Cell Reports
June 1, 2018
Calvin Ly, Alexandra C. Greb, Lindsay P. Cameron et al.
1,158 citations
Serotonergic psychedelics, like ketamine, can robustly increase the growth of neurons and their connections (neuritogenesis and spinogenesis) in the prefrontal cortex, both in lab dishes and in living animals. These structural changes are accompanied by more synapses and enhanced function, as shown by microscopy and electrophysiology. The effects appear to arise from stimulation of TrkB, mTOR, and 5-HT2A signaling pathways, which may explain the clinical effectiveness of these compounds. The findings highlight the therapeutic potential of psychedelics and identify several chemical scaffolds for developing fast-acting, safe antidepressants that promote brain plasticity.
ACS Chemical Neuroscience
April 17, 2018
Lindsay P. Cameron, Charlie J. Benson, Lee E. Dunlap et al.
168 citations
Depression and anxiety impose large economic costs, and many patients do not respond to traditional antidepressants. A single dose of DMT, the main psychoactive compound in ayahuasca, initially increased anxiety-like behaviors in adult male rats but later reduced anxiety by speeding the extinction of conditioned fear memories. DMT also decreased immobility in the forced swim test, a standard measure of antidepressant-like effect. These results indicate that DMT produces both antidepressant and anxiety-reducing behavioral effects in rodents, supporting further research into ayahuasca and similar psychedelics as potential treatments for depression and PTSD.
ACS Chemical Neuroscience
March 4, 2019
Lindsay P. Cameron, Charlie J. Benson, Brian C. Defelice et al.
163 citations
Repeated low doses of DMT, a psychedelic compound, produced antidepressant-like effects and improved fear extinction learning in male rats, without affecting working memory or social interaction. The rats also gained significant body weight during the study. The findings suggest that microdosing psychedelics may help alleviate symptoms of mood and anxiety disorders, but potential risks require further study.
Frontiers in Psychiatry
October 4, 2021
Maxemiliano V. Vargas, Retsina Meyer, Arabo A. Avanes et al.
162 citations
Psychedelics, part of a broader class called psychoplastogens, promote structural and functional neural plasticity in brain circuits relevant to mental health. They produce lasting therapeutic effects after a single dose and show promise for depression, PTSD, anxiety, and substance use disorders. A theoretical framework explains their broad efficacy. Challenges like scalability and hallucinogenic effects may be addressed by non-hallucinogenic psychoplastogens. This shift in neuropsychiatry aims to cure mental illness by repairing underlying pathophysiology, not just treating symptoms.
ACS Chemical Neuroscience
July 23, 2018
Lindsay P. Cameron, David E. Olson
114 citations
DMT is the foundational molecule for all indole-containing serotonergic psychedelics, with its structure embedded in LSD and psilocybin. Unlike those, DMT is produced by many plants and animals, is a key component of ayahuasca, and is one of the few psychedelics made naturally in mammals, though its biological role remains unknown. This review covers DMT's synthesis, pharmacology, metabolism, adverse effects, and potential medical uses, and discusses its history and importance in psychedelic science.
Journal of Psychoactive Drugs
January 23, 2020
Lindsay P. Cameron, Angela Nazarian, David E. Olson
112 citations
A survey of 2,347 people found that psychedelic microdosing—taking sub-hallucinogenic doses on a chronic schedule—is relatively common, with 17% of respondents having tried it. Microdosers reported that the practice subjectively improved their mood, decreased anxiety, and enhanced memory, attention, and sociability. The most common reasons for quitting were the risks of taking an illegal substance (24.28%) and difficulty obtaining psychedelic compounds (22.63%). The findings suggest microdosing is associated with a broad range of self-reported socio-affective, cognitive, and physical outcomes.
ACS Chemical Neuroscience
July 12, 2018
Lee E. Dunlap, Anne M. Andrews, David E. Olson
105 citations
MDMA, known as ecstasy, is a small molecule that shapes youth culture similarly to LSD in the 1960s. Structurally related to amphetamine and mescaline, it produces unique subjective effects distinct from psychostimulants or hallucinogens and reliably induces prosocial states. This review covers MDMA's synthesis, pharmacology, metabolism, adverse effects, and potential medical uses. The authors argue MDMA may be the most important compound for the future of psychedelic science, capable of either advancing new research or triggering a second Dark Age for the field.
Molecular Psychiatry
May 25, 2021
Ju Lu, Michelle Tjia, Brian Mullen et al.
87 citations
A single dose of the psychedelic analog tabernanthalog (TBG) reduces anxiety and reverses stress-induced deficits in sensory processing and cognitive flexibility in mice exposed to unpredictable mild stress. TBG promotes regrowth of dendritic spines lost during stress, lowers baseline neuronal activity, and enhances whisking-related modulation in the somatosensory cortex. In a texture discrimination task, novel textures activate a greater proportion of cortical neurons than familiar ones; this differential response is diminished by stress and restored by TBG. The findings indicate TBG combats stress effects by modulating basal and stimulus-dependent neural activity in cortical networks.
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 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.
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.
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.
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.
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.