Bretisilocin

Last updated

Bretisilocin
5-F-MET.svg
Clinical data
Other namesGM-2505; GM2505; 5-Fluoro-N-methyl-N-ethyltryptamine; 5F-MET; 5-F-MET; 5-Fluoro-MET
Routes of
administration 		Intravenous [1] [2] [3] [4]
Drug class Serotonergic psychedelic; Hallucinogen; Serotonin 5-HT2A and 5-HT2C receptor agonist; Serotonin 5-HT2B receptor partial agonist or antagonist; Serotonin releasing agent
Legal status
Legal status
  • Investigational
Pharmacokinetic data
Onset of action 10–20 minutes (peak) [2]
Elimination half-life 45 (40–50) minutes [2] [3]
Duration of action 60–90 minutes [2] [5]
Identifiers
  • N-ethyl-2-(5-fluoro-1H-indol-3-yl)-N-methylethanamine
CAS Number
PubChem CID
ChemSpider
ChEMBL
Chemical and physical data
Formula C13H17FN2
Molar mass 220.291 g·mol−1
3D model (JSmol)
  • CCN(C)CCC1=CNC2=C1C=C(C=C2)F
  • InChI=1S/C13H17FN2/c1-3-16(2)7-6-10-9-15-13-5-4-11(14)8-12(10)13/h4-5,8-9,15H,3,6-7H2,1-2H3
  • Key:XRWQULAXCLVBPP-UHFFFAOYSA-N

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] [6] [2] [3] It is an analogue of dimethyltryptamine (DMT) and is the 5-fluorinated derivative of methylethyltryptamine (MET). [7] Bretisilocin's route of administration is intravenous infusion. [1] [2] [3] [4]

Contents

The drug acts as a potent and well-balanced serotonin 5-HT2A and 5-HT2C receptor agonist, serotonin 5-HT2B receptor partial agonist or antagonist, and serotonin releasing agent. [2] [8] [7] [9] It produces psychedelic-like effects in animals and similarly produces robust hallucinogenic effects in humans. [8] [3] The duration of bretisilocin is 60 to 90 minutes and is intermediate between the durations of DMT and psilocybin. [2] [5] [10] [4] [11] [7] [2] It has been regarded by its developer as an improvement of DMT. [11]

Bretisilocin is under development by Gilgamesh Pharmaceuticals. [1] As of June 2025, it is in phase 2 clinical trials for the treatment of major depressive disorder. [1] Thed drug was acquired from Gilgamesh Pharmaceuticals by AbbVie in a deal worth up to $1.2 billion in August 2025. [12] [13]

Use and effects

Bretisilocin, given by intravenous injection, produces threshold psychedelic effects at doses of 1 mg and 3.3 mg, has an optimal dose range of 10 to 15 mg, and produces particularly intense effects at a dose of 20 mg. [2] The drug's effects at doses of 15 to 20 mg were described as equivalent to or greater than those of 30 mg psilocybin or 100 to 200 μg LSD based on rating scales. [2] The 20 mg dose of bretisilocin was associated with more challenging experiences including anxiety, cognitive impairment, and dread of ego dissolution, which led to selection of a lower optimal dose range of 10 to 15 mg. [2] Compared to other psychedelics like psilocybin and LSD, bretisilocin has a much shorter duration, but is longer-lasting than DMT. [2] [10] [4] [7] 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. [2] [5] [11] The psychedelic effects of bretisilocin are generally resolved by approximately 2 hours after administration, but have been found to last up to 4 to 6 hours in some individuals. [2] Peak effects occur about 10 to 20 minutes following injection. [2]

The drug, 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] [4] 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 as have been reported in clinical studies. [2] [3] [4]

Side effects

Side effects of bretisilocin include acute sensory processing disorder, altered state of consciousness, abnormal thinking, euphoric mood, fatigue, and small increases in heart rate and blood pressure, among others. [2] [3] [4] Adverse effects like fatigue and headache occur after the psychedelic experience and can persist for up to 24 hours after administration. [2]

Interactions

Pharmacology

Pharmacodynamics

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. [2] [8] [9] In another study however, it was a moderate-efficacy partial agonist of the serotonin 5-HT2B receptor. [9] The drug appears to have negligible activity as a serotonin 5-HT1A receptor agonist. [8] However, another study found that it was a serotonin 5-HT1A receptor full agonist, with an EC50 Tooltip half-maximal effective concentration at this receptor that was about 44-fold less potent than at the serotonin 5-HT2A receptor. [9]

The affinity (Ki) of bretisilocin for the serotonin 5-HT2A receptor was 4.9 nM with DOI as the radioligand and 140–191 nM with ketanserin as the radioligand. [2] [8] Its EC50 Tooltip half-maximal effective concentration (Emax Tooltip maximal efficacy) 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 Tooltip half-maximal inhibitory concentration at the serotonin 5-HT2B receptor was 5.8 nM. [2] [8] It showed much higher efficacy at the serotonin 5-HT2A receptor than its parent compound MET (Emax = 87.6% vs. 36.2%, respectively). [7] Bretisilocin showed very weak activity at the serotonin 5-HT1A receptor (EC50 = 16,918 nM, Emax = 83.0%). [2] [8] [7] 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%. [2] [8] [7] Bretisilocin is also a serotonin reuptake inhibitor to a much weaker extent (IC50 = 418.9 nM). [7] Additional values have also been published. [2] [9]

Bretisilocin is related to DMT and is considered by its developer to be an improved version of DMT. [2] [11] It also induces more serotonin release than DMT, which may provide it with more entactogen-like qualities compared to DMT. [2] [11] Bretisilocin produces the head-twitch response, a behavioral proxy of psychedelic effects, in rodents. [2] [8] [3] [7] It shows antidepressant-like effects in rodents. [8] [10] The drug dose-dependently produces hypolocomotion in rodents similarly to many other serotonergic psychedelics. [7] [14] Likewise, it produces anti-obsessional effects in the form of reduced marble burying in rodents. [7] Bretisilocin does not produce conditioned place preference (CPP) in rodents, suggesting lack of reinforcing properties. [7]

Pharmacokinetics

The pharmacokinetics of bretisilocin have been studied. [2] [3] The time to peak concentrations with intravenous injection is 10 to 20 minutes. [2] Its elimination half-life is approximately 45 minutes (range 40 to 50 minutes). [2] [3]

Chemistry

Bretisilocin, also known as 5-fluoro-N-methyl-N-ethyltryptamine, is a substituted tryptamine derivative. [7] It is a derivative of dimethyltryptamine (DMT) and methylethyltryptamine (MET) as well as of 5-fluorotryptamine (5-FT). [5] [7]

Analogues

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 INN Tooltip International Nonproprietary Name. [15] It is also known by its developmental code name GM-2505. [1] [8] [3]

Research

Bretisilocin is under development as a potential pharmaceutical drug by Gilgamesh Pharmaceuticals. [1] As of June 2025, it is in phase 2 clinical trials for the treatment of major depressive disorder. [1] A phase 2a trial of bretisilocin for major depressive disorder has been completed and the efficacy and safety data for the trial have been released. [1] [16] [17] [18] The drug has since been acquired from Gilgamesh Pharmaceuticals by AbbVie. [12] [13]

See also

References

  1. 1 2 3 4 5 6 7 8 9 "GM 2505". AdisInsight. 5 June 2025. Retrieved 29 July 2025.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 Marek GJ, Makai-Bölöni S, Umbricht D, Christian EP, Winters J, Dvorak D, Raines S, Hughes ZA, Austin EW, Klein AK, Leong W, Krol FJ, Graaf AJV, Juachon MJ, Otto ME, Borghans LGJM, Jacobs G, Kruegel AC, Sporn J. A novel psychedelic 5-HT2A receptor agonist GM-2505: The pharmacokinetic, safety, and pharmacodynamic profile from a randomized trial healthy volunteer. J Psychopharmacol. 2025 Oct 16:2698811251378512. doi : 10.1177/02698811251378512 PMID   41099491
  3. 1 2 3 4 5 6 7 8 9 10 11 12 Hughes Z, Christian E, Dvorak D, Umbricht D, Winters J, Raines S, et al. (December 2023). "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). doi: 10.1038/s41386-023-01755-5 . PMC   10729595 . PMID   38040809.
  4. 1 2 3 4 5 6 7 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 .
  5. 1 2 3 4 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.
  6. ↑ 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. [...]
  7. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 "Methods of treating mood disorders". Google Patents. 2022. Retrieved 14 November 2024.
  8. 1 2 3 4 5 6 7 8 9 10 11 Hughes Z, Klein A, Austin E, Dvorak D, Gatti S, Kiss L, et al. (December 2022). "ACNP 61st Annual Meeting: Poster Abstracts P1 - P270: P254. Gm-2505 is a Novel 5-Ht2a Receptor Agonist and 5-Ht Releaser That Induces Rapid, Robust, and Durable Antidepressant Effects at Doses Associated With Decreased Power in Low Frequency EEG Bands in Rats". Neuropsychopharmacology. 47 (Suppl 1): 63–219 (209–209). doi:10.1038/s41386-022-01484-1. PMC   9714397 . PMID   36456693.
  9. 1 2 3 4 5 WO 2022/256554,Wallach J, Dybek M,"Fluorinated Tryptamine Compounds, Analogues Thereof, and Methods Using Same",published 8 December 2022, assigned to University of the Sciences in PhiladelphiaTable 1. Selected compounds of the present invention. [...] [Compound 12:] [...] Table 3. Functional Activity of Compounds at 5-HT2A (Ca2+), 5-HT2B (Ca2+), 5-HT2c (Ca2+), and 5-HT1A (cAMP inhibition) [...]
  10. 1 2 3 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.
  11. 1 2 3 4 5 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.
  12. 1 2 Taylor NP (25 August 2025). "AbbVie tunes in to Gilgamesh's story, inking $1.2B deal for psychedelic program". Fierce Biotech. Retrieved 15 October 2025.
  13. 1 2 Psychedelic Alpha (25 August 2025). "AbbVie to Acquire Gilgamesh's Bretisilocin for Up to $1.2B". Psychedelic Alpha. Retrieved 15 October 2025.
  14. ↑ 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.
  15. ↑ 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"
  16. ↑ Psychedelic Alpha (27 May 2025). "Gilgamesh's Next-Gen Psychedelic GM-2505 Prints Impressive Results in Phase 2a Major Depressive Disorder Study". Psychedelic Alpha. Retrieved 29 July 2025.
  17. ↑ Taylor NP (27 May 2025). "Gilgamesh links psychedelic to 94% remission rate in midphase depression trial". Fierce Biotech. Retrieved 29 July 2025.
  18. ↑ Dunne R (31 May 2025). "Gilgamesh's psychedelic drug demonstrates exceptional efficacy for treating depression". Mugglehead Investment Magazine. Retrieved 29 July 2025.
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