Psychiatrist Arthur Sackler created the ads that made benzodiazepines popular. His nephew, Richard Sackler, took that to a new level with opioids, resulting in nearly a million U.S. deaths and the removal of the family name from over 20 institutions.
At high doses, overdose deaths rise sixfold, but what is the cause?
STUDY: Särkilä H et al, Acta Psychiatr Scand 2026
STUDY TYPE: Nationwide cohort study
FUNDING: Turku Psychiatric Services; Turku University Central Hospital
Background
High dose benzos carry higher risks, including falls, accidents, impaired cognition, respiratory problems, and withdrawals. This Finnish study looks at their mortality risk.
But first, remember that patients with more severe problems generally get higher doses, and even the best attempts to control for that are only approximations.
The Study
- 48,124 new benzo users age 18–65 (they had not taken benzos for two years before enrollment).
- Doses were tracked over five years (prospectively) and classified by as daily diazepam equivalents:
- LOW: < 10mg diazepam)
- MEDIUM TO HIGH: 10-30mg diazepam
- VERY HIGH: ≥ 30mg diazepam
- Primary outcome: all-cause mortality. Secondary outcomes: overdose, suicide, and accidental death.
- Data adjusted for: sex, age, disability, education, receipt of social benefits, the use of gabapentinoids/opioids, number of psychiatric disorders, number of substance use disorders, Charlson’s comorbidity score, and the order of treatments.
Results
Benzo use was associated with a 28% higher mortality risk compared to non-use periods. The risk rose sharply with daily diazepam dose:
- Low (< 10 mg): no increased risk (aHR 1.00).
- Medium to high (10-30 mg): 58% higher all-cause mortality (aHR 1.58), with overdose deaths tripling (aHR 3.34) and suicides more than doubling (aHR 2.43).
- Very high (≥ 30mg): all-cause mortality nearly tripled (aHR 2.68), with overdose deaths rising sixfold (aHR 6.18), suicides more than fourfold (aHR 4.46), and accidental deaths almost fourfold (aHR 3.77).
Most very-high-dose periods involved more than one benzodiazepine at once. Clonazepam and alprazolam were most likely to lead to dose escalation, while oxazepam was least likely (consistent with earlier research showing greater misuse and overdose liability with those high-potency benzos, and less with the slow-to-act oxazepam).
Using three or more benzodiazepines together carried the highest mortality risk of any combination (aHR 3.12).
Combining a benzodiazepine with a Z-drug like zolpidem or zopiclone also raised risk substantially (aHR 1.86). Z-drugs used alone did not increase mortality.
Clonazepam and alprazolam were the drugs most often seen in the very-high-dose group, consistent with their known misuse potential.
Limitations
Correlation, not causation. Data was not adjusted for severity or past suicide attempts, but was adjusted for comorbidities.
Practice Implications
- Though we can’t conclude that benzos are the cause here, it’s hard to argue that they are preventing death, particularly with so many observational studies pointing to a higher risk of suicide on them.
- This adds to other reports suggesting clonazepam and alprazolam are the riskiest benzos, while oxazepam is lower risk. Lorazepam is also lower risk.
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
