Nature Methods
August 5, 2024
Run Zhang, Maribel Anguiano, Sophia Lin et al.
20 citations
A new technique called CaST (calcium-activated split-TurboID) uses an enzyme to rapidly tag cells that have elevated calcium levels in living animals, marking activated cells within 10 minutes. The tagging signal increases with both calcium concentration and labeling time, acting as a time-gated integrator of total calcium activity. Unlike transcriptional reporters that take hours to produce a signal, CaST provides readout immediately after activity labeling. The method was used to tag prefrontal cortex neurons activated by psilocybin in untethered mice, and the CaST signal correlated with psilocybin-induced head-twitch responses.
ACS Chemical Neuroscience
March 1, 2023
Robert J Tombari, Paige C Mundy, Kelly M Morales et al.
15 citations
Thirteen psychoactive compounds from different chemical classes were screened in larval zebrafish for developmental toxicity. Psychedelic tryptamines and ketamine were less neurotoxic than LSD and psychostimulants. The results provide a reference database for comparing neurotoxicity profiles of novel psychedelics being developed as therapeutics.
ACS Omega
May 7, 2018
Lee E. Dunlap, David E. Olson
15 citations
The quaternary ammonium salt byproduct forms at an exceedingly slow rate when DMT is exposed to dichloromethane (DCM), only accumulating significantly after prolonged contact. The byproduct is readily extracted into water. DMT can be exposed to DCM for less than 30 minutes with minimal risk of degradation, and the byproduct is not observed after aqueous extraction. Alternative solvents should be used for longer contact times. These findings have implications for preparing pharmaceuticals with the DMT structural core in high yields and purities.
Frontiers in Cellular Neuroscience
January 1, 2022
Charles Sutton, Erin Q Williams, Hoomam Homsi et al.
13 citations
Mutations in the dopamine transporter gene cause Dopamine Transporter Deficiency Syndrome (DTDS), a fatal infantile parkinsonism-dystonia with no current treatment. Pharmacological chaperones can rescue some disease-causing variants. This study examined structure-activity relationships for two known chaperones, bupropion and ibogaine. The isoquinuclidine substituent of ibogaine and its analogs is important for chaperone efficacy. For bupropion, the secondary amine group is essential. Additional analogs with varying chemical modifications showed variable chaperone efficacies, contributing to the design of improved dopamine transporter pharmacological chaperones.
Neuropharmacology
September 26, 2024
J. Alfred Bonilla, Giuseppe Giannotti, Nathaniel P. Kregar et al.
12 citations
In a rat model of polydrug use where animals self-administered both intravenous heroin and oral alcohol, the psychedelic compound DOI (0.4 mg/kg) reduced motivation for heroin, measured as the break point in a progressive ratio test. This effect was blocked by a 5-HT2A receptor antagonist but not by a 5-HT2C antagonist, indicating the effect is mediated by 5-HT2A receptors. DOI did not affect motivation for alcohol. The findings suggest that psychedelic drugs acting as 5-HT2A agonists may reduce opioid motivation in individuals with opioid and alcohol co-use.
ACS Chemical Neuroscience
October 13, 2025
Rajiv Agrawal, Daniel J. Gillie, Alison E. Mungenast et al.
8 citations
A new compound called zalsupindole, designed to promote brain cell regrowth without causing hallucinations or dissociation, shows promise for treating depression. In rats, it produced robust structural and functional neuroplasticity in the prefrontal cortex and sustained antidepressant-like effects, comparable to or greater than ketamine, psilocybin, and DMT. Unlike these other compounds, zalsupindole lacked hallucinogenic or dissociative properties, suggesting it could be a safer and more scalable treatment for depression. This work addresses the need for neuroplastogens that promote cortical neuron regrowth without the safety concerns of psychedelics and dissociative anesthetics.
The American journal of psychiatry
January 1, 2025
David E. Olson
8 citations
Psychedelics promote cortical neuron growth in the prefrontal cortex in preclinical studies, but measuring this structural plasticity in humans has been difficult. New positron emission tomography imaging advances could enable measurement of synaptic proteins after psychedelic administration. A translatable biomarker of psychedelic-induced neuroplasticity would help stratify patients, determine optimal dosing, and aid discovery of novel compounds with similar effects on structural neuroplasticity.
The Journal of Organic Chemistry
October 6, 2023
Jeremy R Tuck, Lee E. Dunlap, David E. Olson
7 citations
A novel seven-step formal synthesis of LSD has been developed, focusing on connecting the A- and D-rings first and then bridging the B- and D-rings last. The synthesis uses cross-coupling, intramolecular α-arylation, borrowing hydrogen alkylation, and rhodium-catalyzed C-H insertion to form the tetracyclic ergoline core. The methods enable the first introduction of substitutions on the C-ring, though each strategy faces unique challenges when elaborating to ergoline natural products. These findings provide insights that will guide future synthetic strategies toward ergolines and related compounds.
JACS Au
October 5, 2023
Winston L. Chow, Monica A. Gonzalez, Arabo A. Avanes et al.
7 citations
A general chemical synthesis method for tropane alkaloids—compounds with a characteristic 8-azabicyclo[3.2.1]octane core—enables late-stage structural diversification at positions N8, C3, C6, and C7, which are important for biological activity. The approach constructs the core via aziridination of a cycloheptadiene intermediate followed by vinyl aziridine rearrangement, yielding six tropane alkaloids and several analogues in 5-7 steps. Testing five tropane-containing compounds in cultured cortical neurons for dendritic spine growth—a marker of structural neuroplasticity—suggests that the orientation of the C3 substituent may influence psychoplastogenic effects. This platform supports future structure-activity relationship studies.
Journal of Medicinal Chemistry
July 9, 2024
Hunter T Warren, Winston L. Chow, Milan Chytil et al.
5 citations
Tropane-containing small molecules such as scopolamine can promote neuronal growth (psychoplastogens) but also block all muscarinic receptor subtypes, causing unwanted anticholinergic side effects. Researchers conducted phenotypic structure-activity relationship studies on various tropane subclasses to separate these effects. They identified several novel tropanes that substantially increase cortical neuron growth while showing much weaker activity at all muscarinic receptor subtypes than scopolamine, suggesting that the neuroplasticity-promoting and muscarinic-blocking properties can be decoupled.
bioRxiv : the preprint server for biology
May 14, 2024
Run Zhang, Maribel Anguiano, Isak K Aarrestad et al.
5 citations
preprint
A new enzyme-based method called CaST (Ca2+-activated Split-TurboID) biochemically tags cells with elevated calcium levels in living animals within 10 minutes, without requiring implants or light delivery. The signal increases with calcium concentration and labeling time, acting as a time-gated integrator of calcium activity. Unlike transcriptional reporters that take hours, CaST allows immediate read-out after activity labeling. The approach was used to tag prefrontal cortex neurons activated by psilocybin in untethered mice, and the CaST signal correlated with psilocybin-induced head-twitch responses.
Nature Communications
September 30, 2025
Cassandra J. Hatzipantelis, Min Liu, A. H. G. Love et al.
2 citations
Psilocybin, which increases social connectedness and shows promise for treating mental illness, was tested in a mouse model of peripartum mood disorders. Social stress caused maternal withdrawal and increased stress-related behaviors, and psilocybin did not alleviate these effects. Weeks later, psilocybin-treated mothers were more anxious, regardless of prior stress exposure, while virgin females were unaffected. Reproductive status did not alter psilocybin metabolism, but serotonin receptor transcription and 5-HT2A receptor-dependent responses were reduced in mothers. Offspring exposed to psilocybin through breastfeeding showed anhedonia in adulthood. The findings indicate that both parous parents and their children may be uniquely vulnerable to psychedelic treatment during the postpartum period.
ACS Chemical Neuroscience
September 3, 2025
Arabo A. Avanes, Hunter T Warren, Abinaya Senthil et al.
2 citations
Tropane alkaloids and their derivatives are a diverse group of small molecules with many therapeutic uses. Many tropanes affect dopamine and serotonin transporters in the brain. While blocking the dopamine transporter contributes to the addictive potential of tropanes like cocaine, modulating the serotonin transporter may counteract those effects. Serotonin transporter modulators such as MDMA, ibogaine, and SSRIs show promise for treating depression, addiction, and PTSD. This work profiled various tropane subclasses and identified compounds, notably UCD0168 and UCD0820, that potently modulate the serotonin transporter similarly to fluoxetine, MDMA, or noribogaine. UCD0168 acts as a full serotonin releasing agent, and UCD0820 as a partial one. The tropane scaffold can serve as a starting point for developing new serotonin transporter modulators.
Journal of Medicinal Chemistry
June 18, 2025
Alexandra Sink, Eline Pottie, Samuel J Carter et al.
2 citations
A photoswitchable ligand for the serotonin 2A receptor (5-HT2AR) was designed to independently study G protein- and β-arrestin2-dependent signaling pathways. The cis-photoisomer binds the receptor with greater affinity than the trans-isomer, at nanomolar concentrations. In functional assays, this ligand showed a preference for recruiting β-arrestin2 over mini-Gαq relative to LSD, offering a tool to investigate β-arrestin2's role in 5-HT2AR signaling and its potential involvement in psychedelic effects.
bioRxiv Preprint Server
December 29, 2022
Marc Duque, Alex B. Chen, Eric Hsu et al.
1 citation
preprint
Ketamine, a mood-altering compound, suppresses passivity induced by futility in larval zebrafish, similar to effects in rodent learned helplessness models. Brain-wide imaging in behaving zebrafish shows ketamine elevates intracellular calcium in astroglia for many minutes, followed by persistent calcium downregulation after washout. This calcium elevation depends on astroglial α1-adrenergic receptors and is required for suppression of passivity. Chemo- and optogenetic experiments show that the aftereffects of glial calcium elevation are sufficient to suppress passivity by inhibiting neuronal-astroglial integration of behavioral futility. Imaging in mouse cortex reveals ketamine elevates astroglial calcium through conserved pathways, suggesting ketamine exerts its behavioral effects by persistently modulating evolutionarily ancient neuromodulatory systems spanning neurons and astroglia.
ACS Chemical Neuroscience
May 6, 2026
Maxemiliano V. Vargas, Cassandra J. Hatzipantelis, Lee E. Dunlap et al.
A safer analogue of MDMA, called R-MDDMA, shows promise for treating PTSD and depression without the abuse potential of MDMA. Unlike MDMA, R-MDDMA does not activate 5-HT2B receptors, induce serotonin release, cause head-twitch responses, affect body temperature, or increase locomotion at therapeutic doses. However, it still promotes structural neuroplasticity in cortical neurons, facilitates fear extinction learning, and produces sustained antidepressant-like effects. These results suggest that R-MDDMA might be a safer MDMA analogue with similar therapeutic properties.
ACS Chemical Neuroscience
October 15, 2025
Cassandra J. Hatzipantelis, Lindsay P. Cameron, Min Liu et al.
A new genetic mouse model lacking the enzyme indolethylamine N-methyltransferase (INMT) shows that INMT is not required for the production of endogenous psychedelics, suggesting alternative biosynthetic pathways exist in rodents. INMT knockout mice had no major abnormalities in reproduction or growth but did exhibit altered behaviors across several domains. The study also describes highly sensitive mass spectrometry methods for quantifying endogenous psychedelics in mice. These findings challenge the assumption that INMT is the primary enzyme for endogenous psychedelic production and open new questions about the role of these compounds in health and disease.
The International Journal of Neuropsychopharmacology
August 1, 2025
Cassandra J. Hatzipantelis, David E. Olson, Danielle S. Stolzenberg
In a mouse model of peripartum mood disorder, a single dose of psilocybin did not improve impaired caregiving, maternal withdrawal, or anxiety-like behaviors; treated dams were more anxious and had increased risk of overall behavioral impairments two weeks after injection. In contrast, virgin female mice given the same dose showed reduced anxiety and lower risk of behavioral impairments. Additionally, a single postnatal exposure to psilocybin through breastmilk increased the risk of behavioral phenotypes related to mood and sociability disorders in both male and female offspring when they reached adulthood. These findings suggest psilocybin may pose risks during the postpartum period for mothers and their offspring.
Natural Product Reports
March 4, 2021
Rishab N Iyer, David Favela, Guoliang Zhang et al.
Iboga alkaloids, a family of natural products including the anti-addictive compound ibogaine and the chemotherapeutic precursor catharanthine, have inspired chemists and biologists for over 120 years. This review covers advances from 2000 to 2020 in their biosynthesis and chemical synthesis, as well as their development as next-generation neurotherapeutics for mental illness. The authors provide historical context for recent discoveries and highlight unresolved questions. Although significant progress in chemistry and pharmacology has occurred since the 1960s, the iboga alkaloids continue to drive scientific innovation.
Nature Neuroscience
September 1, 2025
Isak K Aarrestad, Lindsay P. Cameron, Ethan M Fenton et al.
Nonhallucinogenic psychoplastogens like tabernanthalog (TBG) promote cortical neuroplasticity through the same biochemical pathway as classic psychedelics—involving 5-HT2A, TrkB, mTOR, and AMPA receptor activation—but without inducing an immediate glutamate burst or immediate early gene activation. TBG-induced cortical spinogenesis is required for its sustained antidepressant-like behavioral effect in rodents. These findings clarify how certain psychoplastogens can produce neuroplasticity without hallucinogenic effects, challenging assumptions that glutamate burst and IEG activation are necessary for psychedelic-induced neuroplasticity.