MDMA/citalopram

Pharmaceutical compound From Wikipedia, the free encyclopedia

MDMA/citalopram is a combination of the entactogen and monoamine releasing agent 3,4-methylenedioxymethamphetamine (MDMA; also known as midomafetamine or "ecstasy") and the selective serotonin reuptake inhibitor (SSRI) citalopram which is under development for the treatment of post-traumatic stress disorder (PTSD).^[1]^[2]^[3]

MDMAEntactogen; Serotonin–norepinephrine–dopamine releasing agent

CitalopramAntidepressant; Selective serotonin reuptake inhibitor

Other namesCitalopram/MDMA; Midomafetamine/citalopram; Citalopram/midomafetamine

Routes of
administrationOral

Quick facts Combination of, Citalopram ...

MDMA/citalopram
Combination of
MDMA
Citalopram
MDMA	Entactogen; Serotonin–norepinephrine–dopamine releasing agent
Citalopram	Antidepressant; Selective serotonin reuptake inhibitor
Clinical data
Other names	Citalopram/MDMA; Midomafetamine/citalopram; Citalopram/midomafetamine
Routes of administration	Oral

Citalopram is taken after MDMA in the combination, and its inclusion is intended to help reduce the well-known negative after-effects of MDMA such as temporarily worsened mood (sometimes referred to colloquially as "Blue Mondays").^[1]^[4]^[5] MDMA has been found to produce serotonin depletion and neurotoxicity in animals, and this may be importantly involved in its negative after-effects.^[6]

Pretreatment with or simultaneous coadministration of SSRIs with MDMA has been found to markedly attenuate most of the psychoactive and physiological effects of MDMA in humans.^[7]^[5]^[8] This is because SSRIs block MDMA-induced serotonin release, which is the key action of MDMA involved in mediating its effects.^[7]^[9] In addition to blocking the serotonin release and effects of MDMA, SSRIs fully block the serotonergic neurotoxicity of MDMA in animals.^[6] However, delayed administration of SSRIs as late as 3 to 4 hours after MDMA administration is still able to fully block MDMA's serotonergic neurotoxicity in animals.^[6] Conversely, administration of an SSRI 6 hours after MDMA is partially protective, while administration 12 hours after MDMA is ineffective.^[6] The duration of MDMA in humans is 3 to 6 hours, although most of its effects occur in the first 4 hours after dosing.^[10]^[11] By supplementing citalopram a few hours after MDMA in human MDMA users, the serotonergic neurotoxicity and negative after-effects of MDMA may be prevented or diminished while still allowing MDMA to produce most of its desired effects.^[5]

In a small preliminary clinical study of MDMA users who reported typically experiencing a comedown after MDMA, it was found that MDMA produced acute cognitive deficits 5 and 26 hours after administration and the deficits could be prevented by citalopram administration 3 hours after MDMA.^[5]^[12] In addition, the desired acute effects of MDMA were not noticeably altered by post-MDMA citalopram intake.^[5]

The combination is under development by Tactogen.^[1]^[2]^[3] Following the Food and Drug Administration (FDA)'s rejection of Lykos Therapeutics's MDMA formulation for PTSD, Tactogen has said that it is seriously considering prioritizing novel compounds over MDMA.^[1] Phase 2 clinical trials of MDMA/citalopram are planned to begin in 2026.^[13]^[1]^[2]^[3]

References

[1]
Goodwin K (30 September 2024). "MDMA Drug Developers Reprioritize Following Lykos Rejection in PTSD". BioSpace. Retrieved 31 January 2025. The company also hopes to improve tolerability with its program combining MDMA with citalopram, a selective serotonin reuptake inhibitor (SSRI) used to treat depression, for PTSD. Baggott anticipates beginning Phase II trials with the combo in 2025. [...] "The fact that Lykos didn't get their NDA approved on this cycle means that we are seriously considering prioritizing our novel compounds and waiting to move forward with our MDMA product," Baggott said. Tactogen's pipeline includes a number of preclinical molecules that Baggott said he believes will be superior to MDMA.
[2]
Joralemon V (12 March 2024). "Sorry, You Probably Cannot Get MDMA Through Telehealth". Petrie-Flom Center - The blog of the Petrie-Flom Center at Harvard Law School. Retrieved 31 January 2025. [...] there are several other MDMA therapies in clinical trials right now, including Tactogen's Phase 2 MDMA + Citalopram PTSD study, MindMed's Phase 1 R-MDMA Autism Spectrum Disorder study, and EmpathBio's proprietary MDMA derivative PTSD study.
[3]
Michael Haichin (2024). "Psychedelics Drug Development Tracker". Psychedelic Alpha. Retrieved 29 January 2025.
[4]
Lewis BR, Byrne K (July 2023). "A Review of MDMA-Assisted Therapy for Posttraumatic Stress Disorder". Focus (Am Psychiatr Publ). 21 (3): 247–256. doi:10.1176/appi.focus.20220088. PMC 10316220. PMID 37404966.
[5]
Hillier D (15 June 2023). "Why Psychedelics Work Differently for People on Antidepressants". VICE. Retrieved 31 January 2025. "There are several studies that gave MDMA and an SSRI to healthy volunteers and compared the effects to MDMA alone. These studies show that even a single dose of an SSRI can reduce the psychological effects of MDMA by as much as 80 percent," says Matt Baggott, an MDMA research heavyweight and CEO of Tactogen, which develops MDMA-like compounds for medicinal use. [...] Interestingly, Baggott tells VICE that taking an SSRI after a MDMA roll "probably works" in alleviating a comedown. He points to animal studies that suggest SSRIs given shortly after MDMA may protect the brain from the negative effects of this overstimulation. He also ran a small, unpublished study with people who typically recorded a comedown post-MDMA, and did not normally take SSRIs. "When I gave them MDMA in a laboratory setting, they performed worse at a demanding cognitive task at both five and 26 hours after MDMA." In a separate session he gave them MDMA, followed three hours later by the SSRI citalopram. He says that this "prevented MDMA-induced performance difficulties without noticeably changing the main emotional effects of MDMA. This supports the idea that SSRIs can reduce the undesirable after-effects of MDMA."
[6]
Baggott M, Mendelson J (2001). "Does MDMA Cause Brain Damage?". In Holland J (ed.). Ecstasy: The Complete Guide: A Comprehensive Look at the Risks and Benefits of MDMA. Inner Traditions/Bear. pp. 110–145, 396–404. ISBN 978-0-89281-857-0. Retrieved 24 November 2024.
[7]
Price CM, Feduccia AA, DeBonis K (2022). "Effects of Selective Serotonin Reuptake Inhibitor Use on 3,4-Methylenedioxymethamphetamine-Assisted Therapy for Posttraumatic Stress Disorder: A Review of the Evidence, Neurobiological Plausibility, and Clinical Significance". J Clin Psychopharmacol. 42 (5): 464–469. doi:10.1097/JCP.0000000000001595. PMID 36018231. Anecdotal reports for decades have suggested that current SSRI use can significantly dampen or abolish the subjective effects of MDMA and serotonergic hallucinogens,16–22 although this was not always observed.23 Controlled studies beginning in the 2000s began to shed further light on this phenomenon by examining the impact of SSRI and MDMA coadministration in healthy controls. The SSRIs citalopram, paroxetine, and fluoxetine were all shown to reduce most of the psychological effects of MDMA when given as pretreatment, either orally for 3 to 5 days24–26 or intravenously for 90 minutes27,28 before MDMA oral dosing. The psychological effects of MDMA that were attenuated by SSRIs included positive mood/euphoria, alterations in thought process and content, extraversion/self-confidence, and dissociative phenomena. Not all psychological effects of MDMA were attenuated by SSRIs, however; effects on emotional excitability, sensitivity, and anxiety remained even with SSRI pretreatment.25,29 Selective serotonin reuptake inhibitors also reduced the effects of MDMA on various physiological parameters, including increases in blood pressure, heart rate, temperature, and pupil diameter.24–29 [...] 9 Studies in animal models support the idea that such attenuation of MDMA's effects via acute SSRI pretreatment occurs primarily through blockage of the serotonin reuptake transporter (SERT). Serotonin reuptake transporter–knockout animals have a marked reduction in MDMA-mediated serotonin release and subsequent depletion and neurotoxicity.30,31 Pretreatment of rats with SSRIs similarly attenuated MDMA-mediated increases in extracellular serotonin and led to preservation of serotonin metabolite concentrations and SERT binding that is normally depleted by MDMA after 1 week.32–35
[8]
Liechti ME, Baumann C, Gamma A, Vollenweider FX (May 2000). "Acute psychological effects of 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") are attenuated by the serotonin uptake inhibitor citalopram". Neuropsychopharmacology. 22 (5): 513–521. doi:10.1016/S0893-133X(99)00148-7. PMID 10731626.
[9]
Dunlap LE, Andrews AM, Olson DE (October 2018). "Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine" (PDF). ACS Chem Neurosci. 9 (10): 2408–2427. doi:10.1021/acschemneuro.8b00155. PMC 6197894. PMID 30001118.
[10]
Oeri HE (May 2021). "Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy". J Psychopharmacol. 35 (5): 512–536. doi:10.1177/0269881120920420. PMC 8155739. PMID 32909493.
[11]
Straumann I, Avedisian I, Klaiber A, Varghese N, Eckert A, Rudin D, et al. (December 2024). "Acute effects of R-MDMA, S-MDMA, and racemic MDMA in a randomized double-blind cross-over trial in healthy participants". Neuropsychopharmacology. 50 (2): 362–371. doi:10.1038/s41386-024-01972-6. PMC 11631982. PMID 39179638.
[12]
Baggott MJ, Coyle JR, Galloway GP, Mendelson JE (August 2011). "S4-3 The Role of Serotonin in the Emotional and Residual Effects of MDMA". Behavioral Pharmacology. 22 [Abstracts of the 14th Biennial Meeting of the European Behavioural Pharmacology Society, Amsterdam, 26-29 August, 2011]: e1–e73 (e5–e5). doi:10.1097/01.fbp.0000399674.93315.4e. ISSN 0955-8810. Over 25 years ago, Nichols proposed that MDMA represented a novel class of psychoactive. Since then, many have anecdotally described seemingly unusual social-emotional MDMA effects. However, controlled studies are only beginning to examine these claims. We have conducted a series of controlled clinical experiments with MDMA to test anecdotal claims and characterize the drug's effects on self-report, perceptual, attentional, and autobiographical speech measures. We used coadministration of the SSRI citalopram to investigate the contributions of serotonergic mechanisms to these acute effects and to adverse residual effects. We find that MDMA increases sociability and decreases social anxiety while altering assessment of social images. MDMA also produces residual cognitive changes. Many of these effects have mechanisms that involve the serotonin transporter. These results may have implications for understanding the contributions of serotonin to positive and negative affect. MDMA may impair serotonergic modulation of harm sensitivity, yet the pattern of effects additionally suggests activation of biologically-based attachment systems.
[13]
"Tactogen Inc – Pipeline". tactogen.com. 2021-02-08. Retrieved 2026-05-10.

MDMA/citalopram

See also

References

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