cannabis plant material, powder in oil, and CBD-THC products. The exact effects of this variability on bioavailability is not yet known. 

DiolPure products contain PureForm CBD™ transformed from aromatic terpenes for pharmaceutical-grade purity. PureForm CBD™ is bioidentical to CBD extracted from hemp and cannabis, but free of any residual cannabinoids like THC or impurities or chemicals that can associate with traditional plant-derived production processes. 

The foregoing is a report on trends and developments in cannabinoid industry research. No product description herein is intended as a recommendation for diagnosis, treatment, cure or prevention of any disease or syndrome. 

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