4-Hydroxytryptamine (4-HT, 4-HTA), also known as ''N'',''N''-didesmethylpsilocin, is a

naturally occurring A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical ...

tryptamine Tryptamine is an indolamine metabolite of the essential amino acid tryptophan. The chemical structure is defined by an indole—a fused benzene and pyrrole ring, and a 2-aminoethyl group at the second carbon (third aromatic atom, with the firs ...

alkaloid Alkaloids are a broad class of natural product, naturally occurring organic compounds that contain at least one nitrogen atom. Some synthetic compounds of similar structure may also be termed alkaloids. Alkaloids are produced by a large varie ...

. It is closely related chemically to the

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

, the

psychedelic Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states (known as psychedelic experiences or "trips") and a perceived "expansion of consciousness". Also referred to as classic halluci ...

psilocin Psilocin, also known as 4-hydroxy-''N'',''N''-dimethyltryptamine (4-HO-DMT), is a substituted tryptamine alkaloid and a serotonergic psychedelic. It is present in most psychedelic mushrooms together with its phosphorylated counterpart psilocy ...

, and is the active form of the tryptamine alkaloid norbaeocystin. The compound is a

serotonin receptor agonist A serotonin receptor agonist is an agonist of one or more serotonin receptors. They activate serotonin receptors in a manner similar to that of serotonin (5-hydroxytryptamine; 5-HT), a neurotransmitter and hormone and the endogenous ligand of t ...

, including of the serotonin 5-HT_2A receptor, but in contrast to certain closely related compounds like psilocin, appears to be non-

hallucinogen Hallucinogens, also known as psychedelics, entheogens, or historically as psychotomimetics, are a large and diverse class of psychoactive drugs that can produce altered states of consciousness characterized by major alterations in thought, mo ...

ic. 4-HT may occur naturally in '' Psilocybe baeocystis'' and ''

Psilocybe cyanescens ''Psilocybe cyanescens'', commonly known as the wavy cap or potent psilocybe, is a species of potent psychedelic mushroom. The main compounds responsible for its psychedelic effects are psilocybin and psilocin. It belongs to the family Hymenogas ...

''. It may serve as an alternative precursor in the

biosynthesis Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme-Catalysis, catalyzed processes where chemical substances absorbed as nutrients (or previously converted through biosynthe ...

psilocybin Psilocybin, also known as 4-phosphoryloxy-''N'',''N''-dimethyltryptamine (4-PO-DMT), is a natural product, naturally occurring tryptamine alkaloid and Investigational New Drug, investigational drug found in more than List of psilocybin mushroom ...

(4-PO-DMT) in

psilocybin mushroom Psilocybin mushrooms, or psilocybin-containing mushrooms, commonly known as magic mushrooms or as shrooms, are a type of hallucinogenic mushroom and a polyphyletic informal group of fungi that contain the prodrug psilocybin, which turns into t ...

Pharmacology

4-HT is a potent

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

of the serotonin 5-HT_2A receptor similarly to psilocin ( = 38nM and 21nM, respectively). It also shows

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

for the serotonin 5-HT_2C receptor (K_i = 40nM), the serotonin 5-HT_1A receptor (K_i = 95nM), and the serotonin 5-HT_1B receptor (K_i = 1,050nM). The drug produces serotonergic

peripheral A peripheral device, or simply peripheral, is an auxiliary hardware device that a computer uses to transfer information externally. A peripheral is a hardware component that is accessible to and controlled by a computer but is not a core compo ...

effects in animals, shows similar

metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

and

metabolic stability Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. More generally, xenobiotic metabolism (from the Greek xenos "stranger" and biotic "related to living beings") is the set of ...

to psilocin, and appears to cross the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

and hence is centrally penetrant. Surprisingly however, the compound, similarly to baeocystin, norbaeocystin, and norpsilocin, does not produce the

head-twitch response The head-twitch response (HTR), also sometimes known as wet dog shakes (WDS) in rats, is a rapid side-to-side head movement that occurs in mice and rats in association with serotonin 5-HT2A receptor activation. Serotonergic psychedelics like lys ...

, a behavioral proxy of psychedelic effects, in animals, and hence is putatively non-hallucinogenic. In older literature, the

psychoactive A psychoactive drug, psychopharmaceutical, mind-altering drug, consciousness-altering drug, psychoactive substance, or psychotropic substance is a chemical substance that alters psychological functioning by modulating central nervous system acti ...

effects of 4-hydroxylated tryptamines have been said to increase in the series of 4-hydroxytryptamine, 4-hydroxy-''N''-methyltryptamine (norpsilocin], and 4-hydroxy-''N'',''N''-dimethyltryptamine (psilocin). The reason for the lack of hallucinogenic effects with 4-HT and related compounds is unknown, but may be due to biased agonist, biased agonism of the serotonin 5-HT_2A receptor; or, more specifically, biased agonism for the β-arrestin2 signaling pathway. Norbaeocystin is thought to be a

prodrug A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be ...

of 4-HT, analogously to how psilocybin is a prodrug of psilocin and how baeocystin is thought to be a prodrug of norpsilocin.

Chemistry

4-HT, also known as 4-hydroxytryptamine, is a

substituted tryptamine Substituted tryptamines, or simply tryptamines, also known as serotonin analogues (i.e., 5-hydroxytryptamine analogues), are organic compounds which may be thought of as being derived from tryptamine itself. The molecular structures of all trypt ...

derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...

. It is a

positional isomer In chemistry, a structural isomer (or constitutional isomer in the IUPAC nomenclature) of a compound is a compound that contains the same number and type of atoms, but with a different connectivity (i.e. arrangement of bonds) between them. The ...

of the

(5-hydroxytryptamine; 5-HT), an analogue of the

serotonergic psychedelic Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states (known as psychedelic experiences or "trips") and a perceived "expansion of consciousness". Also referred to as classic halluci ...

(4-HO-DMT), and the dephosphorylated form of the tryptamine alkaloid norbaeocystin (4-phosphoryloxytryptamine; 4-PO-T). The predicted log P of 4-HT is 0.65 to 1.1.

Derivatives

A large number of 4-hydroxytryptamine

s are known. These include

(4-HO-DMT), norpsilocin (4-HO-NMT), 4-HO-DALT, 4-HO-DBT, 4-HO-DET, 4-HO-DiPT, 4-HO-DPT,

4-HO-MET 4-HO-MET, also known as 4-hydroxy-''N''-methyl-''N''-ethyltryptamine or as metocin, is a lesser-known psychedelic drug of the tryptamine family related to psilocin. It is a close structural and functional analogue of psilocin (4-HO-DMT) and is ...

, 4-HO-MiPT, 4-HO-MPT, 4-HO-NiPT, 4-HO-pyr-T, and 4-HO-TMT, among others. In addition, 4-

methoxy In organic chemistry, a methoxy group is the functional group consisting of a methyl group bound to oxygen. This alkoxy group has the formula . On a benzene ring, the Hammett equation classifies a methoxy substituent at the ''para'' position a ...

derivatives such as 4-MeO-DiPT, 4-MeO-DMT, and 4-MeO-MiPT; 4- acetoxy derivative such as

4-AcO-DMT 4-Acetoxy-''N'',''N''-dimethyltryptamine (4-AcO-DMT or 4-acetoxy-DMT), also known as ''O''-acetylpsilocin or psilacetin, is a psychedelic drug of the tryptamine family related to psilocybin and psilocin. It is a synthetic derivative of psiloc ...

(psilacetin), 4-AcO-DET, 4-AcO-DALT, 4-AcO-DiPT, 4-PrO-DiPT, and

4-PrO-DMT 4-Propionoxy-''N,N''-dimethyltryptamine (4-PrO-DMT, or O-Propionylpsilocin) is a synthetic psychedelic drug from the tryptamine family with psychedelic effects, and is believed to act as a prodrug for psilocin. It produces a head-twitch response ...

; and 4- phosphoryloxy derivatives such as

(4-PO-DMT), baeocystin (4-PO-NMT), norbaeocystin (4-PO-T), and aeruginascin (4-PO-TMT) are known. Many or all of these compounds are

s and/or

History

4-HT was first described in the

scientific literature Scientific literature encompasses a vast body of academic papers that spans various disciplines within the natural and social sciences. It primarily consists of academic papers that present original empirical research and theoretical ...

by 1959. Its

pharmacology Pharmacology is the science of drugs and medications, including a substance's origin, composition, pharmacokinetics, pharmacodynamics, therapeutic use, and toxicology. More specifically, it is the study of the interactions that occur betwee ...

was first thoroughly characterized in 2024.

References

{{DEFAULTSORT:Hydroxytryptamine, 4- Human drug metabolites 4-Hydroxytryptamines Non-hallucinogenic 5-HT2A receptor agonists Serotonin receptor agonists Tryptamine alkaloids

Pharmacology

Chemistry

Derivatives

History

See also

References