Bretisilocin, also known by its developmental code name GM-2505 and as 5-fluoro-''N''-methyl-''N''-ethyltryptamine (5F-MET or 5-fluoro-MET), is a

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 ...

of the

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 ...

family which is under development for the treatment of

major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive depression (mood), low mood, low self-esteem, and anhedonia, loss of interest or pleasure in normally ...

. It is an analogue of

dimethyltryptamine Dimethyltryptamine (DMT), also known as ''N'',''N''-dimethyltryptamine (''N'',''N''-DMT), is a Psychedelic drug, serotonergic hallucinogen and Investigational New Drug, investigational drug of the substituted tryptamine, tryptamine family tha ...

(DMT) and is the 5-

fluorinated In chemistry, halogenation is a chemical reaction which introduces one or more halogens into a chemical compound. Halide-containing compounds are pervasive, making this type of transformation important, e.g. in the production of polymers, drugs. ...

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 ...

methylethyltryptamine Methylethyltryptamine (MET), also known as ''N''-methyl-''N''-ethyltryptamine (''N'',''N''-MET), is a serotonergic psychedelic of the tryptamine family. It is closely related to dimethyltryptamine (DMT) and to diethyltryptamine (DET). The drug ...

(MET). Bretisilocin's

route of administration In pharmacology and toxicology, a route of administration is the way by which a medication, drug, fluid, poison, or other substance is taken into the body. Routes of administration are generally classified by the location at which the substance ...

intravenous infusion Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...

. The drug acts as a potent and well-balanced

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, ...

5-HT_2A and 5-HT_2C receptor

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 ...

, serotonin 5-HT_2B receptor

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.serotonin releasing agent A serotonin releasing agent (SRA) is a type of drug that induces the release of serotonin into the neuronal synaptic cleft. A selective serotonin releasing agent (SSRA) is an SRA with less significant or no efficacy in producing neurotransmitter ...

. It produces psychedelic-like effects in animals and similarly produces robust

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 effects in humans. The duration of bretisilocin is 60 to 90minutes and is intermediate between the durations of DMT and

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 ...

. It has been regarded by its developer as an improvement of DMT. Bretisilocin is under development by

Gilgamesh Pharmaceuticals Gilgamesh Pharmaceuticals is a pharmaceutical company that is developing psychedelic and related drugs as medicines. It is a "discovery stage" company and is focused on developing new chemical entities. Its drug candidates include the ketamine- ...

. As of March 2024, it is in

phase 2 Michael Lawrence Marrow (August 2, 1955 – December 12, 2019), known as PHASE 2 and Lonny Wood, was an American aerosol paint artist based in New York City. Mostly active in the 1970s, Phase 2 is generally credited with originating the "bubble ...

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s for the treatment of

Effects

Bretisilocin, administered

intravenously Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...

in clinical studies, produces effects in humans including "

altered states of consciousness An altered state of consciousness (ASC), also called an altered state of mind, altered mental status (AMS) or mind alteration, is any condition which is significantly different from a normal waking state. It describes induced changes in one's me ...

, altered visual

depth perception Depth perception is the ability to perceive distance to objects in the world using the visual system and visual perception. It is a major factor in perceiving the world in three dimensions. Depth sensation is the corresponding term for non-hum ...

, abnormal thinking,

euphoric mood Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and danci ...

feeling drunk Substance intoxication is a transient condition of altered consciousness and behavior associated with recent use of a substance. It is often maladaptive and impairing, but reversible. If the symptoms are severe, the term "substance intoxication ...

, feeling of

body temperature Thermoregulation is the ability of an organism to keep its body temperature within certain boundaries, even when the surrounding temperature is very different. A thermoconforming organism, by contrast, simply adopts the surrounding temperature ...

changes, relaxation,

sensory processing disorder Sensory processing disorder (SPD), formerly known as sensory integration dysfunction, is a condition in which multisensory input is not adequately processed in order to provide appropriate responses to the demands of the environment. Sensory ...

(including intense visual effects with color changes),

sensory overload Sensory overload occurs when one or more of the body's senses experiences over-stimulation from the environment. There are many environmental elements that affect an individual. Examples of these elements are urbanization, crowding, noise, mas ...

, and time perception altered". It also produces transient increases in

blood pressure Blood pressure (BP) is the pressure of Circulatory system, circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term ...

. The subjective effects of bretisilocin were described as very robust and consistent in strength with the effects of other psychedelics including

LSD Lysergic acid diethylamide, commonly known as LSD (from German ; often referred to as acid or lucy), is a semisynthetic, hallucinogenic compound derived from ergot, known for its powerful psychological effects and serotonergic activity. I ...

DMT Dimethyltryptamine (DMT), also known as ''N'',''N''-dimethyltryptamine (''N'',''N''-DMT), is a serotonergic hallucinogen and investigational drug of the tryptamine family that occurs naturally in many plants and animals, including humans. D ...

, and

Interactions

Pharmacology

Pharmacodynamics

Bretisilocin acts as a potent and well-balanced

5-HT_2A and 5-HT_2C receptor

, serotonin 5-HT_2B receptor

. In another study however, it was a moderate-

efficacy Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as '' effectiveness'', and it has often been used synonymously, although in pharmacology a distinction is now often made betwee ...

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

of the serotonin 5-HT_2B receptor. The drug appears to have negligible activity as a serotonin 5-HT_1A receptor agonist. However, another study found that it was a serotonin 5-HT_1A receptor

full agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agoni ...

, with an at this receptor that was about 44-fold less potent than at the serotonin 5-HT_2A receptor. The

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 ...

(K_i) of bretisilocin for the serotonin 5-HT_2A receptor was 4.9nM with DOI as the

radioligand A radioligand is a microscopic particle which consists of a Radiopharmaceutical, therapeutic radioactive isotope and the cell-targeting compound - the ligand. The ligand is the target binding site, it may be on the surface of the targeted cancer c ...

and 140nM with

ketanserin Ketanserin, sold under the brand name Sufrexal, is an antihypertensive agent which is used to treat arterial hypertension and vasospasm, vasospastic disorders. It is also used in scientific research as an antiserotonergic medication, agent in th ...

as the radioligand. Its () values were 15.0–20.6nM (80.6–87.6%) at the serotonin 5-HT_2A receptor and 9.5nM (85.1%) at the serotonin 5-HT_2C receptor, whereas its at the serotonin 5-HT_2B receptor was 5.8nM. It showed much higher

at the serotonin 5-HT_2A receptor than its

parent compound In chemistry, a parent structure is the structure of an unadorned ion or molecule from which derivatives can be visualized. Parent structures underpin systematic nomenclature and facilitate classification. Fundamental parent structures have one ...

MET ( = 87.6% vs. 36.2%, respectively). Bretisilocin showed very weak activity at the serotonin 5-HT_1A receptor ( = 16,918nM, = 83.0%). In addition to its actions at the serotonin 5-HT₂ receptors, it is a

partial Partial may refer to: Mathematics *Partial derivative, derivative with respect to one of several variables of a function, with the other variables held constant ** ∂, a symbol that can denote a partial derivative, sometimes pronounced "partial d ...

serotonin releasing agent in rat brain

synaptosome A synaptosome is an isolated synaptic terminal from a neuron. Synaptosomes are obtained by mild homogenization of nervous tissue under isotonic conditions and subsequent fractionation using differential and density gradient centrifugation. Liquid ...

s, with an of 8.4–15.7nM and an of 66.8–71.4%. Bretisilocin is also a

serotonin reuptake inhibitor A serotonin reuptake inhibitor (SRI) is a type of drug which acts as a reuptake inhibitor of the neurotransmitter serotonin (5-hydroxytryptamine, or 5-HT) by blocking the drug action, action of the serotonin transporter (SERT). This in turn lea ...

to a much weaker extent ( = 418.9nM). Additional values have also been published. Bretisilocin is related to

and is considered by its developer to be an improved version of DMT. It also induces more serotonin release than DMT, which may provide it with more

entactogen Entactogens, also known as empathogens or connectogens, are a class of psychoactive drugs that induce the production of experiences of emotional communion, oneness, connectedness, emotional openness—that is, empathy—as particularly observe ...

-like qualities compared to DMT. Bretisilocin produces 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 rodents. It shows

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

-like effects in rodents. The drug dose-dependently produces

hypolocomotion Locomotor activity is a measure of animal behavior which is employed in scientific research. Hyperlocomotion, also known as locomotor hyperactivity, hyperactivity, or increased locomotor activity, is an effect of certain drugs in animals in whi ...

in rodents similarly to many other serotonergic psychedelics. Likewise, it produces anti-obsessional effects in the form of reduced marble burying in rodents. Bretisilocin does not produce

conditioned place preference Conditioned place preference (CPP) is a form of Pavlovian conditioning used to measure the motivational effects of objects or experiences. This motivation comes from the pleasurable aspect of the experience, so that the brain can be reminded of th ...

(CPP) in rodents, suggesting lack of

reinforcing In behavioral psychology, reinforcement refers to consequences that increase the likelihood of an organism's future behavior, typically in the presence of a particular '' antecedent stimulus''. For example, a rat can be trained to push a lever ...

properties.

Pharmacokinetics

The

elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...

of bretisilocin in humans is about 45minutes. Compared to other serotonergic psychedelics like

, bretisilocin is said to have a shorter

duration of action Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms (fo ...

, but is longer-lasting than

. Its duration is about 60 to 90minutes, whereas psilocybin has a duration of multiple hours and DMT has a duration of as short as 10minutes.

Chemistry

Bretisilocin, also known as 5-fluoro-''N''-methyl''-N''-ethyltryptamine, 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 ...

. It is a derivative of

(DMT) and

(MET) as well as of 5-fluorotryptamine (5-FT). Some analogues of bretisilocin include

5-fluoro-DMT 5-Fluoro-''N'',''N''-dimethyltryptamine (5-fluoro-DMT, 5F-DMT) is a tryptamine derivative related to compounds such as 5-bromo-DMT and 5-MeO-DMT. It is known to have affinity for and to act as an agonist of the serotonin 5-HT1A and 5-HT2A r ...

5-fluoro-DET 5-Fluoro-DET (5F-DET, 5-fluoro-''N,N''-diethyltryptamine) is a tryptamine derivative related to drugs such as DET and 5-MeO-DET. It acts as an inhibitor of the enzyme myeloperoxidase, and is also thought to be an agonist An agonist is a chem ...

, 5-fluoro-EPT, 5-fluoro-AMT,

5-fluoro-AET 5-Fluoro-AET, also known as 5-fluoro-α-ethyltryptamine or by the code name PAL-545, is a substituted tryptamine derivative which acts as a serotonin–dopamine releasing agent (SDRA) and as an agonist of the serotonin 5-HT2A receptor. Its va ...

5-MeO-MET 5-MeO-MET, also known as 5-methoxy-''N''-methyl-''N''-ethyltryptamine, is a serotonin receptor modulator, putative serotonergic psychedelic, and relatively rare designer drug of the tryptamine family related to psychedelic drugs like methylethylt ...

, and

7-F-5-MeO-MET 7-F-5-MeO-MET (5-MeO-7-F-MET, 5-Methoxy-7-fluoro-''N''-methyl-''N''-ethyltryptamine) is a tryptamine derivative which acts as a serotonin receptor agonist selective for the 5-HT2 subtypes, with a EC50#Calculation of EC50, pEC50 of 8.71 at 5-HT2A ...

, among others.

Society and culture

Names

''Bretisilocin'' is the generic name of the drug and its .https://iris.who.int/bitstream/handle/10665/380497/9789240107038-eng.pdf "bretisilocinum bretisilocin N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethan-1-amine serotonin (5-HT2A) receptor agonist" It is also known by its developmental code name ''GM-2505''.

Research

Bretisilocin is under development as a potential

pharmaceutical drug Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the ...