Bretisilocin
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| Other names | GM-2505; GM2505; 5-Fluoro-N-methyl-N-ethyltryptamine; 5F-MET; 5-Fluoro-MET |
| Routes of administration | Intravenous[1][2][3] |
| Drug class | Serotonergic psychedelic; Hallucinogen; Serotonin 5-HT2A and 5-HT2C receptor agonist; Serotonin 5-HT2B receptor antagonist; Serotonin releasing agent |
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| Pharmacokinetic data | |
| Elimination half-life | 45 minutes[2] |
| Duration of action | 60–90 minutes[4] |
| Identifiers | |
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| ChEMBL | |
| Chemical and physical data | |
| Formula | C13H17FN2 |
| Molar mass | 220.291 g·mol−1 |
| 3D model (JSmol) | |
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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.[1][5][2] It is an analogue of dimethyltryptamine (DMT) and is the 5-fluorinated derivative of methylethyltryptamine (MET).[6] Bretisilocin's route of administration is intravenous infusion.[1][2][3]
The drug acts as a potent and well-balanced serotonin 5-HT2A and 5-HT2C receptor agonist, serotonin 5-HT2B receptor antagonist, and serotonin releasing agent.[7] It produces psychedelic-like effects in animals and similarly produces robust hallucinogenic effects in humans.[7][2] The duration of bretisilocin is 60 to 90 minutes and is intermediate between the durations of DMT and psilocybin.[4][8][3][9][6] It has been regarded by its developer as an improvement of DMT.[9]
Bretisilocin is under development by Gilgamesh Pharmaceuticals.[1] As of March 2024, it is in phase 2 clinical trials for the treatment of major depressive disorder.[1]
Effects
[edit]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".[2][3] It also produces transient increases in blood pressure.[2][3] 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.[2][3]
Pharmacology
[edit]Pharmacodynamics
[edit]Bretisilocin acts as a potent and well-balanced serotonin 5-HT2A and 5-HT2C receptor agonist, serotonin 5-HT2B receptor antagonist, and serotonin releasing agent.[7] It appears to have negligible activity as a serotonin 5-HT1A receptor agonist.[7]
The affinity (Ki) of bretisilocin for the serotonin 5-HT2A receptor was 4.9 nM with DOI as the radioligand and 140 nM with ketanserin as the radioligand.[7] Its EC50 (Emax) values were 15.0–20.6 nM (80.6–87.6%) at the serotonin 5-HT2A receptor and 9.5 nM (85.1%) at the serotonin 5-HT2C receptor, whereas its IC50 at the serotonin 5-HT2B receptor was 5.8 nM.[7] It showed much higher efficacy at the serotonin 5-HT2A receptor than its parent compound MET (Emax = 87.6% vs. 36.2%, respectively).[6] Bretisilocin showed very weak activity at the serotonin 5-HT1A receptor (EC50 = 16,918 nM, Emax = 83.0%).[7][6] In addition to its actions at the serotonin 5-HT2 receptors, it is a partial serotonin releasing agent in rat brain synaptosomes, with an EC50 of 8.4–15.7 nM and an Emax of 66.8–71.4%.[7] Bretisilocin is also a serotonin reuptake inhibitor to a much weaker extent (IC50 = 418.9 nM).[6]
Bretisilocin is related to DMT and is considered by its developer to be an improved version of DMT.[9] It also induces more serotonin release than DMT, which may provide it with more entactogen-like qualities compared to DMT.[9] Bretisilocin produces the head-twitch response, a behavioral proxy of psychedelic effects, in rodents.[7][2][6] It shows antidepressant-like effects in rodents.[7][8] The drug dose-dependently produces hypolocomotion in rodents similarly to many other serotonergic psychedelics.[6][10] Likewise, it produces anti-obsessional effects in the form of reduced marble burying in rodents.[6] Bretisilocin does not produce conditioned place preference (CPP) in rodents, suggesting lack of reinforcing properties.[6]
Pharmacokinetics
[edit]The elimination half-life of bretisilocin in humans is about 45 minutes.[2] Compared to other serotonergic psychedelics like psilocybin, bretisilocin is said to have a shorter duration of action, but is longer-lasting than DMT.[8][3][6] 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.[4][9]
Chemistry
[edit]Bretisilocin, also known as 5-fluoro-N-methyl-N-ethyltryptamine, is a substituted tryptamine derivative.[6] It is a derivative of dimethyltryptamine (DMT) and methylethyltryptamine (MET).[4][6] 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
[edit]Names
[edit]Bretisilocin is the generic name of the drug and its INN.[11] It is also known by its developmental code name GM-2505.[1][7][2]
Research
[edit]Bretisilocin is under development as a potential pharmaceutical drug by Gilgamesh Pharmaceuticals.[1] As of March 2024, it is in phase 2 clinical trials for the treatment of major depressive disorder.[1]
See also
[edit]References
[edit]- ^ a b c d e f g h "GM 2505". AdisInsight. 22 March 2024. Retrieved 30 August 2024.
- ^ a b c d e f g h i j k "ACNP 62nd Annual Meeting: Poster Abstracts P1 - P250: P238. Subjective and Pharmacodynamic Effects of the Novel 5-HT2A Receptor Agonist GM-2505 in Healthy Volunteers Show High Translatability From Rodent Data and Hold Promise for Future Development in Patients With Depression". Neuropsychopharmacology. 48 (Suppl 1). Springer Science and Business Media LLC: 63–210 (202–203). December 2023. doi:10.1038/s41386-023-01755-5. PMC 10729595. PMID 38040809.
- ^ a b c d e f g Umbricht D, Christian E, Winters J, Raines S, Hughes ZA, Leong W, et al. (2024). "Pharmacokinetic, pharmacodynamic and subjective and effects of the novel 5-HT2A receptor agonist GM-2505 in healthy volunteers". Neuroscience Applied. 3: 104845. doi:10.1016/j.nsa.2024.104845.
- ^ a b c d Peplow M (22 June 2024). "Should Next-Generation Psychedelics Skip the Trip?". Scientific American. Archived from the original on 26 June 2024. Retrieved 20 February 2025.
Gilgamesh is also working on GM-2505, a 5-HT2A agonist that is structurally related to psilocybin and DMT. GM-2505 completed a phase 1 trial late last year and should enter phase 2 for major depressive disorder this year. Its psychedelic effect lasts 60 to 90 minutes — long enough for patients to "explore the altered state of consciousness that might be needed for long-term durable efficacy," Krugel says, yet within a timeframe that is manageable for healthcare systems. "Personally, I believe that the hallucinogenic effects are an important component, as multiple hallucinogenic compounds have demonstrated durable, transformational changes from a single dose in human studies," he adds.
- ^ Witkin JM, Golani LK, Smith JL (April 2023). "Clinical pharmacological innovation in the treatment of depression". Expert Review of Clinical Pharmacology. 16 (4): 349–362. doi:10.1080/17512433.2023.2198703. PMID 37000975.
GM-2505 is a dual-acting compound with both agonist activity at 5-HT 2A receptors and a releaser of 5-HT. [...]
- ^ a b c d e f g h i j k l "Methods of treating mood disorders". Google Patents. 2022. Retrieved 14 November 2024.
- ^ a b c d e f g h i j k "ACNP 61st Annual Meeting: Poster Abstracts P1 - P270". Neuropsychopharmacology. 47 (Suppl 1): 63–219. December 2022. doi:10.1038/s41386-022-01484-1. PMC 9714397. PMID 36456693.
- ^ a b c Hughes Z, Klein A, Dvorak D, Austin E, Kiss L, Marek G, et al. (2023). "22. GM-2505 has Rapid Onset Antidepressant Activity and Causes Dose-Dependent Changes in qEEG With Increasing 5-HT2A Receptor Occupancy". Biological Psychiatry. 93 (9): S102 – S103. doi:10.1016/j.biopsych.2023.02.262.
- ^ a b c d e Gunther M (31 January 2023). "Gilgamesh Tweaks Known Psychedelics To Improve Therapies". Lucid News - Psychedelics, Consciousness Technology, and the Future of Wellness. Retrieved 20 February 2025.
- ^ Halberstadt AL, Geyer MA (2018). "Effect of Hallucinogens on Unconditioned Behavior". Behavioral Neurobiology of Psychedelic Drugs. Curr Top Behav Neurosci. Vol. 36. pp. 159–199. doi:10.1007/7854_2016_466. ISBN 978-3-662-55878-2. PMC 5787039. PMID 28224459.
- ^ 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"