Nature
January 1, 2021
Lindsay P Cameron, Robert J Tombari, Ju Lu et al.
468 citations
Ibogaine, a psychedelic alkaloid, shows anti-addictive effects in humans and animals but has safety issues including toxicity and heart arrhythmias. Researchers engineered tabernanthalog, a water-soluble, non-hallucinogenic, non-toxic analogue made in a single step. In rodents, tabernanthalog promoted structural neural plasticity, reduced alcohol- and heroin-seeking behavior, and produced antidepressant-like effects. This demonstrates that careful chemical design can create safer, non-hallucinogenic variants of psychedelic compounds with therapeutic potential.
Cell reports
March 28, 2023
Vern Lewis, Emma M Bonniwell, Janelle K Lanham et al.
129 citations
The non-hallucinogenic LSD analog 2-Br-LSD acts as a partial agonist at several aminergic G protein-coupled receptors, including 5-HT2A, but does not induce the head-twitch response in mice, indicating it lacks hallucinogenic effects. Unlike LSD, 2-Br-LSD does not activate 5-HT2B, avoiding a risk of cardiac valvulopathy. It produces weak 5-HT2A β-arrestin recruitment and internalization in vitro and does not cause tolerance after repeated dosing. In cultured rat cortical neurons, 2-Br-LSD promotes dendritogenesis and spinogenesis, and in mice it increases active coping behavior—an effect blocked by a 5-HT2A antagonist—and reverses behavioral effects of chronic stress. These findings suggest 2-Br-LSD has an improved pharmacological profile over LSD and potential therapeutic value for mood disorders.
The Journal of neuroscience : the official journal of the Society for Neuroscience
November 8, 2023
Lindsay P Cameron, Joseph Benetatos, Vern Lewis et al.
88 citations
Serotonergic psychedelics like psilocybin and LSD activate serotonin 5-HT2A receptors in cortical brain regions, altering perception, cognition, and emotions. Their ability to promote neuroplasticity—forming new neural connections and rewiring networks—is thought to underlie therapeutic potential for depression, anxiety, and substance use disorders. These compounds also interact with other serotonin receptor subtypes (5-HT1A, 5-HT2C) and neurotrophin receptors, adding complexity to their effects. Research is exploring nonhallucinogenic derivatives that retain therapeutic benefits without intense psychedelic experiences, potentially reducing adverse reactions. The review also discusses psychedelics as substrates for post-translational protein modification as part of their mechanism.
Bioorganic & medicinal chemistry
July 15, 2015
Martin Hansen, Stine Engesgaard Jacobsen, Shane Plunkett et al.
35 citations
N-Benzyl substitution dramatically alters how phenethylamine 5-HT2A receptor agonists bind to and activate serotonin receptors. This work examined how adding an N-benzyl group to 4-bromo-2,5-dimethoxyphenethylamine derivatives affects affinity for 5-HT2A and 5-HT2C receptors, focusing on the 2' and 3' positions of the benzyl ring. Substitutions at these positions were generally well tolerated. Probing the 2' position with various substituents revealed that small changes profoundly affected affinity, and two ligands lacking a 2'-benzyl substituent unexpectedly showed high affinity, contradicting earlier assumptions. Several high-affinity ligands were tested for functional activity and were less efficacious agonists than previously reported N-benzyl phenethylamines.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
April 1, 2024
Thomas J Kelly, Emma M Bonniwell, Lianwei Mu et al.
26 citations
4-OH-DiPT, a fast-acting and shorter-lasting derivative of psilocybin, reduces learned fear responses in mice by enhancing inhibitory signaling in the brain. It activates 5-HT2A receptors on interneurons in the basolateral amygdala, increasing GABAergic inhibition of principal neurons. In female mice, 4-OH-DiPT before extinction training reduced freezing to conditioned cues and later decreased avoidance behaviors in several tests, while male mice showed no significant differences. The compound acts as a near full agonist at 5-HT2A receptors and has comparable activity at mouse and human 5-HT2A/2B/2C receptors. These findings suggest a potential mechanism for suppressing learned fear.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
March 1, 2022
Deborah Rudin, John D McCorvy, Grant C Glatfelter et al.
18 citations
Derivatives of (2-aminopropyl)indole and (2-aminopropyl)benzofuran are new psychoactive substances with stimulant effects. This study characterized six isomers of the sulfur-based analog (2-aminopropyl)benzo[β]thiophene (APBT) in vitro and three isomers in vivo. APBTs inhibited monoamine reuptake and induced transporter-mediated substrate release, similar to MDMA, but did not stimulate locomotion in mice. Instead, they acted as full agonists at 5-HT2 receptor subtypes and induced head-twitch responses, indicating psychedelic-like activity. Replacing oxygen with sulfur enhanced serotonin transporter release potency and 5-HT2 receptor activity, shifting the profile toward psychedelic and entactogenic effects with minimal psychomotor stimulation, suggesting potential for drug-assisted psychotherapy.
ACS chemical neuroscience
December 18, 2024
Grant C Glatfelter, Allison A Clark, Natalie G Cavalco et al.
14 citations
5-MeO-DMT and its analogs bind to multiple serotonin and adrenergic receptors, with potent activity at 5-HT2A and 5-HT1A receptors. In mice, these compounds induce head twitch responses (a proxy for psychedelic-like effects) with varying potencies (ED50 0.2–1.8 mg/kg) and maximal effects (20–60 head twitches per 30 minutes), while higher doses cause hypothermia and reduced movement (ED50 3.2–20.6 mg/kg). Blocking 5-HT1A receptors enhances head twitch responses, unmasking activity in some analogs and increasing maximal responses to 40–90 head twitches per 30 minutes, indicating that 5-HT1A activation dampens 5-HT2A-mediated psychedelic-like effects. Suppression of head twitch responses by 5-HT1A only occurred at high 5-MeO-DMT doses, suggesting other receptors also modulate these effects.
Journal of neurochemistry
September 1, 2024
Ana Sofia Alberto-Silva, Selina Hemmer, Hailey A Bock et al.
10 citations
Three new chemical variants of MDMA—ODMA, TDMA, and SeDMA—show similar activity at serotonin, dopamine, and norepinephrine transporters but reduced activity at 5-HT2A/2B/2C receptors compared to MDMA. They also differ in liver metabolism, with N-demethylation as the only shared route and no phase II metabolites formed. TDMA showed faster clearance. The analogs interacted more weakly with organic cation transporters and plasma membrane monoamine transporter. These bioisosteres may offer therapeutic alternatives to MDMA with a reduced off-target profile, but further studies are needed to determine if they pose lower risks.
The Journal of biological chemistry
September 1, 2023
Omar B Sanchez-Reyes, Gregory Zilberg, John D McCorvy et al.
10 citations
Opioids, cannabinoids, and psychedelics all act by binding to G protein-coupled receptors (GPCRs), which mediate their inebriating, lethal, and therapeutic effects. Recent structural studies reveal the molecular mechanisms of drugs like fentanyl, tetrahydrocannabinol, and lysergic acid diethylamide at their respective GPCR subtypes. These insights facilitate drug discovery, both for developing treatments to combat substance abuse and for harnessing the therapeutic potential of certain drugs.
bioRxiv : the preprint server for biology
April 11, 2024
Ana Sofia Alberto-Silva, Selina Hemmer, Hailey A Bock et al.
preprint
Three new chemical variants of MDMA—ODMA, TDMA, and SeDMA—show similar activity at serotonin and dopamine transporters but reduced activity at serotonin 5-HT2A/2B/2C receptors, which may lower the risk of off-target side effects. They also differ from MDMA in how they are broken down by the liver, with fewer metabolic pathways and no phase II metabolites. The analogs interact more weakly with certain organic cation transporters. These findings suggest the new compounds could be promising therapeutic alternatives to MDMA for conditions like PTSD, though further research is needed to confirm whether they pose lower risks.