Medicinal cannabis drug interactions

Medicinal cannabis is not a simple herbal remedy. The two main cannabinoids, CBD (cannabidiol) and THC (delta-9-tetrahydrocannabinol), are active pharmaceutical ingredients that can change how other medicines work. In New Zealand, medicinal cannabis products are regulated by Medsafe under the Medicinal Cannabis Scheme, and every prescription should be checked against a patient’s full medicine list.

Why CBD and THC alter other medicines

Both CBD and THC are metabolised by enzymes in the liver, primarily the cytochrome P450 family. The most important is CYP3A4, which breaks down a large share of prescribed medicines. The NZ Formulary and Medsafe guidance describe CBD as a moderate inhibitor of CYP3A4 and CYP2C19. In plain terms, CBD can slow the breakdown of certain drugs, raising their blood levels. THC is also metabolised by CYP2C9 and CYP3A4, so it can compete with other drugs that use those same enzymes. The outcome is not always predictable; it depends on the medicine, the dose, the route (oil vs inhaled), and the person’s liver enzyme profile.

Inhibition means the enzyme is blocked, so the other drug stays in the body longer and its levels rise. Induction means the enzyme is stimulated, so the other drug is broken down faster and its levels fall. Both can matter. CBD is the more significant inhibitor of CYP enzymes, particularly CYP3A4 and CYP2C19, while THC is mainly a substrate (it is broken down by those enzymes) and can inhibit some of them at high doses. This is why adding medicinal cannabis can change the effect of other medicines that rely on the same liver enzymes.

Drug classes that need extra monitoring

• Benzodiazepines (e.g., diazepam, clonazepam): additive sedation, increased fall risk.
• Opioids (e.g., morphine, oxycodone): additive sedation; some case reports suggest CBD may increase opioid levels, but evidence is mixed.
• Antidepressants (e.g., SSRIs, SNRIs, tricyclics): possible serotonin syndrome, especially with high THC; monitor for agitation, sweating, tremor.
• Antiepileptics (e.g., clobazam, valproate): CBD can increase clobazam’s active metabolite, leading to sedation; dose adjustments may be needed.
• Warfarin and other anticoagulants: CBD can raise INR, increasing bleeding risk; monitor closely.
• CYP450 inhibitors/inducers (e.g., ketoconazole, rifampicin): can change THC/CBD levels; dose adjustment may be needed.
• Alcohol and sedatives: additive drowsiness, impaired coordination, increased fall risk in older adults.

How CBD and THC differ in the liver

CBD is generally considered the more problematic actor because it inhibits cytochrome P450 enzymes, especially CYP3A4 and CYP2C19. THC is a substrate of CYP2C9 and CYP3A4, so other drugs can raise or lower THC levels. In New Zealand, prescribers are directed to the NZ Formulary and Medsafe, and the Medicinal Cannabis Agency (MCA) sets the scheme’s product standards.

Drug interactions are a clinical topic; the strongest evidence comes from small pharmacokinetic studies and case reports, not large randomised trials. The profile is highly individual. The exact magnitude of a change in blood levels is not predictable for a given person from published data alone. In practice, the prescriber and pharmacist hold the patient’s full medicine list and are the only people who can assess the net effect.

Two interactions that demand immediate attention

The most important interaction to be aware of is with clobazam, an anti-seizure medicine used in refractory epilepsy. CBD can raise clobazam’s active metabolite (norclobazam) by inhibiting CYP2C19 and CYP3A4; this can increase sedation and requires monitoring, but the combination is also the one with the strongest clinical evidence. This is a classic example of a beneficial interaction that still needs dose adjustment and clinician oversight.

Another notable interaction is with warfarin: CBD can raise INR, increasing bleeding risk. This is because CBD inhibits CYP2C9, the enzyme that breaks down warfarin. Similarly, CBD can raise levels of certain anti-epileptics (clobazam, valproate), some benzodiazepines, and some antidepressants. THC is also metabolised by CYP enzymes and can compete with CYP1A2 and CYP2C9 substrates, but the evidence is less consistent than for CBD.

The highest-risk combination

The most dangerous combination is not with a prescription medicine but with alcohol or sedatives: combining THC with CNS depressants can cause profound sedation, respiratory depression, and falls, especially in older adults. Do not drink alcohol or take sedatives with THC unless your prescriber has explicitly approved it after reviewing your full medicine list.

What to tell your pharmacist and prescriber

In New Zealand, the legal framework is the Misuse of Drugs Act 1975, and the Medicinal Cannabis Scheme (MCS) was fully operational in 2020. Under the scheme, products must meet GMP standards and be approved by the Ministry of Health. The NZ Formulary lists the funded and monitored products.

Pharmacists should screen for competition with CYP3A4 and CYP2C19 substrates, as CBD inhibits these enzymes and can raise levels of clobazam, warfarin, and certain antidepressants. THC is primarily metabolised by CYP2C9 and CYP3A4. In New Zealand, clinicians use the NZ Formulary and Medsafe data to check for these effects; the Ministry of Health (2020) notes that the evidence base for cannabis interactions is limited and mostly from case reports and small studies. The prescriber must assess the risk.

Known enzyme-substrate pairs to flag

• CYP3A4 substrates: midazolam, some statins, some azole antifungals
• CYP2C19 substrates: omeprazole, diazepam
• CYP2D6 substrates: some antidepressants, antipsychotics

THC is primarily metabolised by CYP2C9 and CYP3A4; CBD inhibits CYP2C19 and CYP3A4. Grapefruit juice has a similar inhibition profile to CBD (inhibits CYP3A4 and CYP2C9), so label warnings about grapefruit can be a useful starting point for patients. Most interactions are mild to moderate, but severe outcomes are possible with warfarin, clobazam, and some immunosuppressants. Clinically significant events are rare but can be severe. Always check the NZ Formulary for the latest guidance.

When risk is highest and how to manage it

Interaction risk is highest at the start of treatment and during dose changes. Prescribers and pharmacists should ask about all medicines, including over-the-counter and herbal products. Patients should not stop or change any prescribed medicine without talking to their clinician. If you take medicines that could compete, ask about monitoring and dose adjustment. The risk is not zero, but for most patients, the benefits can outweigh the risks if managed properly.

The one fact that sets medicinal cannabis apart from most other prescribed products is this: a single plant-derived preparation contains two active ingredients, CBD and THC, that simultaneously inhibit and compete for the same liver enzymes that process a large share of everyday medicines, making the net effect on any individual patient impossible to predict without monitoring.