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.
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.
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.
ACS Chemical Neuroscience
February 1, 2023
Lindsay P. Cameron, Seona D Patel, Maxemiliano V. Vargas et al.
113 citations
Activation of serotonin 2A receptors (5-HT2ARs) is essential for tryptamine-based psychedelics to produce antidepressant-like effects in rodents. While hallucinogenic properties are generally attributed to 5-HT2AR activation, it was unclear whether these receptors also mediate antidepressant effects, especially because some nonhallucinogenic analogues show antidepressant-like properties. Using pharmacological and genetic tools, the authors demonstrate that 5-HT2AR activation is required for the antidepressant-like effects of tryptamine psychedelics, suggesting that hallucinogenic and therapeutic effects can arise through the same receptor.
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.
Journal of Neurochemistry
July 1, 2022
Hannah N Saeger, David E. Olson
59 citations
Psychedelics show promise for treating depression, PTSD, and substance use disorder, potentially by reversing cortical atrophy through effects on neurotrophic factors, neuronal growth, and immune modulation. This review argues that similar approaches could benefit neurodegenerative disorders like Alzheimer's disease, where the primary psychedelic target, the 5-HT2A receptor, is dysregulated. Evidence also suggests psychedelics might help manage behavioral and psychological symptoms of dementia (BPSD). The authors call for more research in neurodegenerative models, emphasizing that the compounds' robust effects on neuroplasticity and inflammation warrant further investigation.
Neuroscience insights
January 1, 2021
Jamie Peters, David E. Olson
38 citations
Addiction arises from maladaptive neuroplasticity that strengthens reward pathways driving compulsive drug seeking while weakening circuits for executive control. Psychedelics show promise for treating addiction, often attributed to insights gained during hallucinations, but they are also potent psychoplastogens that rapidly rewire the adult brain. Non-hallucinogenic psychoplastogens, such as tabernanthalog (TBG), have anti-addictive properties in preclinical models for alcohol and opioid addiction, suggesting hallucinations may not be necessary for therapeutic effects if pathological neural circuitry is repaired. This review discusses implications for addiction treatments and next steps for advancing TBG and related compounds.
Proceedings of the National Academy of Sciences
April 14, 2025
Jeremy R Tuck, Lee E. Dunlap, Yara A Khatib et al.
32 citations
A newly designed compound, (+)-JRT, structurally similar to LSD but with reduced hallucinogenic effects, promotes the growth of dendritic spines in the cortex—a process that is diminished in neuropsychiatric diseases such as depression, addiction, and schizophrenia. In behavioral tests, (+)-JRT showed antidepressant-like and cognition-enhancing effects without worsening signs related to psychosis. This suggests that nonhallucinogenic compounds that promote neuroplasticity could be safer alternatives to psychedelics for treating conditions where psychedelics pose risks.
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.
Neuron
February 5, 2025
Marc Duque, Alex B. Chen, Eric Hsu et al.
27 citations
A brief exposure to ketamine can produce lasting changes in behavior and mood. In larval zebrafish, a short ketamine treatment suppressed the passive "giving-up" response that normally occurs when swimming fails to produce forward movement. Whole-brain imaging showed that ketamine initially hyperactivates a circuit involving norepinephrine and astrocytes, which controls this passivity. After ketamine is removed, the same circuit becomes less sensitive to futility, resulting in long-term increased perseverance. Experiments using pharmacology, chemogenetics, and optogenetics confirmed that norepinephrine and astrocytes are both necessary and sufficient for this effect. In adult mice, astrocytes in the cortex were similarly activated during a futility test, and ketamine also caused astrocyte hyperactivation. The cross-species conservation of this mechanism suggests new strategies for treating affective disorders.
Psychedelic medicine (New Rochelle, N.Y.)
June 1, 2023
Jasper A Heinsbroek, Giuseppe Giannotti, Joel Bonilla et al.
26 citations
Tabernanthalog (TBG), a novel analogue of ibogaine and 5-methoxy-N,N-dimethyltryptamine, lacks classical psychedelic effects and cardiac arrhythmogenic risk. In a polydrug model of heroin and alcohol co-use in rats, TBG reduced motivation for both substances in a progressive ratio test, where the number of lever presses required for a reward increased exponentially. The study used a two-bottle binge protocol for alcohol exposure, followed by self-administration training for intravenous heroin or oral alcohol, and then sessions with both substances. TBG's efficacy was preserved in animals with a history of heroin and alcohol polydrug use.
Nature chemistry
March 1, 2025
Rishab N Iyer, David Favela, Andras Domokos et al.
22 citations
A new chemical method produces ibogaine in seven steps from pyridine, enabling gram-scale synthesis. This approach also creates three additional iboga alkaloids, the unnatural enantiomer (+)-ibogaine, and four analogues. Biological tests show that (+)-ibogaine does not affect cortical neuron growth like natural ibogaine, while (-)-10-fluoroibogamine strongly promotes neuron growth and potently modulates the serotonin transporter. The work provides a platform for making iboga alkaloids and related compounds for further study, supporting research into their therapeutic potential for addiction and other neuropsychiatric conditions.