Medical Cannabis Adverse Effects and Drug Interactions

Overview

Cannabis-based medicines are generally well tolerated at therapeutic doses but have a clinically significant adverse effect profile and important drug interactions that prescribers and pharmacists must understand. This publication provides a systematic summary of the adverse effect profile, contraindications and drug interactions relevant to clinical practice.

1. Adverse Effect Profile — Overview

The adverse effect profile of cannabis-based medicines varies significantly depending on the cannabinoid composition, dose, route of administration and patient characteristics. THC-containing products carry a substantially different adverse effect burden than CBD-only products.

2. THC-Related Adverse Effects

Acute psychoactive effects

The psychoactive effects of THC are dose-dependent and represent both the primary therapeutic mechanism (in pain, spasticity, nausea) and the most common adverse effects:

• Euphoria/intoxication: Particularly in cannabis-naive patients; may be experienced as pleasant or adverse
• Dizziness and postural hypotension: Common on initiation; risk of falls in elderly patients
• Cognitive impairment: Impaired working memory, attention and executive function; dose-dependent and typically transient but may persist with chronic use
• Sedation: Variable; may be therapeutically useful (sleep) or adverse (daytime functioning)
• Tachycardia: Dose-dependent; relevant in patients with cardiac comorbidities

Psychiatric adverse effects

The most significant psychiatric adverse effects of THC:

• Anxiety and paranoia: Common, particularly at higher doses and in anxious patients; may limit tolerable dose
• Acute psychosis: Rare at therapeutic doses but may occur in susceptible individuals; dose-dependent risk
• Cannabis use disorder: Psychological and physiological dependence can develop with chronic use; estimated prevalence approximately 9% of all users; higher with daily use and early-onset use
• Amotivational syndrome: Proposed association with chronic heavy use; clinical relevance at therapeutic doses unclear

Respiratory effects (inhalation route)

Smoked cannabis is associated with respiratory harm (bronchitis, COPD). Vaporised cannabis has a substantially better respiratory safety profile than smoked cannabis but is not without risk. The oral/oromucosal route avoids respiratory exposure entirely and is the preferred route for most clinical applications.

3. CBD-Related Adverse Effects

CBD has a favourable adverse effect profile compared to THC. Common adverse effects at therapeutic doses:

• Gastrointestinal: Diarrhoea, nausea, reduced appetite — most common adverse effects in Epidiolex trials; dose-related
• Fatigue and somnolence: Common; may be additive with other CNS depressants
• Elevated liver enzymes: Transaminase elevations observed in Epidiolex trials, typically asymptomatic and reversible; monitoring recommended, particularly with concomitant valproate
• Hepatotoxicity: Rare at therapeutic doses; risk increased with high doses and concomitant valproate

4. Contraindications

5. Drug Interactions

Cannabis-based medicines interact with multiple drug classes through pharmacokinetic (CYP enzyme) and pharmacodynamic mechanisms.

Pharmacokinetic interactions — CYP enzymes

Pharmacodynamic interactions

• CNS depressants (opioids, benzodiazepines, alcohol, other sedatives): additive sedation; caution required particularly in elderly patients and those driving
• Opioids: potential opioid-sparing effect (benefit); additive sedation and respiratory depression (risk)
• Anticoagulants (warfarin): multiple case reports of significantly elevated INR with cannabis use; CYP2C9 inhibition mechanism
• Antiepileptics: CBD interacts with multiple antiepileptic drugs through CYP and UGT inhibition; dose adjustments frequently required when initiating CBD in patients on antiepileptic regimens

6. Specific Monitoring Requirements

• Warfarin: Check INR within 1–2 weeks of initiating or changing cannabis-based medicine dose; more frequent monitoring until stable
• Immunosuppressants (tacrolimus, ciclosporin): Therapeutic drug monitoring at baseline and after initiation; levels may change significantly
• Clobazam: Monitor for increased sedation; dose adjustment of clobazam may be needed
• Valproate + CBD: Monitor liver function tests before and during treatment; avoid combination in patients with pre-existing liver disease
• All THC-containing products: Assess driving ability before and after dose changes; advise on legal requirements for drug-impaired driving

7. Reporting Adverse Effects

Healthcare professionals are encouraged to report adverse effects from cannabis-based medicines to national pharmacovigilance systems (Yellow Card in UK, EudraVigilance in EU member states). The adverse effect database for cannabis-based medicines remains limited compared to conventional pharmaceuticals — pharmacovigilance reporting contributes to building the evidence base that will inform future prescribing guidance.

8. References

• Brown JD, Winterstein AG. Potential Adverse Drug Events and Drug–Drug Interactions with Medical and Consumer Cannabidiol (CBD) Use. J Clin Med. 2019.
• Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev. 2014.
• Zendulka O et al. Cannabinoids and Cytochrome P450 Interactions. Curr Drug Metab. 2016.
• Gaston TE et al. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia. 2017.
• European Medicines Agency. Epidiolex Summary of Product Characteristics (Section 4.5 — Interaction with other medicinal products).
• GW Pharmaceuticals. Sativex Summary of Product Characteristics (Section 4.5).
• MHRA. Interactions with Cannabidiol — Drug Safety Update. 2021.