Neuropharmacology
May 1, 2025
Michael Noback, Johnny A Kenton, Adam K. Klein et al.
2 citations
A compound called 2,5-dimethoxy-4-propylamphetamine (DOPR), a psychedelic that activates 5-HT2A receptors, can increase motivation in mice with low baseline motivation without causing hallucinogenic-like effects. In a progressive ratio breakpoint task (PRBT) involving 80 mice, doses as low as 0.0106 mg/kg improved performance only in animals with low initial motivation; high-performing mice were unaffected. The head-twitch response (HTR) assay in 72 mice showed hallucinogenic-like effects only at doses of 0.1 mg/kg or higher. These results suggest that low doses of DOPR might treat amotivated states while avoiding hallucinogenic side effects, warranting further research in rodents with disease-relevant conditions.
Journal of the American Chemical Society
December 16, 2025
J.O.S. Beckett, Ryan Buzdygon, Steven Nguyen et al.
1 citation
A new chemical method uses light to trigger a cyclization reaction that attaches a functional group to the fourth carbon of the indole ring, enabling the efficient synthesis of ring-constrained tryptamine analogs. Amino acids were linked to tryptamine and exposed to UV light to produce lactams bridging specific positions on the indole structure. The resulting reduced lactams, called azocinoindoles, were tested for activity at the serotonin 5-HT2A receptor. In computer models and lab experiments, these compounds acted as full or partial activators of the receptor's Gq signaling pathway. In mice, they suppressed the head-twitch response, a behavior linked to hallucinogenic effects, suggesting these compounds are nonhallucinogenic 5-HT2A agonists.
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.
ACS Chem Neurosci
March 4, 2026
Nina Kastner, Núria Nadal‐gratacós, Selina Hemmer et al.
correction
A correction notice clarifies that two errors in the original paper do not affect the accuracy of the results, interpretations, or conclusions. The first correction addresses a presentation issue in Table 1, confirming the data are correct. The second correction clarifies that thigmotaxis, a measure of anxiety-like behavior, was evaluated in rats given SDA or SDMA compounds. Compared to saline, only the 10 mg/kg dose of SDA significantly increased thigmotaxis, meaning the rats spent less time in the center of the arena.
ACS Chemical Neuroscience
December 2, 2025
Nina Kastner, Núria Nadal‐gratacós, Selina Hemmer et al.
Replacing the 1,3-benzodioxole group in MDMA (ecstasy) with a 1,3-benzoxathiole yields two analogues, SDA and SDMA, that interact with monoamine transporters similarly to MDMA but with key differences. SDA and SDMA inhibit dopamine and norepinephrine transporters more potently than MDMA and act as partial releasers at serotonin and dopamine transporters. Metabolism studies show SDA and SDMA are cleared faster, while MDMA and MDA degrade only weakly. In mice, SDMA does not produce rewarding effects, unlike MDMA, and SDA only shows a preference for the drug-paired compartment at the lowest dose. SDMA shares similar locomotor and hyperthermic profiles with MDMA, whereas SDA induces increased hyperlocomotion and more sustained hyperthermia. SDMA may be a safer candidate for further study.
Journal of Medicinal Chemistry
September 25, 2025
Tyler G. Fenske, J. M. T. Mckee, Natalie G. Cavalco et al.
Selectivity for the 5-HT2A receptor over the closely related 5-HT2C receptor can be achieved by targeting residue L1232.53 in transmembrane 2 of the extended binding pocket through increasing steric aliphatic bulk on the α-methylene group of the N-benzyl chemical scaffold. This selectivity was confirmed across 5-HT2C RNA editing isoforms, TM2 reciprocal mutants, and mouse orthologs, producing the most highly selective 5-HT2A agonists to date. Using structure–activity relationships, molecular docking, and mouse head-twitch response assays, the work demonstrates that such agonists can be rationally designed to improve target engagement, advancing the study of the neurobiological mechanisms of psychedelic effects.
The International Journal of Neuropsychopharmacology
November 12, 2021
Benjamin Z Roberts, Arpi Minassian, Adam L. Halberstadt et al.
People with HIV often develop cognitive problems linked to disrupted fronto-striatal brain circuits, which are also affected by cannabis. HIV transgenic rats, which model HIV-associated neurocognitive disorder, showed a significant prepulse inhibition deficit compared to healthy controls, mirroring the sensorimotor gating impairment seen in people with HIV. Acute treatment with THC (1 and 3 mg/kg) reduced prepulse inhibition in control rats but not in HIV transgenic rats, indicating a relative insensitivity to THC's disruptive effects on fronto-striatal function. Cannabidiol (1, 10, and 30 mg/kg) had only minor, genotype-independent effects on prepulse inhibition. This reduced sensitivity may help explain higher cannabis use rates among people with HIV.
European Journal of Pharmacology
August 15, 2019
Jason Wallach, Tristan Colestock, Julià Agramunt et al.
Fluorolintane, a 1,2-diarylethylamine sold as a 'research chemical' for dissociative effects, was studied pharmacologically for the first time alongside five related isomers. In vitro binding showed fluorolintane has high affinity for NMDA receptors (Ki = 87.92 nM) and even higher affinities for dopamine transporters (DAT) in most cases. Functional experiments in rat hippocampal slices demonstrated that fluorolintane inhibits NMDA receptor-induced field excitatory postsynaptic potentials and blocks long-term potentiation, consistent with NMDA receptor antagonism. In rats, fluorolintane disrupted prepulse inhibition (a measure of sensorimotor gating) with a median effective dose of 13.3 mg/kg, supporting anecdotal reports of dissociative effects in humans.
Pharmacology, biochemistry, and behavior
September 1, 2016
Adam L. Halberstadt, James Hyun, Michael A Ruderman et al.
N-allylnormetazocine (NANM) disrupts prepulse inhibition (PPI) of acoustic startle in mice, a measure of sensorimotor gating. Racemic NANM and its (+)-isomer produced dose-dependent PPI disruption (3-30 mg/kg), while the (-)-isomer had no effect. Blocking kappa opioid or sigma-1 receptors did not prevent this disruption, and a selective kappa agonist also had no effect on PPI. The findings indicate that NANM's effects on sensorimotor gating are mediated through the PCP site of the NMDA receptor, not through kappa or sigma-1 receptors, consistent with evidence that sigma-1 receptors are not linked to hallucinogenic or psychotomimetic effects.
Psychopharmacology
April 1, 2016
Adam L. Halberstadt, Natalia Slepak, James Hyun et al.
Methoxetamine (MXE), a ketamine analog sold online, produces behavioral effects in rats that closely resemble those of other dissociative anesthetics like phencyclidine (PCP) and ketamine. In Sprague-Dawley rats, MXE disrupted prepulse inhibition (PPI) of acoustic startle at doses of 3 and 10 mg/kg, with a potency ranking (PCP > MXE > S-(+)-ketamine > NANM > R-(-)-ketamine) that matches their affinities for the PCP binding site on NMDA receptors. In the behavioral pattern monitor, 10 mg/kg MXE caused locomotor hyperactivity, reduced rearing, increased path roughness, and perseverative locomotion—effects similar to those of PCP. These findings indicate MXE acts as a dissociative drug with abuse potential comparable to PCP and ketamine.
Journal of Psychoactive Drugs
January 1, 2014
George Greer, Charles S. Grob, Adam L. Halberstadt
Greater than 75% reduction in Clinician Administered PTSD Scale (CAPS) symptom scores was reported when patients were using cannabis compared to when they were not, based on a retrospective chart review of 80 patients applying to the New Mexico Medical Cannabis Program from 2009 to 2011. Cannabis is associated with reductions in PTSD symptoms in some patients, and prospective, placebo-controlled study is needed to determine efficacy.