RESEARCH MONOGRAPH · KDC-MN-222

Trimipramine

May 9, 2026 Kodiac biolabs Research Revised May 30, 2026 3 min read

Our opinion on this compound

58/100

The sedating tertiary-amine TCA that breaks the monoamine-reuptake story

Trimipramine is genuinely strange and thats why we kind of like it as a research compound. Of all the TCAs, this is the one where the conventional monoamine-reuptake-inhibition story really doesn't hold. Trimipramine has weak SERT and NET affinity compared to clomipramine or desipramine. Its primary pharmacology is actually H1 antagonism, alpha-1 antagonism, muscarinic antagonism, and 5-HT2A antagonism. It looks more like a low-potency atypical antipsychotic than a textbook tricyclic.

What thats meant historically is that trimipramine is one of the few classical antidepressants that doesn't suppress REM sleep. Most TCAs and SSRIs flatten REM hard. Trimipramine more or less leaves REM architecture intact, which is a striking dissociation if you take seriously the idea that antidepressant efficacy requires REM suppression. It doesn't. The Berger group in Freiburg published on this for years and it's one of the more underappreciated findings in sleep psychopharm.

For research, that REM-preserving profile is the main reason to keep trimipramine on hand. If youre doing sleep architecture work, anxiolytic profiling, or trying to dissect what the sedating-without-REM-suppression mechanism actually looks like in animal models, trimipramine is the obvious pharmacological probe.

What we dont like is the weight gain signal, which is real and tracks with the H1 affinity. In behavioral neuroscience that can confound chronic-dosing paradigms unless you control for it. The anticholinergic burden is also genuinely high and the cardiac signal lives in the usual TCA territory.

Sourcing is acceptable but not great. Maleate salt is the common form, reference standards exist but you wont find ten reputable vendors. HPLC validation is standard.

If you're working sleep neuroscience or want a TCA scaffold that breaks the monoamine-reuptake assumption, this is interesting. Otherwise its mostly historical. Underrated as a pharmacology probe, irrelevant as a clinical workhorse.

Evidence: 65
Mechanism: 72
Reliability: 65
Safety: 55
Sourcing: 60
Value: 55
Signal: 45
Staying power: 50

Plain-language summary Intrigue 50 / 100

Trimipramine (Surmontil) is the odd duck of the tricyclic family. A single methyl group on the side chain disrupts its ability to block the serotonin and norepinephrine pumps, so it does almost none of the standard tricyclic action. Instead its effects come from heavy histamine receptor blockade plus blocking a basket of serotonin, alpha-1, and dopamine receptors. The result is a strongly sedating drug used mainly for depression with prominent insomnia. It is one of the few antidepressants that does not suppress REM sleep. Approved by the FDA in 1979, it remains in use mostly in Europe. The mechanism is interesting precisely because it shows that an antidepressant does not necessarily need monoamine reuptake inhibition to work. Not stocked by Kodiac. This monograph is provided for research and educational reference.

Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.

Tricyclic antidepressant (sedating tertiary amine)

A sedating tertiary amine TCA with weak SERT and NET activity; the principal effect is dopaminergic and antihistaminergic.

Abstract

Trimipramine (3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N,2-trimethylpropan-1-amine; CAS 739-71-9; molecular formula C20H26N2; molecular weight 294.43) is a 2-methylated dibenzazepine TCA approved by the FDA in 1979 under the trade name Surmontil. The methyl substitution at the propanamine's beta carbon disrupts transporter binding: SERT Ki approximately 150 nM, NET Ki approximately 2400 nM, both several orders of magnitude weaker than amitriptyline or imipramine. The therapeutic effect is therefore primarily attributed to potent H1 (Ki approximately 0.27 nM, comparable to first-generation antihistamines), 5-HT2A, alpha-1, and D2 antagonism. The compound is among the most sedating TCAs in clinical use and is used preferentially in depression with severe insomnia. Plasma half-life is 16 to 40 hours; metabolism is via CYP2D6, CYP2C19, CYP3A4. Used as a reference compound for non-transporter TCA mechanism research; the H1 and dopaminergic profiles distinguish it from typical TCA pharmacology.

Mechanism of action

Weak SERT/NET activity; primary therapeutic effect via potent H1 antagonism and 5-HT2A, alpha-1, D2 receptor antagonism. Distinct from typical TCA mechanism.

Reported research dose ranges

Reported research dose ranges in the literature.

References

Settle EC, Ayd FJ. Trimipramine: twenty years' worldwide clinical experience. J Clin Psychiatry 1980.
Eckert A, et al. Trimipramine and monoamine receptor binding. J Neural Transm 1996.
Riemann D, et al. Trimipramine in primary insomnia. Pharmacopsychiatry 2002.

Read the full monograph

Available as a research-use-only PDF download. Note: PDFs for newly added compounds may take a few hours to propagate after this article was published.

KDC-MN-222

The full reference document is provided strictly for research use only. It reports research dose ranges from the published literature, not instructions for use in humans or animals.

Download PDF →

FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.

Kodiac sells research compounds for investigative use only.

Trimipramine

Abstract

Mechanism of action

Reported research dose ranges

References

Read the full monograph

Quick actions

Categories

Help and policies

Abstract

Mechanism of action

Reported research dose ranges

References

Read the full monograph

Adjacent monographs