Can Buspirone and Diazepam Be Combined?
Yes, buspirone and diazepam can be safely combined in typical adults without contraindications, as the FDA label explicitly states that coadministration causes no significant pharmacokinetic interactions and only minor clinical effects (dizziness, headache, nausea), with controlled studies demonstrating that buspirone does not intensify benzodiazepine sedation. 1
Pharmacokinetic Safety Profile
The combination has been extensively studied and shows favorable safety characteristics:
No significant drug-drug interaction exists at the pharmacokinetic level. After adding buspirone to diazepam regimens, steady-state parameters (Cmax, AUC, Cmin) for diazepam remain unchanged, though nordiazepam (active metabolite) increases by approximately 15% 1
Buspirone does not prolong or intensify benzodiazepine sedation. Studies with triazolam and flurazepam demonstrated that buspirone does not enhance the sedative effects of benzodiazepines 1
Psychomotor impairment from combination is less than diazepam alone. Research shows buspirone (10-20 mg) combined with diazepam (10 mg) causes only slight additive interactions, with the psychomotor side effect profile of buspirone being preferable to diazepam monotherapy 2
Clinical Effects of Combination Therapy
When these medications are combined, expect the following:
Minor additive side effects may occur, including dizziness, headache, and nausea, but these are typically mild and transient 1
Buspirone may actually counteract some diazepam effects. In objective testing, buspirone tended to reverse diazepam's impairment on divided attention and learning acquisition, though it prolonged subjective sedation 3
No additional psychomotor decrement occurs with small doses. Combining buspirone (15 mg) with diazepam does not cause clinically significant additional impairment in psychomotor performance beyond diazepam alone 3
Practical Dosing Algorithm
When combining these medications:
Start with standard doses: Diazepam 5-10 mg and buspirone 15 mg daily are appropriate initial doses for most adults 4, 1
Monitor for minor additive effects during the first week, particularly dizziness and headache 1
Adjust based on clinical response, recognizing that buspirone has gradual onset (unlike diazepam's immediate effects) and requires several days to weeks for full anxiolytic efficacy 5
Important Mechanistic Differences
Understanding why these drugs can be safely combined:
Different mechanisms of action: Diazepam enhances GABA activity at GABAA receptors, while buspirone acts primarily on serotonin 5-HT1A receptors with some dopaminergic effects 4, 6
Buspirone lacks benzodiazepine properties: It has no anticonvulsant or muscle-relaxant effects, causes minimal sedation, and does not potentiate alcohol like benzodiazepines do 6
No cross-tolerance or withdrawal concerns: Buspirone does not produce dependence, abuse potential, or withdrawal symptoms characteristic of benzodiazepines 5, 6
Critical Caveats to Avoid
Do not combine with MAO inhibitors: Buspirone is contraindicated with MAOIs due to serotonin syndrome risk; maintain 14-day washout period 1
Avoid grapefruit juice with buspirone: This increases buspirone plasma concentrations 9-fold (AUC) and 4-fold (Cmax), substantially increasing side effects 1
Reduce doses in hepatic impairment: Buspirone concentrations increase 15-fold in hepatic disease, requiring significant dose reduction 7
Exercise caution in elderly patients: While the 2019 AGS Beers Criteria warns against combining multiple CNS agents (including benzodiazepines) due to fall risk, this applies more to chronic polypharmacy than short-term combination therapy 4
When Combination Therapy Makes Sense
This combination may be particularly useful when:
Transitioning from benzodiazepine to buspirone for long-term anxiety management, allowing gradual benzodiazepine taper while buspirone reaches therapeutic effect 5
Treating acute anxiety exacerbations in patients on chronic buspirone therapy, where short-term benzodiazepine provides immediate relief 3
Managing mixed anxiety presentations where immediate anxiolysis (diazepam) and sustained non-sedating anxiolysis (buspirone) are both needed 3