Cannibidiol (CBD) properly handled has a very favorable safety profile. This is why, in small amounts, it is gaining gradual (if slow) regulatory acceptance around the world as a pharmaceutical agent, a cosmeceutical ingredient, and a nutritional supplement. But as CBD gains popularity, its potential for drug-drug interactions remains incomplete. And in higher doses, or in concomitant treatment for certain medical syndromes, there is warrant for caution.
This is reasonable, given what is known about the basic mechanisms of action of CBD and other drugs. It is not impossible that some of them interfere with each other.
CBD metabolizes in the liver by CYP450 enzymes, several isoforms in particular. CBD appears able to inhibit some of these, or inactivate them in the short run, then induce them after repeat administration. In one subfamily of these enzymes, CBD metabolism mimics that of phenobarbitol. CBD is also metabolized via the CYP3A4 enzyme, and this is true of about 60% of other, clinically prescribed, medications as well, that include ketoconazole, itraconazole, ritonavir, and clarithromycin. Drugs that inhibit CYP3A4 could increase exposure to CBD unintentionally. CBD may also increase serum concentrations of cyclosporine, sildenafil, antihistamines, haloperidol, antiretrovirals, and some statins. Interaction of any of these drugs with CYP3A4 necessarily slows CBD degradation. Drugs that induce CYP3A4, on the other hand, like phenobarbital, rifampicin, carbamazepine, or phenytoin, could be expected to reduce CBD bioavailability. CBD even inhibits Breast Cancer Resistance Protein efflux in the placental cotyledon. This means that study needs to be done evaluating co-administration of CBD with known BCRP substrates like nitrofurantoin, cimetidine, and sulfasalazine.
There are many gaps in present knowledge of drug-drug interactions with CBD. But there is much that is known, particularly about anti-epileptics, antidepressants, THC, and alcohol.
CBD has known interactions with clobazam, stiripentol, and valproate. It inhibits CYP2C19 and CYP3A4, which catalyze the metabolism of N-desmethylclobazam (nCLB), for example, and leads to its accumulation. nCLP, an active metabolite of clobazam, is 20-100% more potent than clobazam itself. Recent studies have evaluated the impact of CBD on the steady-state pharmacokinetics of these three drugs, and their reciprocal effect on CBD’s safety and tolerability and its major metabolites. Co-administered, CBD had significant effect on nCLB exposure, though little or no effect on exposure to the three medications themselves, though it did, in a subsequent study, reduce serum levels of clobazam. Conversely, stiripentol decreased exposure to two CBD metabolites. Overall, except for common side effects like diarrhea and sedation, concomitant CBD was moderate. With valproate there was also an increase in elevations of aspartate aminotransferase and alanine aminotransferase. CBD has been shown to potentiate the anticonvulsant effects of phenytoin and phenobarbital. It also reduces the anticonvulsant properties of chlordiazepoxide, clonazepam, and ethosuximide. Gratifyingly, another study has suggested that CBD is effective in reducing seizure frequency and severity by itself, and is not affected by pharmacokinetic interactions with other anti-epileptics. The efficacy of these particular drugs can be modulated by CBD, in other words, but CBD’s anti-epileptic efficacy is unaffected by them. CBD does increase the activity of topiramate, oxcarbazepine, pregabalin, tiagabine, and gabapentin, but does not affect the anticonvulsant effect of lamotrigine and lacosamide. It does attenuate the activity of levetiracetam.
CBD inhibits the hepatic enzyme CYP2D6. This means that it would be reasonable to expect increases in serum concentrations of selective serotonin reuptake inhibitors, tricyclic antidepressants, antipsychotics, beta-blockers, and opioids. CBD can also alter metabolism of omeprazole and risperidone. It also interacts with monoamine oxidase inhibitors like tranylcypromine, phenelzine, and isocarboxazid, slowing their metabolism and clearance. Interestingly, CBD has been observed to produce beneficial synergy with sertraline, an SSRI, on an animal model of PTSD, and with desipramine, a noradrenergic antidepressant. Outright metabolic interference, at the level of cytochrome enzymes, which could increase adverse effects, exists with amitriptyline, gabapentin, pregabalin, citalopram, paroxetine, and mirtazapine.
CBD has divergent effects from opioids. Studies across different animal models have shown interactions to be varied, depending on the opioid. There is synergy with acetic acid, for example. But CBD has been shown to inhibit diamorphine metabolism. With fentanyl, CBD at least does not exacerbate adverse effects. The varying mechanisms of action that underlie CBD’s interactions, or non-interactions, with opioids are far from being understood.
Δ9 -tetrahydrocannabinol (THC)
Studies conflict on whether CBD attenuates or exacerbates the behavioral and cognitive effects of THC, but generally tend to suggest attenuation. In two pain studies, there has appeared to be synergy between the two. We have written extensively about these varied effects, and possible reasons for them, in other blog posts.
CBD and THC are both hepatically metabolized. It is here that the potential exists for pharmacokinetic drug interactions, through inhibition or induction of enzymes or transporters.
Other Pharmaceutical Drugs
There is concern, particularly in elderly patients, over possible pharmacodynamic interactions between CBD and central nervous system depressant drugs. With sympathomimetic agents there may be additive hypertension and tachycardia as well.
CBD may as well amplify the blood-thinning effect of warfarin, as one case study has suggested.
With the immunosuppressants cyclosporine and tacrolimus CBD has the potential to inhibit metabolism and increase serum concentration.
In concomitant use with CBD, dosing even of acetaminophen is judicious, to prevent liver injury.
Other drugs that may interact with CBD are the TRPV-1 antagonist, capsazepine, and, pharmacokinetically, rufinamide, zonisamide, and eslicarbazepine.
This is also true of corticosteroids, like hydrocortisone and prednisolone, both metabolized by the cytochrome P450 enzyme CYP3A, against which CBD is a potent inhibitor. For the same reason interactions are also possible with naproxen, tramadol, celecoxib, etoricoxib, fluoxetine, and tofacitinib.
CBD is an agonist of the 5-HT1A receptors. Possibly for this reason, it has shown to attenuate alcohol consumption and protect against liver and brain damage in chronic alcohol use as well. These protective effects have been demonstrated in numerous animal models. However, in one clinical study, CBD, administered with alcohol, produced significant impairments of motor and psychomotor performances, and distorted self-perception of the amount of alcohol consumed and the level of intoxication. Oddly, CBD has also been observed to lower blood alcohol levels. Much remains to be explored, but it is clear that the timing and dosage of CBD administration can influence alcohol pharmacokinetics.
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The foregoing is a report on trends and developments in the cannabinoid industry. No product described herein is intended to diagnose, treat, cure or prevent any disease or syndrome.
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