CBD Interactions with Other Drugs
CBD is a chemical entity which has caused several inadequately addressed issues facing the CBD industry, the most important of which is the presence of CBD-drug interactions.
Pharmacokinetic Interactions
Most drug-drug interactions are pharmacokinetic in nature. A pharmacokinetic interaction occurs when one drug alters the blood levels of another drug. Drug blood levels are largely correlated with their hepatic metabolization by the cytochrome P450 (CYP450) system of enzymes. When two drugs are metabolized by the same CYP enzyme, an interaction is likely to occur.
The CYP450 system is responsible for the biotransformation of approximately 85% of all ingested substances, including drugs. As with most proteins, a single substance can be both a substrate (the protein acts on the drug) and an inhibitor/inducer (the drug acts on the protein) of the CYP450 enzymes. We must be equally aware of these influences when considering CBD-drug interactions.
CBD and the CYP450 System
CBD is primarily involved with three CYP enzymes: CYP2C9, CYP2C19, and CYP3A4.
CBD is a substrate of CYP3A4 and CYP2C19, and cumulatively, they convert about 93% of ingested CBD to an inactive metabolite. However, CBD also acts as an inhibitor of these two enzymes, slowing their ability to metabolize their other substrates in addition to CBD.
While CBD is both substrate and inhibitor of 3A4 and 2C19, it also functions as an inhibitor of CYP2C9, even though it’s not a substrate of that enzyme. One of the most serious potential interactions occurs when CBD and warfarin are taken at the same time.
Because of these complex relationships with our bodies’ drug metabolization, only pharmacists should be counseling patients on CBD.
Pharmacodynamic Interactions
In addition to pharmacokinetic interactions, CBD is also has several pharmacodynamic interactions with certain classes of medications. A pharmacodynamic interaction occurs when the physiological effect of one drug alters the physiological effect of another drug. An example of this would be the additive effects of barbiturates and benzodiazepines, which share a biological target (the GABAα receptor) but have two distinct mechanisms of action at that target.
In almost all cases, this occurs when two drugs share the same target receptor..
CBD and TRPV
CBD is a partial agonist of the Transient Receptor Potential/Vanilloid Type 1 (TRPV1) receptor, so it can interact with other drugs that act on this receptor, like capsaicin or acetaminophen (through its active metabolite, AM-404)
When TRPV1 receptors are activated, they transmit a pain signal to the brain. The chemicals above, as well as temperatures above 109º Fahrenheit. However, they undergo rapid internalization ——> less receptors ——> less pain signals, even if the painful stimuli remains present. The effect of CBD at this receptor will be compounded in the presence of other drugs which also exert their action via the TRPV1 receptor.
CBD and 5-HT1a
CBD is also a partial agonist of serotonin 5-HT1a receptors. These are serotonin autoreceptors which are present in the amygdala and limbic system, and serve to reduce the likelihood of an action potential in neurons associated with fear and anxiety. These are the receptors ultimately targeted by SSRIs to inhibit the reuptake of serotonin at synapses.
By acting as an agonist of these receptors, CBD indirectly compounds the effects of SSRIs, without leading to serotonin toxicity because the levels of serotonin remain the same.
We will continuously update this article to reflect the latest research regarding CBD drug interactions.
References
[1] CBD affects CYPs 3A4, 3A5, and 3A7
[2] CBD + Clobazam = Increased plasma levels of both.
[3] CBD + stiripentol // CBD + valproate = No change in plasma levels of either
[4] CBD strong inhibitor of CYP2C19
[5] CBD has interactions with secondary metabolic proteins, glucuronidases, and transport proteins.
