# Bretisilocin

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 of the tryptamine family which is under development for the treatment of major depressive disorder. It is an analogue of dimethyltryptamine (DMT) and is the 5-fluorinated derivative of methylethyltryptamine (MET). Bretisilocin's route of administration is intravenous infusion.
The drug acts as a potent and well-balanced serotonin 5-HT$_{2A}$ and 5-HT$_{2C}$ receptor agonist, serotonin 5-HT$_{2B}$ receptor antagonist, and serotonin releasing agent. It produces psychedelic-like effects in animals and similarly produces robust hallucinogenic effects in humans. The duration of bretisilocin is 60 to 90 minutes and is intermediate between the durations of DMT and psilocybin. It has been regarded by its developer as an improvement of DMT.
Bretisilocin is under development by Gilgamesh Pharmaceuticals. As of March 2024, it is in phase 2 clinical trials for the treatment of major depressive disorder.

## Effects

Bretisilocin, administered intravenously in clinical studies, produces effects in humans including "altered states of consciousness, altered visual depth perception, abnormal thinking, euphoric mood, feeling drunk, feeling of body temperature changes, relaxation, sensory processing disorder (including intense visual effects with color changes), sensory overload, and time perception altered". It also produces transient increases in blood pressure. The subjective effects of bretisilocin were described as very robust and consistent in strength with the effects of other psychedelics including LSD, DMT, and psilocybin.

## Pharmacology
### Pharmacodynamics

Bretisilocin acts as a potent and well-balanced serotonin 5-HT$_{2A}$ and 5-HT$_{2C}$ receptor agonist, serotonin 5-HT$_{2B}$ receptor antagonist, and serotonin releasing agent. It appears to have negligible activity as a serotonin 5-HT$_{1A}$ receptor agonist.
The affinity (K$_i$) of bretisilocin for the serotonin 5-HT$_{2A}$ receptor was 4.9 nM with DOI as the radioligand and 140 nM with ketanserin as the radioligand. Its EC$_{50}$Tooltip half-maximal effective concentration (E$_{max}$Tooltip maximal efficacy) values were 15.0–20.6 nM (80.6–87.6%) at the serotonin 5-HT$_{2A}$ receptor and 9.5 nM (85.1%) at the serotonin 5-HT$_{2C}$ receptor, whereas its IC$_{50}$Tooltip half-maximal inhibitory concentration at the serotonin 5-HT$_{2B}$ receptor was 5.8 nM. It showed much higher efficacy at the serotonin 5-HT$_{2A}$ receptor than its parent compound MET (E$_{max}$ = 87.6% vs. 36.2%, respectively). Bretisilocin showed very weak activity at the serotonin 5-HT$_{1A}$ receptor (EC$_{50}$ = 16,918 nM, E$_{max}$ = 83.0%). In addition to its actions at the serotonin 5-HT$_2$ receptors, it is a partial serotonin releasing agent in rat brain synaptosomes, with an EC$_{50}$ of 8.4–15.7 nM and an E$_{max}$ of 66.8–71.4%. Bretisilocin is also a serotonin reuptake inhibitor to a much weaker extent (IC$_{50}$ = 418.9 nM).
Bretisilocin is related to DMT 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-like qualities compared to DMT. Bretisilocin produces the head-twitch response, a behavioral proxy of psychedelic effects, in rodents. It shows antidepressant-like effects in rodents. The drug dose-dependently produces hypolocomotion 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 (CPP) in rodents, suggesting lack of reinforcing properties.

### Pharmacokinetics

The elimination half-life of bretisilocin in humans is about 45 minutes. Compared to other serotonergic psychedelics like psilocybin, bretisilocin is said to have a shorter duration of action, but is longer-lasting than DMT. Its duration is about 60 to 90 minutes, whereas psilocybin has a duration of multiple hours and DMT has a duration of as short as 10 minutes.

## Chemistry

Bretisilocin, also known as 5-fluoro-N-methyl-N-ethyltryptamine, is a substituted tryptamine derivative. It is a derivative of dimethyltryptamine (DMT) and methylethyltryptamine (MET) as well as of 5-fluorotryptamine (5-FT). Some analogues of bretisilocin include 5-fluoro-DMT, 5-fluoro-DET, 5-fluoro-EPT, 5-fluoro-AMT, 5-fluoro-AET, 5-MeO-MET, and 7-F-5-MeO-MET, among others.

## Society and culture
### Names

Bretisilocin is the generic name of the drug and its INNTooltip International Nonproprietary Name. It is also known by its developmental code name GM-2505.

## Research

Bretisilocin is under development as a potential pharmaceutical drug by Gilgamesh Pharmaceuticals. As of March 2024, it is in phase 2 clinical trials for the treatment of major depressive disorder.