What is the effect of combining cannabis with benzodiazepines (BZDs), such as alprazolam (Xanax) or diazepam (Valium)?

Effects of Combining Cannabis with Benzodiazepines

Combining cannabis with benzodiazepines significantly increases the risk of respiratory depression, sedation, cognitive impairment, and potentially fatal adverse events, and should be avoided due to these serious safety concerns. 1

Pharmacological Mechanisms of Interaction

The interaction between cannabis and benzodiazepines occurs through multiple mechanisms:

1. Pharmacodynamic interactions:

   • Both substances have CNS depressant effects that synergistically enhance sedation
   • Combined use increases risk of respiratory depression 2
   • Benzodiazepines enhance GABA activity while cannabis affects cannabinoid receptors, creating compounded sedative effects 2

2. Pharmacokinetic interactions:

   • CBD (cannabidiol) inhibits CYP3A4 and CYP2D6 enzymes that metabolize many benzodiazepines 1
   • This inhibition can lead to increased blood levels and prolonged effects of benzodiazepines 2

Clinical Consequences

Respiratory Effects

• When benzodiazepines and other CNS depressants are used together, respiratory depression risk increases dramatically
• Studies show that while benzodiazepines alone caused minimal respiratory depression, when combined with other substances, hypoxemia occurred in up to 92% of subjects and apnea in 50% 2

Cognitive and Functional Impairment

• Increased risk of:
  • Confusion and disorientation
  • Impaired judgment and decision-making
  • Dizziness and falls (particularly concerning in older adults)
  • Driving impairment 1

Psychiatric Effects

• Potential worsening of anxiety and depression
• Increased risk of paradoxical reactions (agitation instead of sedation)
• Possible interference with therapeutic effects of benzodiazepines 1

Specific High-Risk Scenarios

1. Emergency Department Setting:

   • Guidelines strongly caution against co-prescribing benzodiazepines with other CNS depressants 2
   • Mortality rates are 3-10 times higher when benzodiazepines are combined with other CNS depressants compared to benzodiazepines alone 2

2. Procedural Sedation:

   • When benzodiazepines like midazolam are used with other substances, risk of respiratory events increases significantly 2
   • Careful monitoring is essential if these combinations cannot be avoided 2

3. Chronic Pain Management:

   • Despite some patients using cannabis to reduce benzodiazepine use 3, the combination presents significant risks
   • The risk-benefit ratio must be carefully considered, especially in non-palliative settings 4

Monitoring and Risk Mitigation

If a patient is using both substances despite recommendations against it:

1. Clinical Monitoring:

   • Monitor for signs of excessive sedation, confusion, and respiratory depression
   • Check liver function tests, as CBD can cause liver enzyme elevations, particularly at doses >300 mg/day 1

2. Dosage Considerations:

   • Lower benzodiazepine doses may be necessary
   • Consider benzodiazepines with medium duration of action (temazepam, loprazolam) rather than potent short-acting ones (triazolam) if benzodiazepine therapy is necessary 5

3. Patient Education:

   • Warn about additive sedative effects
   • Emphasize risks of driving or operating machinery
   • Advise against alcohol consumption, which would further increase CNS depression

Conclusion

The combination of cannabis and benzodiazepines presents significant risks with limited therapeutic benefit. The synergistic CNS depressant effects can lead to dangerous respiratory depression, cognitive impairment, and increased mortality risk. Healthcare providers should strongly discourage this combination and consider alternative therapies when possible.