Cannabis and Medications: Important Drug Interactions

The combination of cannabis with other medications is a topic of growing importance. With the increasing adoption of medical cannabis, the number of patients taking cannabinoids alongside their existing medication is also rising. This article provides a comprehensive overview of the most important interactions, the underlying mechanisms, and practical recommendations for patients and physicians.

## Fundamentals: Pharmacokinetic Interactions

Most clinically relevant interactions between cannabis and other medications are based on pharmacokinetic interactions – that is, they affect the absorption, distribution, metabolism, or excretion of the substances involved.

### The CYP450 Enzyme System

The cytochrome P450 system (CYP450) is a family of enzymes in the liver responsible for the majority of drug metabolism. Both THC and CBD are metabolized via CYP450 enzymes and can simultaneously inhibit or induce certain CYP450 enzymes.

**THC** is primarily metabolized via CYP2C9, CYP2C19, and CYP3A4. THC is a mild inhibitor of CYP1A2 and CYP3A4. The clinical relevance of THC-mediated enzyme inhibition is generally moderate, as the inhibition constants (Ki values) are in the higher micromolar range.

**CBD** is a considerably more potent enzyme inhibitor than THC. CBD inhibits CYP2C19, CYP2D6, CYP2C9, and CYP3A4 at clinically relevant concentrations. This makes CBD the "more problematic" cannabinoid regarding drug interactions. Particularly relevant is CYP2C19 inhibition, as this enzyme metabolizes numerous commonly prescribed medications, including clopidogrel, proton pump inhibitors, and certain antidepressants.

### P-Glycoprotein and Other Transporters

Beyond the CYP450 system, cannabinoids also affect drug transporters. CBD inhibits P-glycoprotein (P-gp), an efflux transporter that pumps drugs out of cells. Inhibition of P-gp can increase the bioavailability of P-gp substrates. Affected drugs include digoxin, fexofenadine, and various HIV medications. BCRP (Breast Cancer Resistance Protein) is also inhibited by CBD, which can increase plasma levels of substrates such as rosuvastatin and methotrexate.

### Pharmacodynamic Interactions

In addition to pharmacokinetic interactions, pharmacodynamic interactions exist where cannabis and another medication act at the same target site or on the same physiological process. Typical examples include additive sedation (with benzodiazepines, opioids, antihistamines), additive blood pressure reduction (with antihypertensives), additive anticholinergic effects (with tricyclic antidepressants), and additive heart rate increase (with stimulants).

## Blood Thinners (Anticoagulants)

The interaction between cannabis and blood thinners is among the most clinically significant and potentially dangerous.

### Warfarin and Phenprocoumon

Warfarin (international) and phenprocoumon (more common in Germany as Marcumar) are metabolized via CYP2C9 and CYP3A4. CBD significantly inhibits CYP2C9, slowing the breakdown of these anticoagulants. The consequence: increased plasma levels of the blood thinner, prolonged INR (International Normalized Ratio), and increased bleeding risk. Case reports document INR increases from therapeutic (2.0–3.0) to dangerously high values (above 8.0) after initiation of CBD therapy.

**Practical Recommendation:** In patients on warfarin or phenprocoumon who begin cannabis therapy, INR should be monitored closely – initially twice weekly for the first four weeks. The anticoagulant dose may need to be reduced. Starting with low CBD doses and slow titration is essential.

### DOACs (Direct Oral Anticoagulants)

Newer direct oral anticoagulants (rivaroxaban, apixaban, edoxaban, dabigatran) are also subject to potential interactions. Rivaroxaban and apixaban are metabolized via CYP3A4 and are P-gp substrates – both affected by CBD. Dabigatran is a pure P-gp substrate and may show elevated plasma levels through CBD-mediated P-gp inhibition. The clinical relevance is less well documented than with warfarin, but caution is warranted.

## Antidepressants

Antidepressants are among the most commonly prescribed medications, and many patients combine them with cannabis.

### SSRIs (Selective Serotonin Reuptake Inhibitors)

The most common SSRIs – sertraline, fluoxetine, citalopram, escitalopram, paroxetine – are metabolized via various CYP450 enzymes. Citalopram and escitalopram are primarily metabolized via CYP2C19 – CBD can increase their plasma levels through CYP2C19 inhibition. Sertraline is metabolized via CYP2C19 and CYP2D6 – here too, CBD can raise levels. Fluoxetine is itself a strong CYP2D6 inhibitor and is metabolized via CYP2C9 – the combination with CBD can lead to dual enzyme inhibition. Clinically, increased SSRI levels can lead to enhanced side effects: nausea, dizziness, sexual dysfunction, and in rare cases, serotonin syndrome.

**Practical Recommendation:** Combining cannabis (especially CBD) with SSRIs requires attentive monitoring. SSRI dose may need adjustment. Serotonin syndrome is rare, but symptoms such as agitation, myoclonus, hyperthermia, and diarrhea should be evaluated immediately.

### Tricyclic Antidepressants (TCAs)

Amitriptyline, nortriptyline, and other TCAs are metabolized via CYP2D6 and CYP2C19. CBD can increase TCA levels. Additionally, pharmacodynamic interactions exist: both TCAs and THC have anticholinergic properties (dry mouth, constipation, urinary retention, tachycardia) and sedating effects. The combination can amplify these effects.

### MAO Inhibitors

Combining cannabis with MAO inhibitors (tranylcypromine, moclobemide) requires particular caution. MAO inhibitors affect serotonin and norepinephrine metabolism. Although direct interactions with cannabinoids are not well documented, the theoretical risk of hypertensive crisis or serotonin syndrome is elevated.

### SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors)

Venlafaxine is metabolized via CYP2D6 to its active metabolite O-desmethylvenlafaxine. CBD-mediated CYP2D6 inhibition can shift the ratio of venlafaxine to its metabolite. Duloxetine is metabolized via CYP1A2 and CYP2D6 – interactions are also possible here.

## Benzodiazepines

The combination of cannabis with benzodiazepines is common and clinically relevant.

### Pharmacokinetic Interactions

Diazepam is metabolized via CYP2C19 and CYP3A4 – CBD can slow its breakdown. Midazolam and alprazolam are CYP3A4 substrates – their metabolism can be inhibited by CBD. Lorazepam is primarily glucuronidated and therefore less affected by CYP450 interactions.

### Pharmacodynamic Interactions

The pharmacodynamic interaction is often clinically more significant: both cannabinoids (especially THC) and benzodiazepines are sedating, muscle-relaxing, and anxiolytic. The combination leads to additive or even synergistic sedation with increased risk of excessive sedation, cognitive impairment, fall risk (especially in elderly patients), slowed reaction time, and in extreme cases respiratory depression (although the risk is lower than with opioid-benzodiazepine combinations).

**Practical Recommendation:** The combination should be avoided if possible or dosed very conservatively. Cannabis may offer a long-term alternative to benzodiazepines for anxiety disorders and in some cases enables benzodiazepine tapering.

## Opioids

The combination of cannabis and opioids is a particularly active area of research.

### Opioid-Sparing Effect

Several studies show that concurrent cannabis use can reduce opioid requirements by 30–60 percent. A US registry study found that in states with legal medical cannabis, opioid prescription rates were significantly lower. Preclinical data demonstrate synergistic analgesic effects through interaction between the opioid and endocannabinoid systems.

### Risks of Combination

Additive sedation is the primary risk. Although cannabis alone carries virtually no respiratory depression risk (there are no CB1 receptors in the respiratory center), the combination of THC-induced sedation with opioid-mediated respiratory depression can worsen the overall situation. Particular caution is required during the adjustment phase.

### Pharmacokinetic Aspects

Most opioids (morphine, oxycodone, hydromorphone, tramadol) are metabolized via CYP enzymes influenced by cannabinoids. Oxycodone is metabolized via CYP3A4 and CYP2D6 – CBD can increase plasma levels. Tramadol is metabolized via CYP2D6 to its active metabolite O-desmethyltramadol – CBD can inhibit this activation and reduce tramadol's analgesic effect. Morphine is primarily glucuronidated and therefore less affected by CYP450 interactions.

## Antiepileptics

Interactions between cannabinoids and antiepileptics are particularly well researched, as CBD (as Epidiolex) is itself approved as an antiepileptic.

### Clobazam

The interaction between CBD and clobazam is the best-documented cannabis-drug interaction of all. CBD inhibits CYP2C19, which metabolizes clobazam to its active metabolite norclobazam. The result: norclobazam levels can increase three- to fivefold, leading to increased sedation, ataxia, and cognitive impairment. In clinical trials of Epidiolex, dose reduction of clobazam during concurrent CBD use was the rule, not the exception.

### Valproic Acid

The combination of CBD with valproic acid (valproate) requires particular attention to liver function. Case reports and clinical studies show an increased risk of liver transaminase elevations (ALT, AST) with concurrent CBD-valproate use. The mechanism is not fully understood but may relate to additive hepatotoxic burden. Regular liver function monitoring is mandatory with this combination.

### Other Antiepileptics

Phenytoin is metabolized via CYP2C9 and CYP2C19 – CBD can raise levels. Carbamazepine is a CYP3A4 inducer that can accelerate CBD metabolism and reduce CBD efficacy. Levetiracetam is not metabolized via CYP enzymes and therefore has no known pharmacokinetic interactions with cannabinoids.

## Blood Pressure Medications

### Calcium Channel Blockers

Amlodipine and other calcium channel blockers are metabolized via CYP3A4. CBD can increase their plasma levels, leading to enhanced blood pressure reduction, peripheral edema, and dizziness. THC itself has short-term blood pressure-lowering properties (through vasodilation), which can amplify the hypotensive effect.

### ACE Inhibitors and ARBs

For ACE inhibitors (ramipril, enalapril) and ARBs (candesartan, valsartan), no clinically relevant pharmacokinetic interactions with cannabinoids are known. Pharmacodynamically, however, THC can cause additive hypotension, especially during orthostatic maneuvers (standing up from sitting or lying).

### Beta-Blockers

Metoprolol is metabolized via CYP2D6 – CBD can increase plasma levels. The combination may cause additive bradycardia. Propranolol is also a CYP2D6 substrate with similar interaction potential.

## Immunosuppressants

Patients after organ transplantation or with autoimmune diseases who take immunosuppressants represent a particularly vulnerable group.

### Calcineurin Inhibitors

Ciclosporin and tacrolimus are metabolized via CYP3A4 and are P-gp substrates. CBD can significantly increase plasma levels of both medications, potentially leading to nephrotoxicity and other severe side effects. Concurrent use requires close therapeutic drug monitoring and frequently necessitates dose adjustment of the immunosuppressant.

### mTOR Inhibitors

Sirolimus (rapamycin) and everolimus are also metabolized via CYP3A4. Potential interactions with CBD are comparable to those of calcineurin inhibitors. The therapeutic window of these medications is narrow, meaning even small level changes can be clinically relevant.

## Alcohol

Although alcohol is not a medication in the strict sense, its combination with cannabis deserves special attention.

### Pharmacokinetic Effects

Alcohol increases THC bioavailability. Studies show that concurrent alcohol intake can significantly raise THC plasma levels – by up to 50–100 percent. This is because alcohol accelerates gastric emptying and improves intestinal absorption of THC.

### Pharmacodynamic Effects

The combination of cannabis and alcohol produces additive to supra-additive effects on sedation and cognitive impairment, psychomotor function and reaction time, driving fitness, and nausea and vomiting. The order of consumption influences the effect: cannabis before alcohol may reduce alcohol intake (some studies show slower alcohol consumption), while alcohol before cannabis intensifies the THC effect.

## Practical Guidance for Patients and Physicians

### General Principles

**For Physicians:** Always review the current medication list before prescribing cannabis. CBD-heavy preparations require more attention regarding CYP450 interactions than THC-dominant ones. Close monitoring during the adjustment phase is essential. For high-risk combinations (anticoagulants, immunosuppressants, antiepileptics), plasma levels of co-medications should be monitored regularly.

**For Patients:** Report all medications taken (including dietary supplements) to the treating physician. Report new symptoms (unusual fatigue, dizziness, bleeding, skin changes) immediately. Do not independently alter cannabis dose while taking other medications. Exercise particular caution when combining with sedating medications – no driving.

### Risk Stratification

High risk and contraindicated without close monitoring: warfarin and phenprocoumon plus CBD, clobazam plus CBD, tacrolimus or ciclosporin plus CBD, MAO inhibitors plus THC. Medium risk with monitoring recommended: SSRIs plus CBD (level monitoring), oxycodone plus CBD (sedation monitoring), metoprolol plus CBD (pulse and blood pressure monitoring), valproic acid plus CBD (liver values). Low risk but awareness required: NSAIDs plus cannabis (consider gastroprotection), acetaminophen plus cannabis (hepatotoxicity risk at high doses), metformin plus cannabis (blood glucose monitoring), levetiracetam plus cannabis (no known pharmacokinetic interactions).

### Interaction Checking Tools

Several resources are available for clinical practice: the Penn State College of Medicine CBD Drug Interaction Table, the Flockhart CYP450 Drug Interaction Table, and the electronic interaction database of the ABDA (Federal Union of German Associations of Pharmacists).

## Summary

Drug interactions with cannabis are real, clinically relevant, and in many cases manageable. CBD is the "more interactive" cannabinoid due to its stronger CYP450 inhibition. The most important high-risk combinations involve anticoagulants, certain antiepileptics, and immunosuppressants. Systematic interaction screening before initiating cannabis therapy, close monitoring during the adjustment phase, and informed communication between physician, pharmacist, and patient are the keys to safe use.