ACS pharmacology & translational science
April 9, 2021
Gabrielle Agin-Liebes, Trevor F Haas, Rafael Lancelotta et al.
121 citations
Most people who used mescaline in natural settings reported lasting improvements in depression, anxiety, PTSD, and substance use disorders, with 68–86% of those with a history of these conditions noting subjective improvement after their most memorable experience. Those who improved reported stronger acute mystical-type, psychological insight, and ego dissolution effects (Cohen's d 0.7–1.5). For 35–50% of respondents, the mescaline experience ranked among the top five most spiritually significant or meaningful events of their lives. Psychological insight during the experience was linked to higher odds of improvement in depression, anxiety, and alcohol and drug use disorders. The authors call for controlled clinical trials to confirm these preliminary findings.
ACS pharmacology & translational science
April 9, 2021
Matthew W. Johnson
109 citations
A viewpoint article outlines three major pitfalls in psychedelic research that could hinder their medical use: imprecise use of the term "consciousness," the inappropriate introduction of investigators' or clinicians' religious or spiritual beliefs, and ethical challenges related to clinical boundaries in psychedelic treatments.
ACS pharmacology & translational science
April 9, 2021
Thomas W Flanagan, Gerald B Billac, Alexus N Landry et al.
50 citations
Psychedelic drugs can reduce inflammation, but this effect does not depend on their mind-altering properties. By testing 21 different 5-HT2A receptor agonists in a rat model of allergic asthma, the drug 2,5-dimethoxyphenethylamine (2C-H) was identified as the key structure for anti-inflammatory activity. Specific chemical modifications either enabled or blocked this effect. No link was found between a drug's ability to trigger calcium signaling (a standard measure of receptor activation) and its ability to prevent asthma symptoms or produce behavioral effects. This suggests that anti-inflammatory benefits arise from distinct receptor pathways, not the canonical signaling pathway. These findings could guide development of non-psychoactive anti-inflammatory drugs targeting the 5-HT2A receptor.
ACS pharmacology & translational science
April 9, 2021
Shreyas Bhat, Daryl A Guthrie, Ameya Kasture et al.
37 citations
Protein misfolding caused by missense mutations is rare but collectively leads to serious folding diseases. Ibogaine and noribogaine can correct folding defects in the dopamine transporter (DAT) but rescue only a limited number of DAT mutants linked to infantile Parkinsonism and dystonia. By reconfiguring the ibogaine ring system, a series of analogs were generated and tested for binding to wild-type transporters and for rescuing two synthetic folding-deficient mutants. The most active tropane-based analog (9b) acted as an effective pharmacochaperone in vivo in Drosophila carrying a DAT mutation and rescued 6 out of 13 disease-associated human DAT mutant proteins in vitro, identifying a novel lead compound with potential for medication development for patients with DAT mutations.
ACS pharmacology & translational science
March 8, 2024
Grant C Glatfelter, Eline Pottie, John S Partilla et al.
28 citations
Lisuride, a non-psychedelic analogue of LSD, lacks psychedelic effects because it acts as a partial agonist at the 5-HT2A receptor and a potent agonist at the 5-HT1A receptor, which counteracts psychedelic activity. In vitro, LSD strongly activated 5-HT2A signaling, while lisuride showed only partial efficacy (6-52% of maximum) and blocked LSD's effects. In male mice, LSD caused head twitch responses (a behavioral marker of psychedelic action), whereas lisuride suppressed these responses and induced hypothermia and reduced movement. Blocking the 5-HT1A receptor restored baseline head twitches but did not increase them above normal, indicating that lisuride's lack of psychedelic effects stems from its partial agonist-antagonist activity at 5-HT2A, not solely from 5-HT1A activation.
ACS pharmacology & translational science
April 9, 2021
Joaquín González, Matías Cavelli, Santiago Castro-Zaballa et al.
26 citations
Ibogaine, a psychedelic alkaloid with anti-addictive potential, produces vivid, dream-like experiences while awake. Analyzing intracranial electroencephalograms in rats, ibogaine-induced wakefulness showed gamma oscillations with greater power than control levels but reduced coherence and complexity. This gamma activity profile resembled that of natural REM sleep, providing biological evidence linking the psychedelic state to REM sleep and advancing understanding of ibogaine's oneirogenic effects.
ACS pharmacology & translational science
June 14, 2024
Richard A Glennon, Małgorzata Dukat
21 citations
The compound DOI, first synthesized in 1973, is a serotonin receptor agonist, specifically acting at 5-HT2 receptors in rat and human brain. It emerged from research on hallucinogenic agents and is now studied for potential therapeutic use in neuropsychiatric disorders such as treatment-resistant depression. This review traces the historical and current developments that made DOI a landmark agent in 5-HT2 receptor research.
ACS pharmacology & translational science
July 11, 2025
Zahira Ziva Cohen, Grace Blest-Hopley
9 citations
Ovarian hormone fluctuations, particularly estradiol and progesterone, modulate neurotransmitter systems involved in psychedelic pharmacology, including serotonin, dopamine, GABA, and glutamate. These hormonal changes across the menstrual cycle influence 5-HT2A receptor expression and functional connectivity, potentially affecting both the subjective intensity and therapeutic efficacy of psychedelics. The paper argues that incorporating menstrual phase tracking and hormonal assays into clinical trials and observational studies can reduce data variability, support individualized care, and improve informed consent practices for women. A better understanding of the interplay between female-specific biology and psychedelic pharmacodynamics is needed to advance safe, ethical, and effective therapies.
ACS pharmacology & translational science
July 12, 2024
Albert Dahan, Simone Jansen, Rutger van der Schrier et al.
8 citations
The anesthetic, analgesic, and antidepressant drug ketamine produces dissociation with symptoms of psychosis and anxiety, an effect attributed to neuronal nitric oxide depletion following N-methyl-d-aspartate blockade. There is evidence that dissociation induced by racemic ketamine, containing both ketamine enantiomers (S- and R-ketamine) but not esketamine (the S-isomer) is inhibited by nitric oxide (NO) donor sodium nitroprusside (SNP). We tested whether a similar intervention would reduce racemic and esketamine-induced analgesia in a randomized double-blind placebo-controlled trial. Seventeen healthy volunteers were treated with 0.5 μg.kg-1.
ACS pharmacology & translational science
March 14, 2025
Hongyuan Li, Xiaohui Wang
5 citations
Psychedelic experiences can provide transformative perspectives on dying, potentially easing existential distress and improving quality of life for the terminally ill. Their growing recognition in palliative care, therapy, and spiritual exploration may revolutionize end-of-life care.
ACS pharmacology & translational science
December 8, 2023
Richard A Glennon, Mal Gorzata Dukat
3 citations
Alpha-ethyltryptamine (AET), a centrally acting agent known for over 75 years, was briefly marketed as an antidepressant before being withdrawn and classified as a U.S. Schedule I substance due to concerns about abuse and toxicity. Amid current interest in hallucinogenic tryptamines for treating neuropsychiatric disorders like treatment-resistant depression and anxiety, this review critically examines AET's history and argues that it may have been ahead of its time. AET possesses many antidepressant hallmarks, suggesting that its derivatives and optical isomers warrant further investigation.
ACS pharmacology & translational science
October 10, 2025
Milo Moskovitz
2 citations
Music is central to psychedelic-assisted therapy, yet only three empirical studies have directly examined which music best supports treatment. A critical review finds these studies have important limitations and their findings conflict with other publications and existing recommendations. Understanding of music guidelines has not advanced much since 1970. The paper summarizes music's common impacts during therapy, reviews current knowledge on music selection and guidelines, and suggests priorities for future research.
ACS pharmacology & translational science
July 11, 2025
Cong Zhang, Yibo Wang, Xiaohui Wang
2 citations
Neuropsychiatric disorders arise from disruptions in brain network dynamics that fall along a spectrum from order to complexity to chaos. Psychedelics may work therapeutically by increasing neural entropy, breaking maladaptive patterns, and enabling network reorganization. This framework focuses on dynamic remodeling of the brain's connectome rather than static molecular fixes, proposing that controlled neural destabilization and reconnection offers a new treatment strategy for psychiatric and neurological conditions.
ACS pharmacology & translational science
August 8, 2025
Kate Browne, Ewa Bałkowiec-iskra, André Elferink et al.
1 citation
Marketing authorization applications for psychedelics in the European Union must meet the same regulatory and evidentiary standards as all other medicinal products. The European Medicines Agency identifies key knowledge gaps that complicate pivotal trial design and benefit-risk assessment, including functional unblinding, expectancy and nocebo effects, and the need to align trial populations with the intended therapeutic indication. Development programs should characterize dose-response relationships and the link between subjective experience and therapeutic response. Decisions about incorporating psychological support or psychotherapy affect trial design and conditions of use. Safety characterization requires adequately powered trials, appropriate controls, risk mitigation strategies, continuous monitoring, and ethical consideration.
ACS pharmacology & translational science
June 12, 2026
Tianshu Zhang, Cong Lin, Xiaohui Wang
Classic serotonergic psychedelics like LSD, psilocybin, and DMT show promise for treating neuropsychiatric disorders but are limited by first-pass metabolism, erratic pharmacokinetics, and off-target effects. Advanced delivery systems—including transdermal and microneedle patches, intranasal sprays, sublingual films, and injectable formulations—along with molecular strategies such as prodrugs and selective receptor bias, bypass hepatic metabolism, enable precise control over onset and duration, and minimize peripheral activation. Preclinical and early clinical evidence indicates gains in bioavailability, half-life extension, and conversion of fleeting effects into manageable windows, offering a path to safer, patient-centered therapies despite regulatory and trial-design challenges.
ACS pharmacology & translational science
March 13, 2026
Bo Jarrett Wood, M Frances Vest, Catharine Carfagno et al.
In male mice, chronic treatment with the SSRI fluoxetine (Prozac) reduced the head-twitch response—a behavioral sign of 5-HT2A receptor activation—caused by the psychedelic DOI, while acute fluoxetine had no effect on DOI. The reduced response reversed after a 14-day discontinuation of fluoxetine. Acute fluoxetine also weakened the efficacy (but not potency) of psilocybin, indicating that SSRI-psychedelic interactions may differ depending on the specific psychedelic compound. These results suggest that a history of SSRI use can alter sensitivity to psychedelics in a compound-specific manner, with implications for psychedelic-assisted therapy in people taking SSRIs.