Clomipramine (Anafranil) and Ketamine Therapy | Tovani Health
Anafranil (Clomipramine) — Tricyclic antidepressant (TCA) with serotonin reuptake activity
Verdict at Tovani Health
Most serotonergic TCA, but ketamine itself is not serotonergic — sedation and QT are what we plan around.
Clomipramine is the most serotonergic TCA (functionally SSRI-like), which historically prompted serotonin syndrome monitoring with any ketamine combination. The Veraart 2021 systematic review specifically covering ketamine plus serotonergic antidepressants found no documented serotonin syndrome at therapeutic doses. We have stopped framing it that way. The real consideration is sedation — the one TCA effect that actually stacks with ketamine. The anticholinergic burden and QT effect are intrinsic to clomipramine, not ketamine stacks, but worth knowing for general clinical care.
If you take Anafranil regularly and are considering at-home ketamine therapy, the combination is safe with monitoring or dose adjustment. This page covers the brief pharmacologic context and what we do at intake.
How Anafranil interacts with ketamine
Clomipramine inhibits serotonin reuptake more potently than any other TCA. Its active metabolite is also a strong norepinephrine reuptake inhibitor. Ketamine has minor serotonergic activity that has not produced documented serotonin syndrome in any reviewed series. The TCA's sedation is the only meaningful ketamine stack; QT and anticholinergic effects are clomipramine's intrinsic profile.
What we do at intake
Disclose dose and any recent dose changes. Baseline EKG over age 50. We brief patients on the early signs of serotonin syndrome (agitation, tremor, sweating, hyperthermia) and ask them to call immediately if those appear in the 24 hours after a session.
Bottom line
Clomipramine is the most serotonergic TCA (functionally SSRI-like), which historically prompted serotonin syndrome monitoring with any ketamine combination. The Veraart 2021 systematic review specifically covering ketamine plus serotonergic antidepressants found no documented serotonin syndrome at therapeutic doses. We have stopped framing it that way. The real consideration is sedation — the one TCA effect that actually stacks with ketamine. The anticholinergic burden and QT effect are intrinsic to clomipramine, not ketamine stacks, but worth knowing for general clinical care.
Frequently Asked Questions
Why was clomipramine historically treated differently for SS risk?
Because pharmacologically it acts more like an SSRI. The historical framing presumed ketamine had more serotonergic activity than the published literature now supports.
Has serotonin syndrome from clomipramine plus ketamine actually been reported?
No documented cases at standard doses in the published literature. We treat clomipramine like the other TCAs for KAP planning.
Ready to find out if at-home ketamine fits your situation?
We’ll note that you’re on Anafranil (Clomipramine) at intake. The eligibility check takes 5 minutes and gives you an honest answer about whether at-home ketamine fits your specific situation.
FL and NJ residents only. Benjamin Soffer, DO — Tovani Health.
Sources
The verdict and clinical guidance on this page are based on the following peer-reviewed literature and FDA prescribing information.
- Pharmacodynamic Interactions Between Ketamine and Psychiatric Medications Used in the Treatment of Depression: A Systematic Review. Veraart JKE, Smith-Apeldoorn SY, Bakker IM, et al.. International Journal of Neuropsychopharmacology. 2021. PMID: 34170315
Systematic review of pharmacodynamic interactions between ketamine and psychiatric medications used in depression treatment.
- Real-world effectiveness of ketamine in treatment-resistant depression: A systematic review & meta-analysis. Alnefeesi Y, Chen-Li D, Krane E, et al.. Journal of Psychiatric Research. 2022. PMID: 35688035
Meta-analysis of 2,665 patients across 79 studies — 45% response and 30% remission with ketamine in treatment-resistant depression.
Clinically reviewed
Reviewed by Benjamin Soffer, DO on May 15, 2026. Dr. Soffer is a board-certified physician (American Board of Internal Medicine) licensed in Florida and New Jersey, prescribing at-home ketamine therapy through Tovani Health.
This page is general information about how this medication interacts with at-home ketamine therapy at Tovani Health. It is not a substitute for medical advice from your prescribing physician about your specific situation. Always discuss medication changes with the doctor who prescribed them.