Lithium + ACE Inhibitors/ARBs: When "Never Combine" Becomes "Possibly Fine"
- Jason Cafer MD
- 4 days ago
- 2 min read
For years, the teaching has been that adding an ACE inhibitor to lithium is a dangerous move. The most frequently cited figure — a 36.1% rise in steady-state lithium concentration — comes from a small retrospective case-control study of 20 hypertensive patients previously stabilized on lithium, in which four developed symptoms suggestive of toxicity.
The Lithium Handbook (Meyer & Stahl) and Prescribing Lithium (Cafer) single out lisinopril as the one agent that should genuinely be avoided with lithium. The rationale traces to a the case of a 46-year-old man whose serum lithium jumped roughly five-fold — peaking at 3.4 mEq/L — after being switched from fosinopril to lisinopril.
2026 Ontario study
❖ Lithium users ≥50 starting an ACE inhibitor/ARB or beta-blocker (Ahmadi et al, 2026)
➤ ACE inhibitor/ARB: 47/2,267 hospitalized for lithium toxicity within 90 days (2.1%)
➤ Beta-blocker: 54/2,110 (2.6%)
➤ Weighted RR 0.72 (95% CI 0.47–1.11)
➤ No higher 90-day hospitalized-toxicity risk detected versus beta-blockers
❖ What it does not prove
➤ Not “no interaction” or universal safety
➤ Hospitalizations only: outpatient toxicity + asymptomatic level increases missed
➤ ACE inhibitors + ARBs pooled; individual drugs not compared
Why monitoring still matters
❖ Earlier Ontario study: lithium users ≥66 (Juurlink et al, 2004)
➤ ACE inhibitor initiation associated with hospitalization within 1 month: RR 7.6
❖ Highest concern
➤ Adding several renal stressors simultaneously
➤ Older age
➤ Concurrent thiazide/NSAID
Updated approach
❖ ACE inhibitors/ARBs are not contraindicated in lithium
❖ Lisinopril is not uniquely banned
❖ Avoid simultaneously starting a thiazide when feasible
❖ Check 12-hr lithium before adding/switching ACE inhibitor/ARB
❖ Recheck at ~1 week and again ~4 to 6 wk
Bottom line
❖ “Never combine” is too strong
❖“No interaction” is also wrong
ACE inhibitor/ARB effects on lithium are variable, occasionally severe, and often manageable with patient selection + early and delayed monitoring.
References
Ahmadi F, Muanda FT, McArthur E, Weir M, Garg AX. Lithium toxicity from angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker co-prescription: a population-based cohort study. J Psychopharmacol. 2026. PMID 42557813
Finley PR, O’Brien JG, Coleman RW. Lithium and angiotensin-converting enzyme inhibitors: evaluation of a potential interaction. J Clin Psychopharmacol. 1996;16(1):68–71. PMID 8834421
Juurlink DN, Mamdani MM, Kopp A, Rochon PA, Shulman KI, Redelmeier DA. Drug-induced lithium toxicity in the elderly: a population-based study. J Am Geriatr Soc. 2004;52(5):794–798. PMID 15086664
Meyer JM, Dollarhide A, Tuan IL. Lithium toxicity after switch from fosinopril to lisinopril. Int Clin Psychopharmacol. 2005;20(2):115–118. PMID 15729089
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