Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
January 1, 2023
Abigail E. Calder, Gregor Hasler
303 citations
Classic psychedelics like LSD, psilocybin, and ayahuasca may help treat depression, anxiety, and addiction, with clinical improvements lasting months or years. The leading theory is that these drugs rapidly and persistently stimulate neuroplasticity. This review examines evidence that psychedelics promote neuroplasticity, including dendritogenesis, synaptogenesis, neurogenesis, and plasticity-related gene expression, particularly in the prefrontal cortex and hippocampus. It also considers the doses required—hallucinogenic versus microdoses—and how long neuroplastic changes last. The authors discuss consequences for patients and healthy individuals and identify key research questions for future study.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
November 1, 2020
N L Mason, K P C Kuypers, F Müller et al.
261 citations
A double-blind, placebo-controlled study using ultra-high field brain imaging found that psilocybin (0.17 mg/kg) caused region-dependent changes in glutamate levels in the human brain. Higher medial prefrontal cortical glutamate was linked to negatively experienced ego dissolution, while lower hippocampal glutamate was linked to positively experienced ego dissolution. These results suggest a neurochemical basis for the therapeutic effects of psychedelics on disorders involving distortions of self-experience, such as depression.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
September 1, 2023
Guy M Goodwin, Megan Croal, David Feifel et al.
166 citations
A single 25 mg dose of synthetic psilocybin (COMP360) given alongside psychological support to adults with treatment-resistant depression who continued taking a selective serotonin reuptake inhibitor led to a mean reduction of 14.9 points on the Montgomery-Åsberg Depression Rating Scale at three weeks. Twelve of nineteen participants (63.2%) experienced mild treatment-emergent adverse events that resolved the same day, with no serious events or increased suicidal ideation. Response and remission occurred in 8 participants (42.1%). The authors suggest larger controlled trials are needed to determine whether this approach can benefit patients who cannot safely withdraw from antidepressants.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
September 1, 2022
Deepak Cyril D'Souza, Shariful A Syed, L Taylor Flynn et al.
156 citations
A potent, rapid-onset psychedelic drug, dimethyltryptamine (DMT), was tested intravenously in a small pilot study with 7 treatment-resistant depressed individuals and 3 healthy controls. DMT was mostly safe and tolerated; no participants dropped out. Depression scores on the HAMD-17 scale dropped significantly the day after the higher dose (0.3 mg/kg), with an average decrease of 4.5 points. Side effects like increased blood pressure, heart rate, and anxiety resolved within 20-30 minutes. The findings suggest DMT may have next-day antidepressant effects in treatment-resistant depression, but more rigorous trials are needed to confirm and assess durability.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
April 1, 1996
H D Abraham, A M Aldridge, P Gogia
155 citations
Hallucinogenic drugs have been used throughout history, and their purification led to hopes for therapeutic use, but abuse and adverse effects have complicated that promise. This review covers the history of hallucinogens, current abuse epidemiology, links between LSD and prolonged psychoses or hallucinogen persisting perception disorder, and attempts to show therapeutic efficacy. It also discusses human subject issues in hallucinogen research and suggests future studies in humans, animals, and tissue cultures.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
October 1, 2023
Laura Ley, Friederike Holze, Denis Arikci et al.
127 citations
At equally strong doses, the classic psychedelics mescaline, LSD, and psilocybin produce comparable subjective experiences, with no evidence of qualitative differences in altered states of consciousness. Autonomic effects were moderate; psilocybin increased diastolic blood pressure more than LSD, while LSD showed a trend toward higher heart rate than psilocybin. Mescaline had the longest effect duration (mean 11.1 hours), followed by LSD (8.2 hours) and psilocybin (4.9 hours). Mescaline and LSD, but not psilocybin, raised circulating oxytocin. None altered brain-derived neurotrophic factor. Tolerability was similar, though mescaline caused slightly more subacute adverse effects 12–24 hours later.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
March 1, 2024
Mehdi Sekssaoui, Joël Bockaert, Philippe Marin et al.
76 citations
A single injection of psychedelic or non-hallucinogenic drugs that activate the serotonin 5-HT2A receptor can produce antidepressant- and anxiety-reducing effects in mice with a depression-like condition, lasting up to 15 days. The non-hallucinogenic drug lisuride was effective, suggesting hallucinogenic properties are not required for antidepressant action. In mice lacking the 5-HT2A receptor, the psychedelic DOI was ineffective, but psilocybin still worked, indicating psilocybin's effects can occur through other mechanisms. Blocking other serotonin or dopamine receptors did not stop psilocybin's effects in these mice. These results suggest that 5-HT2A receptor agonists can relieve depression through multiple pathways, independent of whether they cause hallucinations.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
August 1, 2023
Sarah J Jefferson, Ian Gregg, Mark Dibbs et al.
57 citations
5-MeO-DMT, a short-acting psychedelic, produces a dose-dependent increase in head-twitch response in mice that is shorter in duration than psilocybin at all doses tested. It also substantially suppresses social ultrasonic vocalizations during mating behavior. The compound causes long-lasting increases in dendritic spine density in the mouse medial frontal cortex, driven by an elevated rate of spine formation, but unlike psilocybin, it does not affect the size of dendritic spines. These findings reveal behavioral and neural mechanisms of 5-MeO-DMT, highlighting similarities and differences with psilocybin.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
January 1, 2023
James Glazer, Conor H Murray, Robin Nusslock et al.
52 citations
Single low doses of LSD increase reward-related brain activity in healthy adults. In a double-blind, placebo-controlled experiment, 18 participants received 13 μg or 26 μg of LSD or a placebo across three sessions. Brain electrical activity was recorded during a monetary incentive delay task. Compared to placebo, the 13 μg dose enhanced three event-related potential components: Reward-Positivity (RewP), Feedback-P3 (FB-P3), and Late-Positive Potential (LPP), indicating increased hedonic, motivational, and affective processing of reward feedback. The 26 μg dose also increased FB-P3 amplitudes for positive feedback. These effects were not linked to most subjective drug effects. The findings provide the first evidence that low LSD doses boost reward-related brain activity, with potential implications for treating depressive disorders.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
November 1, 2023
Daniel Ryskamp Rijsketic, Austen B Casey, Daniel A N Barbosa et al.
49 citations
Psilocybin increased neural activity (c-Fos expression) in the neocortex, caudoputamen, central amygdala, and parasubthalamic nucleus while decreasing it in the hypothalamus, cortical amygdala, striatum, and pallidum of mice, largely regardless of whether the mice were in their home cage or an enriched environment. Network analyses showed that psilocybin disrupted co-activity between highly correlated brain regions, reduced modularity, and attenuated communication between modules. Context and psilocybin each had widespread effects on brain activity and network architecture, but interactions between the two were surprisingly sparse.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
May 1, 2025
Johan Saelens, Anna Gramser, Victoria Watzal et al.
47 citations
A systematic review and network meta-analysis of 69 randomized controlled trials with 10,285 adults who had not responded to at least two antidepressant trials compared 25 treatments for treatment-resistant depression. Six treatments showed higher response rates than placebo or sham: electroconvulsive therapy (ECT) had the strongest effect, followed by minocycline, theta-burst stimulation, repetitive transcranial magnetic stimulation, ketamine, and aripiprazole. Odds ratios ranged from 1.9 for aripiprazole to 12.86 for ECT. Moderate heterogeneity was observed. These findings may help guide evidence-based treatment choices for treatment-resistant depression.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
January 1, 2024
Jihye Kim, Michelle J He, Alina K Widmann et al.
47 citations
Neurotrophic factors help neurons grow, survive, and connect. For decades, scientists thought that too little neurotrophic support caused the loss of synapses and cells seen in psychiatric disorders. Traditional antidepressants raise neurotrophic levels over weeks, matching when they start working. Newer treatments like ketamine and psychedelics work within hours and quickly release neurotrophins into synapses. This has changed how researchers understand neurotrophins and their receptors. This review discusses these new insights into receptor signaling and their clinical importance, building on what is already known about neurotrophic factors in psychiatric disorders and treatments.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
December 1, 2023
Isabelle Straumann, Laura Ley, Friederike Holze et al.
41 citations
Co-administering MDMA (100 mg) with LSD (100 µg) does not improve the quality of the acute subjective effects compared with LSD alone in healthy adults. The combination prolongs the duration of subjective effects and increases blood pressure, heart rate, and pupil size more than LSD alone. Oxytocin levels rise more with MDMA alone or the combination than with LSD alone. The findings suggest that combining MDMA with LSD offers no relevant benefits over LSD alone for psychedelic-assisted therapy.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
April 1, 2024
Hanna Molla, Royce Lee, Ilaria Tare et al.
37 citations
A single low dose of LSD (26 µg) produces more pronounced positive mood effects and stronger altered states of consciousness in people with mild depressive symptoms than in those without. In a randomized, double-blind, crossover trial, 39 adults received either LSD or placebo. Those scoring 17 or higher on the Beck Depression Inventory reported greater increases in vigor, elation, and positive psychedelic effects, and showed a larger decline in depression scores 48 hours after the dose, compared with placebo. The drug caused only mild physiological and subjective effects overall.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
May 1, 2025
Marcelo Falchi-Carvalho, Fernanda Palhano-Fontes, Isabel Wießner et al.
35 citations
Vaporized DMT, a short-acting psychedelic, rapidly reduced depression symptoms in patients with treatment-resistant depression. In an open-label trial, 14 patients received inhaled DMT at 15 mg and then 60 mg. The treatment was safe and well-tolerated, with no serious adverse events. By day 7, depression scores on the Montgomery-Asberg Depression Rating Scale dropped by an average of 21.14 points. The response rate was 85.71%, and the remission rate was 57.14%, with effects lasting up to 3 months. Suicidal ideation also decreased significantly, with no severe ideation the day after dosing. Vaporized DMT offers a non-invasive, time-efficient alternative to longer-acting psychedelics and traditional antidepressants.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
July 1, 1999
C Zubaran, M Shoaib, I P Stolerman et al.
31 citations
In rats trained to distinguish ibogaine from a placebo, the metabolite noribogaine produced the same discriminative effect as ibogaine but at roughly half the dose. Noribogaine was found in blood and brain tissue after either ibogaine or noribogaine was given. At doses that produced the discriminative effect, noribogaine concentrations in plasma, cerebral cortex, and striatum were similar whether ibogaine or noribogaine was administered. The findings suggest noribogaine may lack the NMDA antagonist and kappa-opioid agonist effects of ibogaine and may be primarily responsible for ibogaine's discriminative stimulus effect in rats.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
June 1, 2024
Conor H Murray, Joel Frohlich, Connor J Haggarty et al.
30 citations
Neural complexity, a measure of brain signal diversity, increases after low doses of LSD (13 and 26 µg) even when volunteers do not report an altered state of consciousness. In three separate placebo-controlled experiments with 73 healthy adults, LSD dose-dependently raised neural complexity, while THC and methamphetamine did not. LSD also reduced delta and theta brain wave power, and those reductions correlated with feelings of elation. THC reduced alpha power, which was linked to altered states, and methamphetamine increased alpha power. The findings show that increased neural complexity is neither necessary nor sufficient for an altered state of consciousness, and that different drugs affect brain activity and subjective experience through distinct mechanisms.
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
October 1, 2023
Tim Hirschfeld, Johanna Prugger, Tomislav Majić et al.
24 citations
LSD produces a sigmoid-like increase in altered states of consciousness that plateaus around 100 micrograms, with the strongest effects on perception and illusory imagination, followed by positive ego-dissolution. Anxiety and dread of ego dissolution show only small effects. Considerable variability in most measures indicates that non-pharmacological factors also shape subjective experiences. These dose-response relationships can serve as general references for future research to compare observed with expected effects and to explore phenomenological differences between psychedelics.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
April 9, 2025
Ellen R Bradley, Kimberly Sakai, Gisele Fernandes-Osterhold et al.
23 citations
In an open-label pilot trial, 12 people with mild to moderate Parkinson's disease plus depression or anxiety received psilocybin (10 mg then 25 mg) with psychotherapy. No serious adverse events occurred, and no worsening of Parkinson's symptoms was observed. Non-motor and motor symptoms improved, and gains in some cognitive domains were sustained one month later. Depression and anxiety scores improved to a clinically meaningful degree and remained improved three months after dosing. These first results in any neurodegenerative disease suggest psilocybin therapy for Parkinson's disease warrants further study.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
March 1, 2025
Manoela V Fogaça, Fernanda Daher, Marina R Picciotto
22 citations
Ketamine produces sustained antidepressant effects in mice by first decreasing and later increasing the activity of GABA neurons in the medial prefrontal cortex. Calcium recordings showed an initial transient drop in GABA neuron activity lasting about 60 minutes, alongside a brief rise in excitation/inhibition balance and a longer-lasting increase in glutamatergic activity from 30 to 120 minutes. Previous ketamine treatment enhanced GABA neuron activity during behavioral tests 24 and 72 hours later. Chemogenetically inhibiting GABA interneurons during the later surge of activity or just before those tests blocked ketamine's behavioral effects. Thus, time-dependent modulation of GABAergic activity is necessary for ketamine's lasting antidepressant-like actions, pointing to GABAergic plasticity as a target for new antidepressants.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
January 1, 2024
Maurizio Fava
22 citations
New molecular targets and novel treatments for neuropsychiatric diseases, including psychedelics and gene and cell therapies, require more efficient clinical trials. This review examines factors that hinder the detection of therapeutic signals, such as excessive placebo or sham responses and imprecise diagnostic and outcome measures. It also presents methodological approaches to improve trial performance, including the sequential parallel comparison design and independent confirmation of subject enrollment, along with designs that increase the precision of mechanistic trials.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
October 1, 2024
Michelle K Piazza, Ege T Kavalali, Lisa M Monteggia
21 citations
Synaptic plasticity includes both homeostatic and Hebbian mechanisms that regulate AMPA receptor activity and glutamatergic transmission. Ketamine, a rapidly acting antidepressant, induces homeostatic plasticity to increase glutamatergic transmission. This study demonstrates that Hebbian plasticity, specifically long-term potentiation (LTP), remains intact in synapses that have undergone homeostatic scaling induced by ketamine, whether delivered systemically or perfused onto hippocampal brain slices. In mice exposed to chronic corticosterone (CORT) to model stress, CORT produced an anhedonia-like behavior but did not impair LTP induction. CORT exposure also did not disrupt the interaction between homeostatic and Hebbian plasticity; synapses from CORT-exposed mice showed intact ketamine-induced plasticity followed by LTP. These findings explain how ketamine treatment for depression does not compromise learning and memory processes that rely on LTP.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
December 1, 2024
Isabelle Straumann, Isidora Avedisian, Aaron Klaiber et al.
20 citations
The two mirror-image forms of MDMA, S-MDMA and R-MDMA, produce different acute effects in humans. S-MDMA (125 mg) caused stronger feelings of stimulation, happiness, and openness, and larger increases in blood pressure than R-MDMA (125 or 250 mg) or racemic MDMA (125 mg). R-MDMA did not produce more psychedelic-like effects than S-MDMA. S-MDMA also increased plasma prolactin, cortisol, and oxytocin more than the other forms. The body eliminated S-MDMA faster (half-life 4.1 hours) than R-MDMA (half-life 12-14 hours). The findings suggest that S-MDMA's stronger stimulant effects are due to its higher potency rather than a qualitative difference, and that equivalent effects may occur at doses of 100 mg S-MDMA, 125 mg racemic MDMA, and 300 mg R-MDMA.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
October 1, 2024
Reinoud Kaldewaij, Paula C Salamone, Adam Enmalm et al.
19 citations
Ketamine, a drug that temporarily disrupts the sense of self, reduces the brain's ability to distinguish between one's own touch and touch from another person. In a double-blind, placebo-controlled crossover study, 30 healthy adults received intravenous ketamine or placebo while undergoing functional MRI. Ketamine weakened neural activity in the right temporoparietal cortex, a region involved in touch perception and social cognition, especially when participants were touched by someone else. This reduction correlated with decreased interoceptive awareness. Ketamine also increased connectivity between the temporoparietal cortex and somatosensory cortex and insula during other-touch, which correlated with the strength of dissociation. The findings suggest ketamine disrupts self-other-differentiation by altering top-down signaling, making predictable self-generated and unpredictable other-generated touch more similar.