Cyproheptadine (DB00434): A Comprehensive Monograph on its Pharmacology, Clinical Utility, and Safety Profile

Section 1: Drug Identification and Physicochemical Properties

This section establishes the fundamental identity of Cyproheptadine, providing a comprehensive catalog of its identifiers and detailing its chemical and physical nature. This foundational knowledge is essential for understanding its formulation, stability, and interactions at a molecular level.

1.1 Nomenclature and Key Identifiers

Cyproheptadine is a first-generation antihistamine with a complex pharmacological profile that extends well beyond its primary classification. To ensure unambiguous identification across global databases, regulatory systems, and scientific literature, it is cataloged under numerous identifiers.

• Primary Name: Cyproheptadine.[1]
• Systematic (IUPAC) Name: The formal chemical name is 1-methyl-4-{tricyclo[9.4.0.0$^{3,8}$]pentadeca-1(15),3,5,7,9,11,13-heptaen-2-ylidene}piperidine.[3] An alternative systematic name is 4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-methylpiperidine.[4]
• Key Database Identifiers:
• DrugBank ID: DB00434.[1]
• CAS Number: The Chemical Abstracts Service has assigned several numbers corresponding to different forms of the molecule: 129-03-3 for the free base; 969-33-5 for the hydrochloride (HCl) salt; 41354-29-4 for the hydrochloride sesquihydrate; and 58131-49-0 for the ketoglutarate salt.[1]
• FDA UNII: 2YHB6175DO.[1]
• ATC Code: R06AX02, classifying it under "Other antihistamines for systemic use".[2]
• ChEBI ID: CHEBI:4046.[1]
• Synonyms and Brand Names: Over its long history since its approval in 1961, Cyproheptadine has been marketed under various names. Common synonyms include Eiproheptadine, Periactinol, and Dronactin.[4] Prominent brand names include Periactin, Peritol, and Glutodine.[2]

1.2 Chemical Structure and Synthesis

Cyproheptadine is a synthetic organic compound belonging to the piperidine class of antihistamines and is chemically classified as a tertiary amine.[1] Its structure is characterized by a tricyclic benzocycloheptene framework, which is crucial to its diverse pharmacological activities.[10]

• Molecular Formula and Weight: The molecular formula of the free base is C21​H21​N, corresponding to a molecular weight of 287.39 g/mol.[2] The clinically utilized hydrochloride sesquihydrate form has the formula C21​H21​N⋅HCl⋅1.5H2​O and a molecular weight of 350.89 g/mol.[6]
• Chemical Definition: The molecule is formally described as the product resulting from the oxidative coupling of position 5 of 5H-dibenzo[a,d]cycloheptene with position 4 of 1-methylpiperidine. This reaction forms a defining double bond that links the two molecular fragments.[1]
• Synthesis Process: A documented method for synthesizing the hydrochloride salt involves the acid-catalyzed dehydration of a precursor molecule, 1-methyl-4-(5-hydroxy-5-dibenzo[a,e]cycloheptatrienyl)piperidine. This precursor is dissolved in an ethanol-water solution and treated with concentrated hydrochloric acid. The mixture is heated to approximately 90°C for one hour to drive the dehydration reaction, forming the double bond. The final product, cyproheptadine hydrochloride, is then isolated through filtration, crystallization, and purification.[13]

1.3 Physical and Chemical Characteristics

The physical properties of Cyproheptadine vary significantly between its free base and salt forms, a distinction that is critical for its pharmaceutical formulation and clinical delivery.

• Appearance: In its solid state, Cyproheptadine is a white to slightly yellowish crystalline powder. It is generally odorless and possesses a slight bitter taste.[1]
• Melting Point: The free base has a melting point of 112.3–113.3 °C.[1] In contrast, the hydrochloride salt exhibits a much higher melting point of 254–256.5 °C.[14]
• Solubility: The solubility profile is highly dependent on the chemical form.
• Free Base: It is practically insoluble in water, with a measured solubility of only 317.6 µg/L.[7]
• Hydrochloride Salt: This form is soluble in water, freely soluble in methanol, sparingly soluble in ethanol, and soluble in chloroform. It remains practically insoluble in ether.[1] This marked increase in aqueous solubility is the primary reason the hydrochloride salt is used in pharmaceutical preparations.
• pKa: The estimated pKa of the tertiary amine is 8.87, indicating it is protonated at physiological pH.[7]
• Stability and Storage: The hydrochloride salt is noted to be hygroscopic.[14] It should be stored at room temperature or under refrigeration (2–8°C), protected from excess heat and moisture, to ensure stability.[4]

The profound difference in physicochemical properties between the free base and its hydrochloride salt is not a minor detail but rather the key to its viability as a medication. The free base molecule, with its poor water solubility, would have very low oral bioavailability. The chemical process of converting it into a hydrochloride salt transforms it into a substance that can be readily dissolved in water. This deliberate chemical modification is what enables the creation of effective oral formulations, such as tablets that dissolve in the gastrointestinal tract and, importantly, the aqueous syrup that is crucial for its use in pediatric populations.[11]

Furthermore, the chemical architecture of Cyproheptadine—a dibenzocycloheptene ring system attached to a methylpiperidine group—provides strong clues to its complex pharmacology. This tricyclic core is a well-known pharmacophore shared by other centrally-acting drugs, most notably the tricyclic antidepressants (TCAs) like amitriptyline. TCAs are infamous for their "dirty" pharmacology, interacting with a wide array of receptors beyond their primary target, leading to antihistaminic (sedative), antimuscarinic (anticholinergic), and antiserotonergic effects. Cyproheptadine exhibits this exact same pharmacological signature, a direct consequence of its molecular structure. This structural analogy is a powerful predictor of its broad range of clinical effects and its extensive side-effect profile, which closely mirrors that of the TCAs.[1]

Table 1: Key Identifiers and Physicochemical Properties of Cyproheptadine

Property	Value (Free Base)	Value (Hydrochloride Salt/Sesquihydrate)	Source(s)
IUPAC Name	4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-methylpiperidine	4-(5H-dibenzo(a,d)cyclohepten-5-ylidene)-1-methylpiperidine hydrochloride sesquihydrate	4
DrugBank ID	DB00434	DB00434	1
CAS Number	129-03-3	969-33-5 (HCl); 41354-29-4 (HCl Sesquihydrate)	1
ATC Code	R06AX02	R06AX02	2
Molecular Formula	C21​H21​N	C21​H21​N⋅HCl⋅1.5H2​O	2
Molecular Weight	287.39 g/mol	350.89 g/mol	4
Appearance	Solid	White to slightly yellowish crystalline powder	1
Melting Point	112.3–113.3 °C	254–256.5 °C	7
Water Solubility	317.6 µg/L (practically insoluble)	Soluble	7
pKa	8.87 (uncertain)	Not Applicable	7

Section 2: Comprehensive Pharmacological Profile

Cyproheptadine's clinical utility and its extensive side-effect profile are rooted in its complex pharmacology. It is a multi-receptor antagonist, and understanding its interactions with various physiological systems is key to explaining its diverse applications, moving far beyond its simple classification as an antihistamine.

2.1 Mechanism of Action: A Multi-Receptor Antagonist

Cyproheptadine exerts its effects not through a single mechanism but by competitively antagonizing several key neurotransmitter receptors.

2.1.1 Histamine H1​ Receptor Antagonism

The primary and originally intended mechanism of action for Cyproheptadine is its function as a potent first-generation histamine H1​ receptor antagonist, or more accurately, an inverse agonist.[1] It competitively blocks the action of histamine at

H1​ receptors located on effector cells in the gastrointestinal tract, blood vessels, and respiratory tract.[19] This action effectively mitigates the classic symptoms of allergic reactions, such as vasodilation, increased capillary permeability, and smooth muscle contraction, forming the basis for its approved use in treating allergic rhinitis, urticaria, and pruritus.[1] As a first-generation agent, it readily crosses the blood-brain barrier, where its blockade of central

H1​ receptors is the principal cause of its most common side effect: sedation.[21]

2.1.2 Serotonin (5-HT) Receptor Antagonism

A feature that distinguishes Cyproheptadine from most other antihistamines is its potent, competitive antagonism of serotonin (5-hydroxytryptamine, 5-HT) receptors.[1] It demonstrates particularly high affinity for the 5-

HT2​ receptor subfamily, including 5-HT2A​ and 5-HT2C​ receptors.[23] The clinical significance of this activity is substantial, as demonstrated by positron emission tomography (PET) studies in humans, which have shown that oral doses of 12 mg/day can block 85% of brain 5-

HT2​ receptors, with this figure rising to 95% at 18 mg/day.[9]

This potent anti-serotonergic activity is the mechanistic foundation for many of its most important off-label uses:

• Appetite Stimulation: The antagonism of 5-HT2C​ receptors in the hypothalamus is believed to disinhibit downstream orexigenic (appetite-stimulating) pathways, leading to increased appetite and weight gain.[10]
• Serotonin Syndrome Treatment: Its robust blockade of 5-HT2A​ receptors makes it a first-line antidote for serotonin syndrome, a condition of excessive serotonergic activity, by directly counteracting the overstimulation of these receptors.[20]
• Migraine Prophylaxis: The therapeutic effect in preventing migraines may be related to the blockade of 5-HT2B​ receptors on cranial blood vessels, preventing serotonin-mediated neurogenic inflammation.[9]

2.1.3 Muscarinic (Anticholinergic) Receptor Activity

Cyproheptadine possesses significant anticholinergic properties, acting as an antagonist at muscarinic acetylcholine receptors (M1, M2, and M3).[1] This atropine-like action is responsible for a well-known constellation of side effects, including xerostomia (dry mouth), blurred vision, urinary retention, and constipation.[9]

2.1.4 Other Receptor and Channel Interactions

At higher concentrations, the drug's activity spectrum broadens further:

• Calcium-Channel Blocking: Cyproheptadine has been shown to possess calcium-channel blocking actions.[1] In vitro studies suggest that it inhibits prolactin release from pituitary cells by blocking calcium influx, an action independent of its serotonin antagonism.[28]
• Dopamine Receptor Antagonism: It also exhibits weak antidopaminergic activity, which may contribute to some of its central effects.[9]
• Local Anesthetic Properties: Like many other first-generation antihistamines, it has local anesthetic properties, likely through blockade of sodium channels.[6]

2.2 Pharmacodynamic Effects

The multi-receptor mechanism of action translates into a broad range of systemic effects.

• Central Nervous System (CNS): The most prominent effects are sedation, drowsiness, and dizziness, resulting directly from H1​ and muscarinic receptor blockade in the CNS.[11] In some individuals, particularly children, a paradoxical reaction of excitation and restlessness can occur.[11]
• Metabolic: A well-documented and clinically utilized effect is the stimulation of appetite and subsequent weight gain, a pharmacodynamic outcome of its 5-HT2C​ antagonism.[9]
• Endocrine: Through its anti-serotonergic actions and direct effects on the pituitary, Cyproheptadine can lower serum prolactin levels, which has potential implications for interfering with lactation.[28]
• Gastrointestinal: Its anticholinergic action can decrease gastrointestinal motility, leading to constipation.[17] Conversely, its 5- HT2A​ antagonism is leveraged in the treatment of certain functional gastrointestinal disorders.[29]

The pharmacology of Cyproheptadine creates a unique clinical scenario where a single pharmacodynamic effect can be interpreted as either a desired therapeutic outcome or an undesirable adverse effect, depending entirely on the clinical context. For instance, weight gain is listed as a common side effect, yet appetite stimulation is one of its primary and most valued off-label uses.[9] Similarly, sedation is the most frequently reported adverse event, yet this very property is harnessed for the off-label treatment of insomnia.[17] This duality highlights that the drug's utility is not intrinsic but is defined by the physician's therapeutic goal. The "side effect" of sedation becomes the "treatment" for insomnia, a hallmark of pharmacologically non-selective or "dirty" drugs that necessitates sophisticated clinical decision-making.

This profile also positions Cyproheptadine as a pharmacological antidote for conditions of neurotransmitter excess. Its role in serotonin syndrome is the most prominent example, where its potent 5-HT2A​ blockade directly counteracts the core pathophysiology of the condition.[25] It can also be conceptualized as an antidote for the iatrogenic side effects of other medications, such as reversing SSRI-induced anorgasmia or mitigating antipsychotic-induced akathisia.[30] This positions the drug not just as a primary therapy but as a critical tool in iatrogenic medicine—a "rescue" agent for the consequences of other treatments.

Table 2: Receptor Binding Profile and Pharmacological Actions

Receptor Target	Action	Associated Therapeutic Effects	Associated Adverse Effects
Histamine H1​	Antagonist / Inverse Agonist	Relief of allergic symptoms (rhinitis, urticaria, pruritus)	Sedation, drowsiness, dizziness, weight gain
Serotonin 5-HT2A​	Antagonist	Treatment of serotonin syndrome, akathisia; migraine prophylaxis; antipsychotic effects	Potential reversal of SSRI antidepressant effects
Serotonin 5-HT2C​	Antagonist	Appetite stimulation	Weight gain
Muscarinic (M1-M3)	Antagonist	Potential utility in movement disorders	Dry mouth, blurred vision, urinary retention, constipation, tachycardia, confusion
Calcium Channels	Blocker	Potential contribution to smooth muscle relaxation and endocrine effects	Not well defined

Section 3: Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

A detailed analysis of Cyproheptadine's journey through the body—its absorption, distribution, metabolism, and excretion (ADME)—is critical for optimizing dosing regimens, anticipating its duration of action, and identifying patient populations at higher risk for toxicity.

3.1 Absorption and Bioavailability

• Administration and Absorption: Cyproheptadine is administered orally in tablet or solution form and is well absorbed from the gastrointestinal tract.[15] The presence of food may slightly delay the rate of absorption but does not appear to significantly affect the overall amount of drug absorbed (bioavailability).[21]
• Time to Peak Concentration (Tmax​): Following oral administration, peak plasma concentrations of the parent drug are achieved relatively quickly, within 1 to 3 hours.[21] However, studies using radiolabeled drug show that the peak concentration of total radioactivity, which represents the sum of the parent drug and its metabolites, occurs much later, at 6 to 9 hours post-dose.[33] This significant delay suggests extensive first-pass metabolism.
• Sublingual Administration: An alternative route, sublingual administration, has been investigated but found to be clinically ineffective. A comparative study demonstrated that sublingual absorption is markedly lower and slower than oral absorption. The mean peak concentration (Cmax​) after an 8 mg dose was 30.0 µg/L for the oral route versus only 4.0 µg/L for the sublingual route. Consequently, the sublingual route is not considered a viable option for achieving therapeutic concentrations.[20]

3.2 Distribution and Protein Binding

• Plasma Protein Binding: Once in the bloodstream, Cyproheptadine is highly bound to plasma proteins, with estimates ranging from 96% to 99%.[9] This extensive binding can have implications for potential drug-drug interactions, where other highly bound drugs could displace Cyproheptadine, transiently increasing its free concentration.
• Volume of Distribution: The volume of distribution is described as large, indicating that the drug distributes extensively into body tissues rather than remaining confined to the bloodstream.[14]

3.3 Hepatic Metabolism and Metabolites

• Site and Extent of Metabolism: Cyproheptadine undergoes extensive, almost complete, metabolism in the liver.[9]
• Metabolic Pathways: The primary metabolic pathways include glucuronidation, which is the conjugation of the drug with glucuronic acid to form a more water-soluble compound, as well as aromatic ring hydroxylation, N-demethylation (removal of the methyl group from the piperidine nitrogen), and heterocyclic ring oxidation.[9]
• CYP450 Enzyme Involvement: The metabolism is mediated, at least in part, by the cytochrome P450 enzymes CYP3A4 and CYP2D6.[21]
• Metabolites: The principal metabolite identified in human urine is a quaternary ammonium glucuronide conjugate of Cyproheptadine.[11] Additionally, an active metabolite, norcyproheptadine, is formed. The presence of this active metabolite is significant as it likely contributes to the drug's prolonged duration of clinical action.[21]

3.4 Excretion and Elimination Half-Life

• Routes of Excretion: The metabolites of Cyproheptadine are eliminated from the body via both renal and fecal routes.[9]
• Renal Excretion: Approximately 40% of an administered dose is excreted in the urine, almost exclusively in the form of metabolites. In patients on chronic therapy, no detectable amounts of unchanged parent drug are found in the urine.[9]
• Fecal Excretion: Between 2% and 20% of the dose is excreted in the feces. A small fraction of this, corresponding to less than 5.7% of the total original dose, is unchanged parent drug.[11]
• Elimination Half-Life (T1/2​): The pharmacokinetic profile reveals a notable difference between the half-life of the parent drug and its metabolites. The elimination half-life of the parent Cyproheptadine is approximately 8.6 hours.[9] However, its metabolites have a significantly longer half-life of around 16 hours.[19] In pediatric patients, the half-life is even more prolonged, ranging from 12 to 21 hours.[21]

3.5 Pharmacokinetic Considerations in Special Populations

• Renal Insufficiency: Elimination is diminished in patients with impaired renal function, which can lead to the accumulation of metabolites and increased risk of toxicity. Dose adjustment is likely necessary in this population.[11]
• Hepatic Insufficiency: Given its extensive hepatic metabolism, patients with liver disease are at a greater risk for adverse effects. Cautious use and lower initial doses are recommended.[16]
• Pediatrics and Geriatrics: The longer half-life observed in children necessitates careful dosing.[21] Similarly, age-related declines in hepatic and renal function in geriatric patients warrant caution, typically starting with doses at the lower end of the adult range.[16]

A critical observation from the pharmacokinetic data is that the metabolites, not the parent drug, likely drive the sustained clinical effect. The parent drug's half-life of approximately 8.6 hours would normally suggest a dosing frequency of three to four times daily. However, the much longer half-life of its metabolites (~16 hours), combined with the existence of at least one pharmacologically active metabolite (norcyproheptadine), explains why a twice or three times daily dosing regimen is effective.[19] In this sense, Cyproheptadine functions partly as a prodrug, where the prolonged clinical effects, such as sedation, are maintained by its longer-lasting metabolites.

This ADME profile also directly foreshadows the drug's key safety concerns. The rare but serious risk of hepatotoxicity is likely a direct consequence of its extensive hepatic metabolism. Idiosyncratic drug-induced liver injury often arises when a reactive metabolic intermediate is formed, which in susceptible individuals can overwhelm cellular detoxification mechanisms.[17] Thus, the very process that clears the drug from the body is also the source of this potential toxicity. Similarly, the significant reliance on renal excretion for its metabolites provides a clear mechanistic basis for the warning against its use in patients with renal insufficiency, as accumulation would inevitably lead to toxicity.[11]

Table 3: Summary of Pharmacokinetic Parameters (ADME)

Parameter	Value	Clinical Significance/Comment	Source(s)
Absorption (Tmax​ - Parent)	1–3 hours	Rapid onset of action.	21
Absorption (Tmax​ - Metabolites)	6–9 hours	Suggests extensive first-pass metabolism.	33
Distribution (Protein Binding %)	96–99%	High potential for displacement interactions with other highly bound drugs.	9
Metabolism (Primary Site)	Liver	Extensive hepatic metabolism; caution required in liver disease.	9
Metabolism (Key Pathways)	Glucuronidation, N-demethylation, Hydroxylation	Almost complete metabolism; little parent drug is excreted unchanged.	33
Metabolism (CYP Enzymes)	CYP3A4, CYP2D6	Potential for interactions with inhibitors/inducers of these enzymes.	21
Elimination (T1/2​ - Parent)	~8.6 hours	Relatively short half-life for the parent compound.	9
Elimination (T1/2​ - Metabolites)	~16 hours	Long-acting metabolites contribute significantly to the overall duration of effect.	19
Elimination (T1/2​ - Pediatric)	12–21 hours	Longer half-life in children requires careful dosing.	21
Excretion (% Renal)	~40% (as metabolites)	Primary route of elimination for metabolites; dose adjustment needed in renal failure.	11
Excretion (% Fecal)	2–20%	Minor route of elimination; <5.7% of total dose is excreted as unchanged drug.	11

Section 4: Clinical Applications and Therapeutic Efficacy

Cyproheptadine's clinical story is one of a significant divergence between its narrow, decades-old regulatory approvals and its broad, empirically-driven application in diverse medical fields. This section bridges the gap between its pharmacology and its real-world clinical practice, critically evaluating the evidence for both its approved and off-label uses.

4.1 Approved Indications: Management of Allergic and Pruritic Conditions

The primary approved indications for Cyproheptadine in the United States are directly related to its potent histamine H1​-receptor blocking activity. These include the management of:

• Perennial and seasonal allergic rhinitis
• Vasomotor rhinitis
• Allergic conjunctivitis due to inhalant allergens and foods
• Mild, uncomplicated allergic skin manifestations of urticaria and angioedema
• Cold urticaria and dermatographism
• Amelioration of allergic reactions to blood or plasma
• Adjunctive therapy for anaphylactic reactions after acute manifestations have been controlled with epinephrine.[1]

While effective for these conditions, its utility is often limited by its side-effect profile. Modern, second-generation antihistamines like loratadine and cetirizine, which do not readily cross the blood-brain barrier, offer similar efficacy for allergic conditions with significantly less sedation and fewer anticholinergic effects, making them the preferred first-line agents in most cases.[9]

4.2 Prominent Off-Label Applications

The majority of contemporary Cyproheptadine use is for off-label indications, driven by its unique antiserotonergic properties.

4.2.1 Appetite Stimulation and Management of Underweight Conditions

This is arguably the most common off-label use of Cyproheptadine. It is widely prescribed to stimulate appetite and promote weight gain in various populations, including underweight children, patients with chronic illnesses like cystic fibrosis, and individuals with anorexia nervosa or other wasting syndromes.[1] The mechanism is attributed to its antagonism of 5-

HT2C​ receptors in the hypothalamus.[10] The evidence for this use is strong enough that the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition has recommended it for children under 5 years of age.[10]

4.2.2 Prophylaxis of Migraine and Vascular Headaches

Cyproheptadine is frequently used as a preventive treatment for migraine headaches, particularly in the pediatric population.[4] This effect is believed to stem from its anti-serotonergic properties, possibly through the blockade of 5-

HT2B​ receptors, which prevents neurogenic inflammation in the trigeminal system.[1] While its efficacy is supported by decades of clinical experience and expert consensus, robust evidence from large, randomized controlled trials is limited.[16]

4.2.3 Management of Serotonin Syndrome

Due to its potent 5-HT2A​ receptor antagonism, Cyproheptadine is considered a primary antidote for serotonin syndrome, a potentially fatal condition caused by excessive serotonergic activity. It directly counteracts the effects of serotonin at the postsynaptic receptor, making it a crucial intervention in moderate to severe cases.[1]

4.3 Other Investigated and Niche Psychiatric and Neurological Uses

The drug's broad receptor profile has led to its exploration in a variety of niche applications:

• SSRI-Induced Side Effects: It is used to manage treatment-emergent side effects of serotonergic antidepressants, such as sexual dysfunction (anorgasmia) and hyperhidrosis (excessive sweating).[30]
• Antipsychotic-Induced Side Effects: It has been used off-label to treat movement disorders caused by antipsychotic medications, including akathisia (a state of inner restlessness) and tardive dyskinesia.[9]
• Sleep and Anxiety: Its sedative properties are sometimes harnessed for short-term management of insomnia (especially when induced by stimulants) and anxiety, although long-term use for these indications is generally discouraged.[21]
• Post-Traumatic Stress Disorder (PTSD): Case reports and small studies suggest it may reduce the frequency and intensity of nightmares in patients with PTSD, an effect attributed to REM sleep suppression via its antiserotonergic and anticholinergic actions.[29]
• Autism Spectrum Disorder (ASD): One randomized controlled trial found that the combination of Cyproheptadine and haloperidol was superior to haloperidol alone for managing behavioral dyscontrol in individuals with ASD.[30]

4.4 Use in Functional Gastrointestinal Disorders and Other Conditions

• Functional GI Disorders: Cyproheptadine is effective in treating a range of functional gastrointestinal disorders, especially in children, including functional dyspepsia, functional abdominal pain, and irritable bowel syndrome (IBS).[10]
• Cyclical Vomiting Syndrome: It is a commonly used off-label therapy for this distressing condition in infants and children.[9]
• Cushing's Syndrome: It has been used to normalize cortisol levels in some patients with Cushing's syndrome, a condition of excess corticosteroid hormones.[15]

A central theme in Cyproheptadine's clinical story is the profound disconnect between its limited, decades-old approved indications for allergies and its vast, modern, and diverse off-label use. This "evidence-experience gap" highlights that the drug's contemporary role has been largely defined by clinical pragmatism. Physicians have leveraged its unique pharmacology to solve complex clinical problems—from underweight children to serotonin toxicity—often in the absence of high-level evidence from large clinical trials.[9]

Furthermore, a cross-analysis of these off-label uses reveals a recurring pattern: many of the most prominent applications are concentrated in the pediatric population. Migraine prophylaxis, appetite stimulation, cyclical vomiting syndrome, and functional abdominal pain are all conditions where Cyproheptadine has found a specific pediatric niche.[9] This convergence suggests that, despite its first-generation side effects, it fills a therapeutic void in pediatrics where treatment options may be more limited or where its unique combination of effects (e.g., anti-nausea, anti-migraine, and appetite stimulation) is uniquely beneficial. The long-standing availability of a palatable syrup formulation has undoubtedly facilitated this widespread pediatric use.[16]

Section 5: Safety, Tolerability, and Risk Management

This section provides a systematic review of Cyproheptadine's safety profile, categorizing adverse effects by system and severity. It places special emphasis on high-risk populations, contraindications, and the management of toxicity, providing a comprehensive guide for risk mitigation in clinical practice.

5.1 Profile of Adverse Drug Reactions

The adverse effects of Cyproheptadine are highly predictable based on its non-selective antagonism of histamine, muscarinic, and serotonin receptors.

5.1.1 Central Nervous System Effects

• Common: The most frequently reported adverse effects are CNS-related, including sedation, somnolence (sleepiness), dizziness, and disturbed coordination. These effects are often transient but can be significant enough to impair daily functioning. Patients must be warned about engaging in activities requiring mental alertness, such as driving a car or operating machinery.[9]
• Less Common/Paradoxical: A subset of patients may experience paradoxical CNS stimulation, including restlessness, confusion, excitement, nervousness, irritability, and insomnia. This reaction is particularly noted in young children.[9]
• Severe (Rare): In rare cases, more severe CNS effects such as hallucinations, euphoria, neuritis, and convulsions have been reported.[9]

5.1.2 Anticholinergic Effects

• Common: These effects are a direct result of muscarinic receptor blockade and commonly include dryness of the mouth, nose, and throat; blurred vision; and constipation.[8]
• Serious: More serious anticholinergic effects include urinary retention or difficulty urinating (especially in patients with prostatic hypertrophy) and tachycardia. The mydriatic (pupil-dilating) effect can increase intraocular pressure and precipitate an attack of acute narrow-angle glaucoma in susceptible individuals.[8]

5.1.3 Metabolic and Endocrine Effects

Increased appetite and subsequent weight gain are common and are often the intended therapeutic goal in off-label use. However, when not desired, they are considered adverse effects.[9]

5.1.4 Other Adverse Effects

• Cardiovascular: Hypotension, palpitations, and tachycardia can occur.[17]
• Hematologic (Rare): Serious but rare hematologic adverse reactions have been reported, including hemolytic anemia, leukopenia, agranulocytosis, and thrombocytopenia.[27]
• Dermatologic: Allergic skin manifestations such as rash and urticaria can occur. Photosensitivity has also been reported, and patients should be advised to use sun protection.[9]

5.2 Special Report: Cyproheptadine-Induced Liver Injury (Hepatotoxicity)

• Incidence and Severity: Cyproheptadine has been linked to rare instances of clinically apparent liver injury.[1] The LiverTox database, a comprehensive resource on drug-induced liver injury, assigns it a Likelihood Score of "C," indicating it is a probable but rare cause of hepatotoxicity.[17]
• Clinical Presentation: The onset of injury typically occurs 1 to 6 weeks after initiating therapy. The pattern of liver enzyme elevation is usually cholestatic (affecting bile flow) or mixed (both cholestatic and hepatocellular). Unlike many drug-induced liver injuries, immunoallergic features like fever and eosinophilia are generally absent.[17]
• Mechanism: The underlying cause is unknown but is presumed to be idiosyncratic, meaning it occurs in susceptible individuals through an unpredictable mechanism, possibly related to the formation of a toxic metabolite during its extensive hepatic processing.[17]
• Outcome: Most reported cases have been mild-to-moderate in severity and have resolved upon discontinuation of the drug. Recurrence of injury upon rechallenge has been documented, confirming causality. To date, acute liver failure due to Cyproheptadine has not been described.[17]

5.3 Contraindications, Warnings, and Precautions

The entire safety profile of Cyproheptadine can be understood as a direct consequence of its "first-generation" pharmacology—its risks stem directly from its lack of receptor selectivity. The contraindications are designed to protect patient populations who are uniquely vulnerable to these non-selective effects.

• Absolute Contraindications:
• Concomitant use with Monoamine Oxidase Inhibitors (MAOIs).[8]
• Use in newborn or premature infants, who are highly susceptible to CNS depression.[16]
• Use in breastfeeding mothers, as the drug may be excreted in milk and can lower prolactin levels.[16]
• Patients with angle-closure glaucoma, stenosing peptic ulcer, symptomatic prostatic hypertrophy, or bladder neck obstruction, as its anticholinergic effects will exacerbate these conditions.[8]
• Debilitated elderly patients.[16]
• Warnings and Precautions:
• Special Populations: It should be used with extreme caution in the elderly, who are more susceptible to dizziness, sedation, confusion, and hypotension (it is included on the Beers Criteria list of potentially inappropriate medications for older adults).[15] Caution is also required in children due to the risk of paradoxical excitation.[11]
• Disease-Related Concerns: Caution is advised in patients with a history of bronchial asthma (due to thickening of bronchial secretions), hyperthyroidism, cardiovascular disease, or hypertension.[15]
• Pregnancy: Cyproheptadine is classified as Pregnancy Category B. While human studies have not shown a clear risk of abnormalities, it has demonstrated fetotoxicity in animal studies at high doses. Therefore, it should be used during pregnancy only if the potential benefit justifies the potential risk.[11]

5.4 Overdosage: Presentation and Management

• Symptoms: Overdosage can manifest as a spectrum of symptoms ranging from severe CNS depression (sedation, stupor, coma) to CNS stimulation (hallucinations, convulsions), with stimulation being more common in children. Prominent atropine-like (anticholinergic) signs are common, including dry mouth, fixed and dilated pupils, flushing, and fever. In severe cases, respiratory and cardiac arrest can occur.[11]
• Management: Treatment is primarily supportive. If ingestion is recent and the patient is conscious, gastric decontamination with induced emesis (syrup of ipecac) or gastric lavage followed by administration of activated charcoal may be considered to reduce absorption. Vital signs must be monitored closely. Vasopressors may be required to treat severe hypotension.[11]

Section 6: Clinically Significant Drug-Drug Interactions

The complex, multi-receptor pharmacology of Cyproheptadine creates a high potential for clinically significant drug-drug interactions. These interactions are highly predictable and are predominantly pharmacodynamic in nature, arising from additive or antagonistic effects at the receptor level.

6.1 Pharmacodynamic Interactions

6.1.1 Central Nervous System Depressants

• Interacting Agents: This broad category includes alcohol, benzodiazepines (e.g., alprazolam), barbiturates, opioids, other sedating antihistamines, and tranquilizers.[8]
• Effect: A major and highly significant interaction. Concomitant use results in additive or synergistic CNS and respiratory depression. This can lead to profound sedation, dizziness, and severe impairment of judgment, thinking, and psychomotor skills.[20]
• Management: Patients must be strongly counseled to avoid or strictly limit alcohol consumption. Co-administration with other CNS depressants should be done with extreme caution, often requiring dose reduction and close monitoring for excessive sedation.[38]

6.1.2 Monoamine Oxidase Inhibitors (MAOIs)

• Interacting Agents: Includes drugs such as phenelzine, tranylcypromine, and isocarboxazid.[8]
• Effect: This combination is contraindicated.[8] MAOIs are known to prolong and significantly intensify the anticholinergic effects of antihistamines like Cyproheptadine, increasing the risk of severe toxicity.[16]
• Management: This combination must be avoided entirely.

6.1.3 Anticholinergic Agents

• Interacting Agents: This includes tricyclic antidepressants, certain antipsychotics, antispasmodics (e.g., dicyclomine), and anti-Parkinson's drugs (e.g., benztropine).[42]
• Effect: The anticholinergic effects are additive. This combination increases the risk of peripheral symptoms (severe dry mouth, blurred vision, constipation, urinary retention) and central anticholinergic toxicity, which can manifest as confusion, disorientation, hallucinations, and delirium, particularly in the elderly.[21]
• Management: Use with caution, especially in vulnerable populations. Patients should be monitored for signs of anticholinergic toxicity. A reduction in the dosage of one or both agents may be necessary if excessive adverse effects develop.[46]

6.1.4 Serotonergic Agents (e.g., SSRIs)

• Interacting Agents: Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, sertraline, and paroxetine.[33]
• Effect: This represents a complex, bidirectional interaction that requires careful clinical judgment. On one hand, Cyproheptadine's potent serotonin antagonism can directly oppose and reverse the therapeutic antidepressant effects of SSRIs.[16] On the other hand, this same antagonism is harnessed to treat certain SSRI-induced side effects, such as anorgasmia.[30] This creates a pharmacological paradox where Cyproheptadine is both an antagonist and a "treatment" for the effects of an SSRI. The underlying pharmacology suggests that Cyproheptadine may block the unwanted effects of serotonin overstimulation at specific receptors (e.g., 5- HT2A​/2C) while hopefully preserving the desired antidepressant effects mediated by other receptors (e.g., 5-HT1A​).
• Management: This requires a sophisticated clinical approach. If used to treat side effects, as-needed (PRN) dosing 1-2 hours before sexual activity may be preferable to scheduled daily use to minimize the risk of negating the primary antidepressant effect.

6.2 Pharmacokinetic Interactions

While Cyproheptadine is known to be a substrate of CYP3A4 and CYP2D6, specific clinical data on interactions with potent inhibitors or inducers of these enzymes were not detailed in the available materials.[21] However, the potential for such interactions exists. The most critical and well-documented interactions are pharmacodynamic. The absolute contraindication with MAOIs and the major warnings regarding CNS depressants and anticholinergics all stem from additive effects at the receptor level. This indicates that the primary clinical danger of Cyproheptadine arises from a patient's total "pharmacodynamic load"—particularly their cumulative anticholinergic and sedative burden—rather than from altered metabolism.

Table 4: Clinically Significant Drug-Drug Interactions

Interacting Drug Class	Example Agents	Mechanism of Interaction	Clinical Effect	Management Strategy
CNS Depressants	Alcohol, Benzodiazepines, Opioids, Barbiturates	Pharmacodynamic (Additive CNS Depression)	Increased sedation, dizziness, psychomotor impairment, respiratory depression.	Moderate Interaction. Counsel patient to avoid alcohol. Use with caution and monitor for excessive sedation. Dose reduction may be needed.
MAO Inhibitors	Phenelzine, Tranylcypromine	Pharmacodynamic (Potentiation of Anticholinergic Effects)	Prolonged and intensified anticholinergic effects (dry mouth, urinary retention, delirium).	Major Interaction / Contraindicated. Avoid combination entirely.
Anticholinergic Agents	Tricyclic Antidepressants, Antispasmodics, some Antipsychotics	Pharmacodynamic (Additive Anticholinergic Effects)	Increased risk of dry mouth, blurred vision, constipation, urinary retention, and central anticholinergic toxicity (confusion, hallucinations).	Moderate Interaction. Use with caution, especially in the elderly. Monitor for signs of toxicity.
SSRIs/Serotonergic Agents	Fluoxetine, Sertraline	Pharmacodynamic (Antagonism at Serotonin Receptors)	Bidirectional: Can reverse therapeutic antidepressant effects. Can also be used to treat SSRI-induced side effects (e.g., anorgasmia).	Moderate Interaction. Requires careful clinical judgment. Consider PRN dosing if used for side effects. Monitor for loss of antidepressant efficacy.

Section 7: Dosage, Administration, and Formulations

This section consolidates practical information regarding the available forms of Cyproheptadine and provides evidence-based dosing guidelines for its various indications across different patient populations.

7.1 Commercially Available Formulations

Cyproheptadine is available in two primary oral formulations, which facilitates its use across a wide age range:

• Tablets: Containing 4 mg of Cyproheptadine HCl.[11]
• Oral Solution/Syrup: Containing 2 mg of Cyproheptadine HCl per 5 mL.[15] The availability of a liquid formulation is a key factor in its widespread and successful use in pediatric populations.

7.2 Dosing and Administration Guidelines

The dosing of Cyproheptadine varies significantly based on the patient's age and the specific therapeutic goal, reflecting the drug's different mechanisms of action. For example, scheduled dosing throughout the day is used to maintain receptor blockade for allergies or appetite stimulation, while a single bedtime dose is used to leverage its peak sedative effect for insomnia.

• General Administration: The medication can be taken with or without food. For consistent therapeutic levels, it should be taken at approximately the same time(s) each day.[15]
• Adult Dosing:
• Allergic Conditions: The typical starting dose is 4 mg administered three times daily. The dose should be adjusted based on patient response, with a usual therapeutic range of 4 to 20 mg per day. The total daily dose should not exceed 0.5 mg/kg/day. An occasional patient may require up to 32 mg per day for adequate relief.[11]
• Cushing's Syndrome (Off-Label): Treatment is typically initiated at 8 mg per day in divided doses, with a gradual increase up to a maximum of 24 mg per day.[16]
• Anorexia Nervosa (Off-Label): A common regimen starts at 2 mg four times daily and is gradually increased over several weeks to a target of up to 8 mg four times daily (total 32 mg/day).[16]
• Pediatric Dosing:
• Safety: The safety and efficacy have not been established in children under 2 years of age.[16]
• Children 2–6 years: The usual dosage is 2 mg two or three times daily. The maximum daily dose in this age group should not exceed 12 mg.[16]
• Children 7–14 years: The usual dosage is 4 mg two or three times daily. The maximum daily dose should not exceed 16 mg.[16]
• Adolescents ≥15 years: Dosing is the same as for adults, with a maximum limit of 0.5 mg/kg/day.[16]
• Geriatric Dosing:
• Due to the increased risk of side effects (dizziness, sedation, hypotension) and the higher likelihood of age-related decreases in hepatic and renal function, dosage should be selected with caution. It is recommended to start at the low end of the adult dosing range.[15]

Table 5: Dosing Regimens by Indication and Age Group

Indication (Status)	Age Group	Starting Dose	Usual Dose Range	Maximum Daily Dose
Allergic Conditions (On-label)	Adults & Adolescents ≥15 yrs	4 mg TID	12–16 mg/day	0.5 mg/kg/day (up to 32 mg)
	Children 7–14 yrs	4 mg BID-TID	8–12 mg/day	16 mg
	Children 2–6 yrs	2 mg BID-TID	4–6 mg/day	12 mg
Appetite Stimulation / Anorexia Nervosa (Off-label)	Adults & Adolescents ≥13 yrs	2 mg QID	Titrate up to 8 mg QID	32 mg
	Children 2–12 yrs	2 mg BID-TID	Titrate based on response	12 mg (2-6 yrs); 16 mg (7-12 yrs)
Migraine Prophylaxis (Off-label)	Adults & Adolescents ≥15 yrs	4 mg BID-TID	8–16 mg/day	20 mg
	Children 2–14 yrs	2 mg BID-TID	4–12 mg/day	12 mg (2-6 yrs); 16 mg (7-14 yrs)
Serotonin Syndrome (Off-label)	Adults & Adolescents	12 mg initial dose, then 2 mg q2h or 4-8 mg q6h	As needed based on symptoms	32 mg/day
Cushing's Syndrome (Off-label)	Adults	8 mg/day (divided)	Titrate up to 24 mg/day	24 mg

Section 8: Conclusion: Synthesis and Future Perspectives

Cyproheptadine is a first-generation medication whose clinical identity is defined by a complex, multi-receptor pharmacology. Patented in 1959 and brought to market as an antihistamine, its most significant clinical impact today stems not from its approved indications but from its potent antiserotonergic properties, which drive a wide and diverse array of off-label uses. This comprehensive analysis reveals a drug that is both a relic of a less selective era of pharmacology and a uniquely versatile tool for modern clinicians.

The therapeutic utility of Cyproheptadine is inextricably linked to its adverse effect profile. The same receptor interactions that enable its use as an antidote for serotonin syndrome or as an appetite stimulant in wasting conditions also cause its burdensome sedative and anticholinergic side effects. This creates a challenging risk-benefit calculation that rightly limits its first-line use for simple allergic rhinitis in an era of more selective, better-tolerated alternatives. Its place in modern therapy is therefore not as a primary agent but as a niche "pharmacological problem-solver." It is often reserved for complex cases or specific populations, particularly in pediatrics, where its broad spectrum of action is advantageous or where other therapeutic options have failed or are unavailable. Its status as a generic, inexpensive medication also ensures its continued relevance and use, particularly in resource-limited settings.

The most striking feature of Cyproheptadine's modern story is the profound gap between the high-level evidence supporting its use and the breadth of its clinical application. This discrepancy calls for further rigorous investigation. Well-designed, randomized controlled trials are urgently needed to formally establish the efficacy, safety, and optimal dosing of Cyproheptadine for its most common off-label applications, especially appetite stimulation in children and migraine prophylaxis. Furthermore, given the rare but serious risk of idiosyncratic hepatotoxicity, future pharmacogenomic studies could be invaluable. Identifying genetic markers that predispose individuals to forming the putative toxic metabolite could allow for more personalized risk stratification and safer prescribing, ensuring that this old but uniquely useful drug can continue to be applied effectively and safely for years to come.

Works cited

1. Cyproheptadine | C21H21N | CID 2913 - PubChem, accessed September 14, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Cyproheptadine
2. Cyproheptadine - brand name list from Drugs.com, accessed September 14, 2025, https://www.drugs.com/ingredient/cyproheptadine.html
3. cyproheptadine | Ligand page - IUPHAR/BPS Guide to PHARMACOLOGY, accessed September 14, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=277
4. CAS No : 129-03-3| Product Name : Cyproheptadine - API - Pharmaffiliates, accessed September 14, 2025, https://www.pharmaffiliates.com/en/129-03-3-cyproheptadine-api-pa3093000.html
5. Cyproheptadine - the NIST WebBook - National Institute of Standards and Technology, accessed September 14, 2025, https://webbook.nist.gov/cgi/cbook.cgi?ID=129-03-3
6. Cyproheptadine HCl hydrate | CAS#129-03-3 | 41354-29-4 | antihistamine | MedKoo, accessed September 14, 2025, https://www.medkoo.com/products/7507
7. Cyproheptadine | 129-03-3 - ChemicalBook, accessed September 14, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB7782550.htm
8. Cyproheptadine (Periactin): Uses & Side Effects - Cleveland Clinic, accessed September 14, 2025, https://my.clevelandclinic.org/health/drugs/18511-cyproheptadine-tablets
9. Cyproheptadine - Wikipedia, accessed September 14, 2025, https://en.wikipedia.org/wiki/Cyproheptadine
10. (PDF) Off-Label Cyproheptadine in Children and Adolescents: Psychiatric Comorbidities, Interacting Variables, Safety, and Risks of Hepatotoxicity - ResearchGate, accessed September 14, 2025, https://www.researchgate.net/publication/367138344_Off-Label_Cyproheptadine_in_Children_and_Adolescents_Psychiatric_Comorbidities_Interacting_Variables_Safety_and_Risks_of_Hepatotoxicity
11. cyproheptadine hydrochloride tablets usp - accessdata.fda.gov, accessed September 14, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/087056s045lbl.pdf
12. pubchem.ncbi.nlm.nih.gov, accessed September 14, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Cyproheptadine#:~:text=Cyproheptadine%20is%20the%20product%20resulting,and%20calcium%2Dchannel%20blocking%20actions.
13. CYPROHEPTADINE HYDROCHLORIDE synthesis - chemicalbook, accessed September 14, 2025, https://www.chemicalbook.com/synthesis/cyproheptadine-hydrochloride.htm
14. CYPROHEPTADINE HYDROCHLORIDE | 969-33-5 - ChemicalBook, accessed September 14, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB2698687.htm
15. Cyproheptadine: MedlinePlus Drug Information, accessed September 14, 2025, https://medlineplus.gov/druginfo/meds/a682541.html
16. Cyproheptadine Hydrochloride Monograph for Professionals - Drugs.com, accessed September 14, 2025, https://www.drugs.com/monograph/cyproheptadine-hydrochloride.html
17. Cyproheptadine - LiverTox - NCBI Bookshelf, accessed September 14, 2025, https://www.ncbi.nlm.nih.gov/books/NBK548422/
18. Definition of cyproheptadine hydrochloride - NCI Drug Dictionary - National Cancer Institute, accessed September 14, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/cyproheptadine-hydrochloride
19. Cyproheptadine | Drug Lookup | Pediatric Care Online - AAP Publications, accessed September 14, 2025, https://publications.aap.org/pediatriccare/drug-monograph/18/5637/Cyproheptadine
20. Cyproheptadine: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed September 14, 2025, https://go.drugbank.com/drugs/DB00434
21. CYPROHEPTADINE - Prescriber's Guide – Children and Adolescents, accessed September 14, 2025, https://www.cambridge.org/core/books/prescribers-guide-children-and-adolescents/cyproheptadine/2091A6E1F719319B027176A056EC3301
22. Safety of Cyproheptadine, an Orexigenic Drug. Analysis of the French National Pharmacovigilance Data-Base and Systematic Review, accessed September 14, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8525494/
23. Serotonin Syndrome | DrugBank Online, accessed September 14, 2025, https://go.drugbank.com/indications/DBCOND0005988
24. Cyproheptadine (Standard) | 5-HT2 Receptor Antagonist | MedChemExpress, accessed September 14, 2025, https://www.medchemexpress.com/cyproheptadine-standard.html
25. What is the mechanism of Cyproheptadine Hydrochloride? - Patsnap Synapse, accessed September 14, 2025, https://synapse.patsnap.com/article/what-is-the-mechanism-of-cyproheptadine-hydrochloride
26. go.drugbank.com, accessed September 14, 2025, https://go.drugbank.com/drugs/DB00434#:~:text=Cyproheptadine%20appears%20to%20exert%20its,binding%20at%20their%20respective%20receptors.&text=Antagonism%20of%20serotonin%20on%20the,ability%20to%20stimulate%20the%20appetite.
27. Cyproheptadine (Cyproheptadine Hydrochloride): Side Effects, Uses, Dosage, Interactions, Warnings - RxList, accessed September 14, 2025, https://www.rxlist.com/cyproheptadine-drug.htm
28. The mechanism of action of cyproheptadine on prolactin release by cultured anterior pituitary cells - PubMed, accessed September 14, 2025, https://pubmed.ncbi.nlm.nih.gov/3923287/
29. Role of Cyproheptadine in Various Psychiatric Conditions - Indian Journal of Private Psychiatry, accessed September 14, 2025, https://www.ijiapp.com/journal/IJPP/role-of-cyproheptadine-in-various-psychiatric-conditions-10.5005_jp-journals-10067-0034/full
30. Cyproheptadine: a psychopharmacological treasure trove? | CNS Spectrums, accessed September 14, 2025, https://www.cambridge.org/core/journals/cns-spectrums/article/cyproheptadine-a-psychopharmacological-treasure-trove/4D1A2DAD89BC07379E6C7D23A9AC5ADF
31. Cyproheptadine - Drugs and Lactation Database (LactMed®) - NCBI Bookshelf, accessed September 14, 2025, https://www.ncbi.nlm.nih.gov/books/NBK501693/
32. Off-Label Cyproheptadine in Children and Adolescents: Psychiatric, accessed September 14, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9922522/
33. Cyproheptadine: uses, dosing, warnings, adverse events, interactions - MedCentral, accessed September 14, 2025, https://www.medcentral.com/drugs/monograph/8879-382541/cyproheptadine-oral
34. A comparison of the pharmacokinetics of oral and sublingual cyproheptadine - PubMed, accessed September 14, 2025, https://pubmed.ncbi.nlm.nih.gov/15083941/
35. Cyproheptadine Disease Interactions - Drugs.com, accessed September 14, 2025, https://www.drugs.com/disease-interactions/cyproheptadine.html
36. Off-Label Cyproheptadine in Children and Adolescents: Psychiatric Comorbidities, Interacting Variables, Safety, and Risks of Hepatotoxicity - PubMed, accessed September 14, 2025, https://pubmed.ncbi.nlm.nih.gov/36788882/
37. Cyproheptadine - Cincinnati Children's Hospital, accessed September 14, 2025, https://www.cincinnatichildrens.org/health/c/cyproheptadine
38. Cyproheptadine | Davis's Drug Guide for Rehabilitation Professionals, accessed September 14, 2025, https://fadavispt.mhmedical.com/content.aspx?bookid=1873§ionid=139006849
39. cyproheptadine - Drug Summary, accessed September 14, 2025, https://www.pdr.net/drug-summary/Cyproheptadine-Hydrochloride-Syrup-cyproheptadine-hydrochloride-2646
40. Cyproheptadine Hydrochloride Tablets, USP Rx only - DailyMed, accessed September 14, 2025, https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=98e71865-83dd-4e29-8308-c56e36731d96&type=display
41. Cyproheptadine - Drug Information Page 1 of 2 1/9/2024 file:///C:/Program%20Files%20(x86)/VPR/DrugInfo.htm, accessed September 14, 2025, https://aliciapacvet.com/wp-content/uploads/2024/01/DrugInfo-Cyproheptadine.pdf
42. Side Effects of Periactin (cyproheptadine): Interactions & Warnings - MedicineNet, accessed September 14, 2025, https://www.medicinenet.com/side_effects_of_periactin_cyproheptadine/side-effects.htm
43. Drug Interaction Report: cyproheptadine, Xanax - Drugs.com, accessed September 14, 2025, https://www.drugs.com/interactions-check.php?drug_list=765-0,133-54&professional=1
44. reference.medscape.com, accessed September 14, 2025, https://reference.medscape.com/drug/cyproheptadine-343389#:~:text=Contraindicated.-,Comment%3A%20MAO%20inhibitors%20may%20prolong%20and%20intensify%20the%20anticholinergic%20effects,serotonergic%20effect%20of%20MAO%20inhibitors.&text=cyproheptadine%20decreases%20effects%20of%20metyrapone%20by%20pharmacodynamic%20antagonism.
45. go.drugbank.com, accessed September 14, 2025, https://go.drugbank.com/drugs/DB00434#:~:text=Benmoxin%20may%20increase%20the%20anticholinergic%20activities%20of%20Cyproheptadine.&text=Benperidol-,The%20risk%20or%20severity%20of%20CNS%20depression%20can%20be,Cyproheptadine%20is%20combined%20with%20Benperidol.&text=Benzatropine-,The%20risk%20or%20severity%20of%20adverse%20effects%20can%20be,Benzatropine%20is%20combined%20with%20Cyproheptadine.
46. Drug Interaction Report: cyproheptadine, PMS Relief, accessed September 14, 2025, https://www.drugs.com/interactions-check.php?drug_list=765-0,75-15614&professional=1