Neuropsychopharmacology
July 21, 2023
47 citations
Over the last five years, clinical research into psychedelic medicines has expanded rapidly, with data from a Phase 3 industry trial, a multicenter Phase 2 industry trial, and multiple early-phase trials now published in peer-reviewed journals. This narrative review summarizes recent findings and ongoing clinical trials involving various classes of psyche-manifesting substances that may help treat a broad range of conditions. The review also discusses methodological considerations, unique challenges, and next steps for research, emphasizing the experiential nature of these therapies.
Neuropsychopharmacology
September 12, 2020
46 citations
Among people receiving Mindfulness-Oriented Recovery Enhancement for opioid misuse, those who showed higher levels of endogenous theta brainwave activity during meditation subsequently required lower doses of opioids. Theta oscillations, which are linked to relaxation and focused attention, may serve as a neural marker predicting treatment response.
Neuropsychopharmacology
April 25, 2023
Peter Bedford, Daniel J. Hauke, Zheng Wang et al.
43 citations
Lysergic acid diethylamide (LSD) predominantly strengthens interregional connections and reduces self-inhibition across the brain, except in occipital and subcortical regions where connections weaken and self-inhibition increases. These patterns suggest LSD perturbs the brain's excitation/inhibition balance. Whole-brain effective connectivity, assessed via regression dynamic causal modelling of resting-state fMRI data from 45 participants in two placebo-controlled trials, discriminated LSD from placebo with 91.11% accuracy and correlated with global subjective effects, indicating potential for decoding subjective experiences.
Neuropsychopharmacology
November 20, 2020
Felix Müller, Friederike Holze, Patrick C. Dolder et al.
43 citations
The non-hallucinogenic drug MDMA reduces functional connectivity within several resting-state brain networks, including the default mode network, visual networks, and the sensorimotor network. These decreases closely match those previously reported for hallucinogenic drugs like LSD. The findings suggest that such connectivity changes are not specific to serotonergic hallucinogens but can be induced by monoaminergic stimulation without marked subjective drug effects. However, alterations within the default mode network may help explain the antidepressant effects of some of these substances.
Neuropsychopharmacology
April 23, 2024
Julia Colcott, Olivia Carter, Sally Meikle et al.
37 citations
A comprehensive systematic review and meta-analysis of 13 studies found that MDMA-assisted psychotherapy (MDMA-AP) is associated with increased odds of side effects compared to control conditions. In Phase 2 trials, MDMA-AP roughly doubled the odds of any side effect during medication sessions and in the following week. In Phase 3 trials, the odds of any adverse event during treatment were about 3.5 times higher with MDMA-AP than with placebo-assisted psychotherapy. Most side effects were transient and mild or moderate. However, the evidence had very low to moderate certainty, most trials had high risk of bias, and none adequately followed CONSORT Harms 2022 reporting guidelines, highlighting the need for further safety research.
Neuropsychopharmacology
January 24, 2020
Carla Agurto, Guillermo Cecchi, Raquel Norel et al.
33 citations
Computer-extracted speech features from acoustic, semantic, and psycholinguistic domains can detect mental states after controlled administration of MDMA and intranasal oxytocin. In a double-blind, placebo-controlled study with 31 healthy adults, speech tasks during peak drug effects yielded cross-validated accuracies up to 87% in the training/validation set and 92% in independent datasets for classifying drug conditions. Oxytocin-driven changes were mostly captured by acoustic features related to emotion and prosody, while MDMA-related mental states manifested across multiple speech domains. The experimental task—whether involving interaction with another individual—also affected speech responses. These results suggest speech analysis can provide objective markers of drug-induced mental states.
Neuropsychopharmacology
March 8, 2019
M. Madsen, Patrick M. Fisher, Daniel Burmester et al.
21 citations
correction
No Summary
Neuropsychopharmacology
September 1, 2017
Elizabeth G Pitts, Adelaide R Minerva, Erika B Chandler et al.
20 citations
MDMA and its enantiomers increase affiliative social behaviors and vocalizations in group-housed squirrel monkeys, while methamphetamine has only modest effects. Pretreatment with a 5-HT_2A receptor antagonist or a 5-HT_2C receptor agonist reduces MDMA-induced social behaviors, whereas a 5-HT_1A receptor antagonist does not affect affiliative vocalizations and even increases social contact. These results indicate that the prosocial effects of MDMA depend on 5-HT_2A, but not 5-HT_1A, receptors, aligning with findings in humans and rodents. Understanding these neurochemical mechanisms may aid in developing therapeutics that retain MDMA's social benefits with fewer drawbacks.
Neuropsychopharmacology
April 19, 2023
N. Murphy, Amanda J. F. Tamman, Marijn Lijffijt et al.
18 citations
A single low-dose infusion of ketamine in older military veterans with treatment-resistant depression temporarily increases the brain's neural complexity, measured by electroencephalogram (EEG) markers Lempel-Ziv complexity and multiscale entropy, within 30 minutes after infusion. These effects vary over time, with some complexity measures decreasing later. However, these changes in complexity were not linked to reductions in depressive symptoms after seven days. The findings suggest that ketamine produces broad, time-varying effects on brain dynamics beyond previously studied gamma oscillations, offering a potential non-linear marker of the drug's action.
Neuropsychopharmacology
August 25, 2020
M. Madsen, Gitte M. Knudsen
15 citations
No Summary
Neuropsychopharmacology
December 19, 2024
Livio Erne, Severin B Vogt, Lorenz Müller et al.
14 citations
Continuous intravenous infusions of DMT produce dose-dependent subjective effects that plateau after 30 minutes, with a ceiling effect for good drug effect at 1.8 mg/min. The highest dose tested (2.4 mg/min) caused greater anxious ego dissolution and significant anxiety compared to placebo. DMT showed dose-proportional pharmacokinetics and moderate acute tolerance. When participants could self-titrate their dose, they chose moderate to strong psychedelic effects comparable to the 1.8 mg/min rate. These findings can guide dose selection in future DMT research and show that subjective effects can be rapidly adjusted through dose titration.
Neuropsychopharmacology
November 12, 2025
Hannah M. Kramer, Meghan Hibicke, Jason W. Middleton et al.
7 citations
Psilocybin has shown remarkable potential in enhancing neuroplasticity, with studies indicating a 30% reduction in depressive symptoms among participants. In trials involving over 200 individuals, this hallucinogen significantly influenced serotonin receptors, leading to increased synaptic plasticity in the prefrontal cortex. Notably, psilocybin acts as a glutamate receptor agonist, promoting excitatory postsynaptic potential and dendritic spine growth. These findings highlight the promising role of psychedelics in addressing mental health challenges through their impact on neurotransmitter systems and behavior, paving the way for innovative therapeutic approaches.
Neuropsychopharmacology
August 6, 2024
Nathan H. Heller, Frederick S. Barrett
4 citations
No Summary
Neuropsychopharmacology
February 18, 2026
Itishree Sahoo, Sairam Masadi, Ashwath Maheswari et al.
3 citations
Adolescent mice given psilocybin every other day from postnatal days 40-50 showed long-term changes in brain structure and function when tested in adulthood. Brain imaging revealed reduced volume and altered water diffusivity in several regions, with males more affected than females. Functional connectivity increased globally and regionally, notably between the prefrontal cortex and hypothalamus, thalamus, and midbrain. Mice showed reduced brain sensitivity to rewarding and aversive odors, and males had lower levels of epigenetic and neuroplasticity protein markers in the prefrontal cortex. Behaviorally, female mice showed reduced mobility in the open field test, while no differences appeared in the light/dark box test. These findings indicate that adolescent psilocybin exposure produces lasting developmental consequences, especially in males.
Neuropsychopharmacology
February 13, 2026
Fabrizio Ascone, Valeria Buzzelli, Francesca Mottarlini et al.
2 citations
In a rat model of Fragile X Syndrome (FXS), psilocybin microdosing rescued deficits in novel object recognition memory. This benefit persisted even when serotonin receptors (5HT2AR or 5HT1AR) were blocked, but was abolished by blocking the TrkB receptor, indicating that the effect depends on BDNF/TrkB signaling rather than classical serotonergic pathways. At the molecular level, psilocybin normalized mature BDNF, increased TrkB, and restored downstream AKT signaling in the prefrontal cortex—pathways linked to synaptic plasticity and cognition. These results suggest psilocybin microdosing could be a promising therapeutic strategy for neurodevelopmental disorders like FXS and autism spectrum disorder, potentially dissociating therapeutic benefits from hallucinogenic effects.
Neuropsychopharmacology
January 16, 2026
Philip D. Harvey, Charles B. Nemeroff
2 citations
Interest in psychedelic therapies is booming, yet no psychedelic treatment has been approved for any psychiatric condition. The one large-scale MDMA development program that reached the FDA was disapproved for reasons that could also apply to classical psychedelic trials. This review defines psychedelics, surveys current therapies, targeted conditions, compounds under investigation, and research strategies. Some interventions combine drugs with psychotherapy, bringing both benefits and challenges. Debate continues over whether the psychedelic experience itself is essential for therapeutic effect, complicating blinded trials. The review also addresses societal issues like deregulation of formerly illegal substances and regulatory hurdles, including alternatives to blinded trials and whether targets like adjustment disorder pose problems under current standards.
Neuropsychopharmacology
September 12, 2025
2 citations
The brain's function depends on its structural wiring, and psychedelics alter this relationship. Using connectome harmonic decomposition, a method linking brain activity to the network of white matter pathways, the authors show that under N,N-dimethyltryptamine (DMT), the brain's harmonic repertoire shifts similarly to that seen with psilocybin, LSD, and ketamine. Repertoire entropy—a measure of the diversity of brain states—increases under DMT. For the first time, the energy spectrum difference and repertoire entropy of connectome harmonics track the intensity of subjective experience in real time, indicating a close coupling between brain network dynamics and conscious experience.
Neuropsychopharmacology
April 22, 2025
Johannes G. Ramaekers
1 citation
No Summary
Neuropsychopharmacology
July 10, 2026
Christopher W. Thomas, Kayleigh S. Lamalfa, Tobias P. Whelan et al.
Psilocybin and ketamine acutely increased reward responsiveness in rats, and the effect persisted 24 hours after dosing. The increase from psilocybin, but not ketamine, was blocked by a 5-HT2A receptor antagonist. Other psychedelics, DMT and DOI, also acutely increased reward responsiveness but the effect did not last 24 hours. The non-psychedelic 5-HT2A agonist lisuride and the SSRI fluoxetine had no positive effects. These results suggest psychedelics can produce acute and enduring increases in reward responsiveness, partly through the 5-HT2A receptor, though the time course varies and clinical implications require further validation.
Neuropsychopharmacology
July 7, 2026
Wojciech Pasławski, D Doyon, Carl Johan Ekman et al.
Psilocybin, a rapid-acting antidepressant, reduces levels of the neuropeptide galanin and noradrenaline in cerebrospinal fluid, suggesting that normalization of these co-transmitters is a key pharmacodynamic effect. This finding comes from a secondary analysis of a randomized, placebo-controlled trial with multimodal biomarker measurements. The results indicate a selective effect of psilocybin on these specific neurotransmitters, offering insight into its mechanism of action in major depressive disorder.
Neuropsychopharmacology
June 18, 2026
Abigail E. Calder, Vincent J Diehl, Morten P. Lietz et al.
A single 100 µg dose of lysergic acid diethylamide (LSD) improved offline motor learning the next day and, one week later, reduced perceived stress and increased aspects of cognitive flexibility in 45 healthy adults. Electroencephalography showed that LSD acutely decreased N1 and P2 auditory event-related potential amplitudes, with P2 still modulated after one week. Transcranial magnetic stimulation revealed increased motor-evoked potential amplitude and faster latency under LSD. Brain-derived neurotrophic factor levels were unchanged. The findings suggest lasting effects of LSD on learning and neural signals, while highlighting challenges in measuring long-term potentiation in humans.
Neuropsychopharmacology
October 31, 2025
LSD and MDMA, two psychoactive drugs being explored for psychiatric use, alter how the striatum—a brain region involved in reward and motivation—communicates with other areas. Using resting-state fMRI data from prior studies, researchers examined striatal connectivity after acute drug administration. Neither drug changed connectivity within the striatum's own networks. However, MDMA reduced connections between the limbic striatum and the amygdala, while LSD increased connections between the associative striatum and frontal, sensorimotor, and visual cortices. These changes occurred mostly outside standard striatal networks, supporting the idea that psychedelics reduce the brain's usual network segregation, potentially explaining their therapeutic and psychological effects.
Neuropsychopharmacology
May 13, 2024
Conor H. Murray
MDMA-assisted psychotherapy shows promise for treating psychiatric conditions, with clinical trials over the past decade demonstrating safety and efficacy for posttraumatic stress disorder (PTSD). In 2024, the U.S. Food and Drug Administration granted priority review for a new drug application involving MDMA-assisted psychotherapy for PTSD, following a Breakthrough Therapy designation in 2017. Australia became the first country to authorize MDMA prescriptions for PTSD. Beyond PTSD, evidence from clinical trials indicates that MDMA-assisted psychotherapy is safe, tolerable, and effective for alcohol use disorder, autism, and end-of-life anxiety.
Neuropsychopharmacology
April 16, 2024
The abstract indicates that the neural effects of psychedelics are primarily characterized by increased complexity in brain activity. This suggests that psychedelics alter brain dynamics by promoting more diverse and flexible patterns of neural connectivity, which may underlie their therapeutic potential and ability to induce altered states of consciousness. The focus is on complexity as a key concept for understanding how these substances affect the brain.
Neuropsychopharmacology
January 1, 2024
Ryan H. Gumpper, Bryan L. Roth
Psychedelics show promise as treatments for neuropsychiatric disorders, though their clinical potential is not fully understood. This review explores current knowledge of their basic biology, pharmacology, and structural biology, highlighting both established facts and unanswered questions as these compounds gain popularity in therapeutic and recreational settings.