Cyproheptadine

Cyproheptadine is a first-generation antihistamine with strong antiserotonin (5-HT2 antagonist), anticholinergic, and calcium-channel-blocking activity, sold under the brand name Periactin among others. Mainstream medicine uses it for allergic conditions, appetite stimulation, migraine prevention in children, and serotonin syndrome. Ray Peat considered it one of the safer anti-serotonin drugs, useful short-term because chronic excess serotonin drives inflammation, prolactin elevation, and inefficient metabolism, but all antiserotonin drugs, cyproheptadine included, serve as a bridge to fixing thyroid and hormone status rather than a long-term fix in themselves.

Cyproheptadine
Chemical structure of cyproheptadine
Formula	C21H21N
Class	First-generation antihistamine / serotonin antagonist
Administration	Oral (tablets, syrup)
Solubility	Practically insoluble in water; freely soluble in methanol
Legal status	Prescription only in most countries; OTC in some regions for allergy use
Brand names	Periactin, Ciplactin, Peritol, Cyheptine, Practin
Bioavailability	Well absorbed (≥80% oral)
Recommended dose	2-4 mg at bedtime (low-dose, anti-serotonin use); 4-20 mg/day divided (clinical allergy/appetite/prolactin use)
Upper limit	32 mg/day (serotonin-syndrome treatment protocols)
LD50	295 mg/kg (rat, oral); 59 mg/kg (mouse, oral)
Ray's verdict	Depends on context A comparatively safe serotonin antagonist for short-term use while the underlying cause of excess serotonin (hypothyroidism, estrogen excess, chronic inflammation) is corrected with diet, thyroid, and progesterone, not as permanent therapy.

Periactin redirects here.

Dosing

Dose varies widely by indication:

• Low-dose, anti-serotonin use (Peat): start at about 0.5 mg at bedtime to judge sensitivity, then typically 2-4 mg at bedtime.
• Allergy (standard): 4 mg every 6-8 hours in adults, adjusted for children by weight.
• Appetite stimulation: commonly 2-4 mg, 1-3 times daily, titrated to effect and tolerated sedation.
• Hyperprolactinemia / galactorrhea (studied): 16-24 mg/day, divided.
• Serotonin syndrome: 12 mg orally, then 2 mg every 2 hours until symptoms resolve, up to about 32 mg/day.

Structure / Chemical properties

Cyproheptadine (C₂₁H₂₁N, molecular weight 287.4) is a tetracyclic piperidine derivative, structurally related to the tricyclic antidepressants and to the antihistamine ketotifen. It is practically insoluble in water but freely soluble in methanol; oral bioavailability is high, at 80% or more. Reported oral LD50 values are 295 mg/kg in rats and 59 mg/kg in mice, indicating a wide margin between the therapeutic dose (single-digit milligrams) and acute lethal toxicity.

Function / Mechanism of action

Cyproheptadine blocks histamine H1 receptors (the basis of its antihistamine and sedating effects) and antagonizes serotonin receptors, mainly 5-HT2A and 5-HT2C, reducing serotonin-mediated vasoconstriction, gut spasm, and pituitary effects. It also has meaningful anticholinergic (muscarinic-blocking) and L-type calcium-channel-blocking activity, which contribute to drowsiness, appetite stimulation, and its aldosterone-antagonist effect.

Cyproheptadine, 2 to 4 mg at bedtime... also has calcium blocking action, aldosterone antagonism, and antagonizes serotonin's antidiuretic effect.

— Ray Peat

Ray Peat placed cyproheptadine in the historical context of the "serotonin theory" of migraine: by the end of the 1950s it was widely accepted that migraine and its associated nausea and visual disturbances were caused by excess serotonin, and antiserotonin drugs of various types, cyproheptadine among them, were developed for that reason.

By the end of the 1950s, it was widely accepted that migraine headaches and associated symptoms including nausea and visual disturbances were caused by an excess of serotonin, and antiserotonin drugs of various types were being used for treatment.

— Ray Peat

Peat grouped cyproheptadine with progesterone, thyroid hormone, and niacinamide as substances that reduce serotonin formation or oppose its effects, reserving the drug itself for acute or clinical situations rather than routine use.

Medical uses / Effects

Allergic conditions

As a first-generation H1 antihistamine, cyproheptadine treats allergic rhinitis, urticaria, and other histamine-mediated allergic symptoms, at the cost of more sedation than second-generation antihistamines.

Appetite stimulation

In a 12-week double-blind trial in people with cystic fibrosis, cyproheptadine produced more weight gain than placebo (mean 3.45 kg vs 1.1 kg), with transient mild sedation as the only notable side effect.

Cyproheptadine is used off-label to promote weight gain in underweight children and adults, largely through appetite stimulation and possibly reduced serotonin-driven satiety signaling. A systematic review of French pharmacovigilance data (93 reported adverse events since 1985) found neurological effects such as drowsiness were common but mild, and hepatotoxicity rare (an estimated 0.27 to 1.4 cases per 1,000), concluding cyproheptadine is a reasonably safe orexigenic drug at standard doses.

Migraine prophylaxis

Cyproheptadine has long been used for pediatric migraine prevention because of its mild side-effect profile and available liquid formulation.

In 12 adults with frequent migraine refractory to (or intolerant of) lomerizine, valproic acid, and topiramate, 4 mg cyproheptadine hydrochloride at bedtime, raised to 8 mg/day when sleepiness allowed, reduced attack frequency within 7 to 10 days. Mean frequency during three months of treatment was 2.6 episodes per month versus more than 10 per month before treatment. See Migraine.

Serotonin syndrome

Cyproheptadine is a standard emergency treatment for serotonin syndrome, typically 12 mg orally followed by 2 mg every 2 hours until symptoms resolve, up to about 32 mg/day. A later 11-year retrospective review of poison-control cases questioned how much benefit cyproheptadine adds over supportive care alone, since most reported "responses" occurred without a clear dose-response relationship. Ray Peat himself considered cyproheptadine "a safe antiserotonin drug" specifically in this context.

I think Cyproheptadine is a safe antiserotonin drug [serotonin syndrome].

— Ray Peat

Hyperprolactinemia and galactorrhea

In a study of 15 women with galactorrhea-amenorrhea and mildly elevated prolactin, 16-24 mg/day of cyproheptadine significantly lowered serum prolactin at 8 and 16 weeks; 10 of 15 resumed menstrual bleeding, at the cost of transient drowsiness and weight gain.

Functional abdominal pain and IBS

In a double-blind, placebo-controlled trial of 29 children and adolescents (ages 4.5-12) with functional abdominal pain, 86% of the cyproheptadine group had improvement or resolution of pain, versus 35.7% on placebo. IBS management in the same vein includes cyproheptadine alongside checking thyroid and vitamin D status. A retrospective chart review of children with functional gastrointestinal disorders found cyproheptadine improved symptoms in 100% (10/10) of IBS cases, 72% of abdominal migraine cases, and 75% of cyclic vomiting syndrome cases.

Beyond its antiserotonin and antihistamine effects, cyproheptadine also blunts ACTH and cortisol secretion, which may be relevant since IBS patients show an exaggerated ACTH and colonic response to corticotropin-releasing hormone (CRH) compared to healthy controls. Stress reactivity may drive IBS symptoms.

Depression (in a specific subgroup)

A small double-blind, placebo-controlled crossover trial in six patients with major depression found cyproheptadine lowered Hamilton Depression Rating Scale scores in the four patients who had a suppressible dexamethasone suppression test, but was poorly tolerated (anxiety, irritability) in the two who did not. The sample is too small to generalize from, but it fits Peat's broader framing of excess serotonin as a driver of some depressive states.

Pregnancy (Cushing's disease)

A case report described two pregnancies in a woman with Cushing's syndrome treated with cyproheptadine; in one pregnancy the drug was stopped at 3 months gestation, yet the prior clinical improvement in Cushing's symptoms persisted, glucose tolerance stayed normal, and the pregnancy proceeded without birth complications. The evidence is limited to a small number of case reports, and cyproheptadine is no longer a standard treatment for Cushing's disease.

Slow-wave sleep

Intravenous cyproheptadine (5 mg) increased slow-wave sleep and decreased REM sleep in healthy men while suppressing sleep-related growth hormone release and early-morning cortisol rise. Oral cyproheptadine increased slow-wave sleep in 12 healthy controls but not in 12 patients on maintenance tricyclic antidepressants, with REM reduced in both groups.

A 2026 single case report described a 74-year-old man with post-viral dysautonomia and insomnia refractory to zolpidem, trazodone, gabapentin, diazepam, and lemborexant. His Oura Ring sleep scores, often 30–40 over the prior 10 months, rose to about 75 the first night after bedtime cyproheptadine was started together with phosphatidylcholine, alpha-GPC, coenzyme Q10, and removal of scented household products; a low-histamine diet with loratadine and famotidine, added at four weeks, preceded patient-reported gains in energy and cognition. The authors list the limits themselves: one patient, several interventions started at once, no mast-cell testing such as tryptase or urinary histamine metabolites, no blinding or control for natural post-viral recovery, and sleep staging from a consumer wearable rather than polysomnography. Cyproheptadine's sedative and antiserotonergic effects alone could explain faster sleep onset without any histamine mechanism.

It works extremely well (for insomnia), but it's important to start with a much smaller dose than is usually recommended, 1 mg, or even less, can be effective, and 4 mg sometimes makes people goofy the next day. I know people who use it for nocturnal episodes of asthma or epilepsy-like episodes.

— Ray Peat

See Sleep, Insomnia.

Cancer

A case report described a 62-year-old woman with advanced hepatocellular carcinoma and bone metastases who achieved long-term remission on cyproheptadine monotherapy, with normalized alpha-fetoprotein and non-malignant repeat biopsies. This is a single case, not a trial, and should be read as a lead rather than an established treatment. A broader mechanistic hypothesis on the Ray Peat forum treats mast-cell histamine as promoting tumor progression by way of myeloid-derived suppressor cells, with antihistamines like cyproheptadine as one way to oppose that pathway.

Side / Adverse effects

• Sedation and drowsiness from H1 and anticholinergic blockade, the most commonly reported effect across pharmacovigilance data.
• Weight gain from appetite stimulation, expected and sometimes intentional, but unwanted for allergy-only or serotonin-syndrome use.
• Anticholinergic effects: dry mouth, blurred vision, urinary retention, constipation; caution in the elderly and in narrow-angle glaucoma.
• Hepatotoxicity is a rare but real reported adverse effect, estimated at roughly 0.3 to 1.4 cases per 1,000 users in pharmacovigilance data.
• Uncertain benefit specifically for serotonin syndrome: a retrospective poison-control review found no clear dose-response relationship for symptom resolution, suggesting supportive care may account for much of the reported improvement.
• Peat's general caution on antiserotonin drugs: he considered cyproheptadine comparatively safe but expected any antiserotonin drug to eventually cause side effects with prolonged use, and preferred correcting thyroid and progesterone status directly where possible.

I think any of the antiserotonin drugs will eventually cause side effects, and should only be used until a problem is corrected, for example when an enlarged pituitary is normalized. I think the same effects can be produced with nutrition and hormones, without the possible problems.

— Ray Peat

Brands and sources

Marketed as Periactin (and Periactin-branded generics), Ciplactin, Peritol, Cyheptine, and Practin, among others. Generic cyproheptadine is inexpensive and widely available in most countries; it is prescription-only in most places but sold over the counter in some regions for allergy use.

Cyproheptadine$39.99

See also

• Bromocriptine