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.
Science
February 16, 2023
Maxemiliano V. Vargas, Lee E. Dunlap, Chunyang Dong et al.
467 citations
Decreased dendritic spine density in the cortex is a hallmark of several neuropsychiatric diseases, and the ability to promote cortical neuron growth has been hypothesized to underlie the rapid and sustained therapeutic effects of psychedelics. Activation of 5-HT2ARs is essential for psychedelic-induced cortical plasticity, but it is unclear why some 5-HT2AR agonists promote neuroplasticity while others do not. Using molecular and genetic tools, the authors demonstrate that intracellular 5-HT2ARs mediate the plasticity-promoting properties of psychedelics, explaining why serotonin does not engage similar plasticity mechanisms. This work emphasizes location bias in 5-HT2AR signaling, identifies intracellular 5-HT2ARs as a therapeutic target, and raises the possibility that serotonin might not be the endogenous ligand for intracellular 5-HT2ARs in the cortex.
ACS Pharmacology & Translational Science
December 10, 2020
David E. Olson
328 citations
Psychedelics are promising experimental medicines for neuropsychiatric disorders because they can rapidly and sustainably promote neural plasticity after a single dose. While peak mystical experiences are often considered essential to their therapeutic effects, the evidence is mostly correlational. New data suggest that subjective psychedelic effects may not be required for lasting changes in mood and behavior. Clarifying the role of these subjective effects will inform basic neuroscience and help expand patient access to future psychedelic-derived treatments.
Nat Neurosci
October 24, 2022
Alex C. Kwan, David E. Olson, Katrin H. Preller et al.
291 citations
This review synthesizes the neurobiology of psychedelic drugs, which are serotonin 2A receptor agonists that alter perception, cognition, and mood. It covers the chemistry of diverse psychoactive molecules, their potency and pharmacokinetics, and the roles of serotonin receptors and downstream signaling pathways. The review describes effects on neuronal spiking in cortical and subcortical regions, transcriptional changes, and structural plasticity. Neuroimaging findings highlight impacts on association cortices and thalamocortical connectivity, informing theories of psychedelic action. The authors integrate knowledge across chemical, molecular, neuronal, and network levels to explain acute and enduring behavioral effects.
Cell
April 28, 2021
Chunyang Dong, Calvin Ly, Lee E. Dunlap et al.
207 citations
A genetically encoded fluorescent sensor called psychLight, based on the 5-HT2A receptor structure, detects behaviorally relevant serotonin release and correctly predicts whether structurally similar 5-HT2AR ligands will cause hallucinogenic behavioral effects. Using psychLight, a non-hallucinogenic psychedelic analog was identified that produced rapid-onset and long-lasting antidepressant-like effects after a single administration. The sensor enables in vivo detection of serotonin dynamics, early identification of designer drugs of abuse, and development of non-hallucinogenic therapeutics targeting the 5-HT2AR.
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 Pharmacology & Translational Science
September 11, 2020
Calvin Ly, Alexandra C. Greb, Maxemiliano V. Vargas et al.
127 citations
Cortical neuron atrophy, including neurite retraction and spine loss, is a hallmark of depression. Psychoplastogens are small molecules hypothesized to reverse these changes. Ketamine and LSD, from two structurally distinct chemical classes, promote sustained growth of cortical neurons after brief stimulation. This growth occurs in two phases: an initial stimulation phase requiring TrkB activation, followed by a growth period needing sustained mTOR and AMPA receptor activation. These temporal details suggest that rapidly excreted psychoplastogens could be effective neurotherapeutics with advantages over ketamine and LSD.
Biochemistry
January 21, 2022
David E. Olson
121 citations
Psychedelic compounds can produce beneficial behavioral changes relevant to treating neuropsychiatric disorders that last long after the drugs are cleared from the body. One hypothesis for these enduring effects is that psychedelics promote structural and functional neuroplasticity in the prefrontal cortex (PFC), a brain region where neuron atrophy is a hallmark of stress-related diseases like depression, PTSD, and addiction. Psychedelics appear to be effective catalysts for regrowing these neurons and restoring synaptic connectivity. Evidence suggests the hallucinogenic effects are not directly linked to the neuroplasticity-promoting ability. Fully characterizing the molecular mechanisms of psychedelic-induced neuroplasticity is needed to develop improved alternatives. This review covers current understanding of biochemical signaling pathways activated by psychedelics and related molecules, focusing on key unanswered questions.
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.
J Neurosci
November 1, 2022
Steven F. Grieco, Eero Castrén, Gitte M. Knudsen et al.
83 citations
Psychedelic drugs are being reexamined as treatments for brain disorders, with hundreds of clinical trials underway by 2022. Emerging evidence suggests these drugs may produce lasting therapeutic effects by inducing structural and functional neural plasticity. The work reviews basic and clinical research on mechanisms, including receptor binding, gene expression, dendritic changes, and effects on microcircuitry and brain-wide circuits. It also outlines unmet clinical needs and unanswered neuroscience questions for future study.
Neuropsychopharmacology
July 24, 2023
Boris D. Heifets, David E. Olson
66 citations
Psychedelics and entactogens can produce rapid and lasting therapeutic effects, but there is a disconnect between how they are used in human clinics and how they are studied in animals. Human research emphasizes extra-pharmacological factors like set, setting, and integration, which are poorly modeled in animal experiments. Animal studies focus on neuronal activation and structural plasticity, which are hard to measure in humans. The paper proposes bridging this gap by focusing on the circuits these compounds modulate rather than single molecular targets, suggesting that selective circuit modulation of behavioral phenotypes may be more fruitful for identifying novel compounds with similar therapeutic effects.
Annu Rev Physiol
November 6, 2023
Cassandra J. Hatzipantelis, David E. Olson
28 citations
A single dose of a psychedelic can rapidly alter subjective experience and produce lasting changes in brain circuits related to mood, fear, reward, and cognitive flexibility. These effects stem from psychedelics interacting with key neuroreceptors across the brain, activating signaling cascades that change neuronal structure and function. The acute effects involve serotonergic and glutamatergic neurotransmission, while long-lasting effects involve structural and functional neuroplasticity in the cortex. The neurobiological changes behind acute and sustained effects may be distinct, offering opportunities to engineer compounds with improved safety and efficacy.
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.
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.
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.
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.