Journal of Science Policy & Governance • July 2, 2026 • Matthew A. Boehm, Oriana Mayorga
Psychedelic compounds like psilocybin, MDMA, LSD, and DMT show promise for treating mental health conditions, with the FDA granting Breakthrough Therapy designations for several uses. Despite this, most remain Schedule I under the Controlled Substances Act, indicating no accepted medical use and high abuse potential, which imposes strict regulations. Over 150 active clinical trials are assessing their safety and efficacy, and federal research agencies, bipartisan congressional activities, and state-level reforms support their medical applications. A recent Executive Order calls for federal reforms to accelerate research and access, including timely rescheduling after Phase 3 trials. Rescheduling could reduce costs and administrative barriers while maintaining safety. The article outlines potential paths for rescheduling various Schedule I psychedelics given emerging clinical applications.
Archives of toxicology • July 1, 2026 • Kamil Jurowski, Alicja Krośniak, Damian Kobylarz et al.
Lysergamide analogs such as ALD-52, 1P-LSD, 1B-LSD, 1 V-LSD, and 1cP-LSD are new psychoactive substances with hallucinogenic potential whose toxicological profiles are largely unknown. A comprehensive in silico assessment using multiple platforms predicted acute toxicity LD50 values in rats from 49 to 85 mg/kg. Organ-specific risks included elevated pulmonary risk for 1 V-LSD (92%) and 1cP-LSD (81%), and highest hematotoxicity for 1P-LSD (76%) and 1B-LSD (75%). Genotoxicity alerts were identified for ALD-52 and 1cP-LSD (up to 90% predicted probability), while all compounds were classified as non-mutagenic by OCHEM. Cardiotoxicity assessment showed strongest hERG channel inhibition for 1 V-LSD (IC50 = 1.4 µM), suggesting elevated proarrhythmic potential. Structural modifications at the N-1-acyl position influence toxicity patterns, particularly affecting cardiopulmonary and genotoxic endpoints.
Journal of psychopharmacology (Oxford, England) • June 25, 2026 • Pavan S Brar, Rebecca B Price, Stephen Ross et al.
Psychedelic compounds like psilocybin and LSD are being studied again as potential treatments, but research usually excludes people at risk for psychosis. This narrative review examines the historical and theoretical links between psychedelics and schizophrenia spectrum disorders (SSDs), including the psychotomimetic hypothesis. The authors compare the phenomenological experiences induced by psychedelics with those of SSDs, finding both overlap and important qualitative differences that challenge a simple equivalence. They review neural mechanisms involving serotonin, dopamine, and glutamate. Clinical evidence shows psychedelics can worsen existing psychotic illness and may trigger psychosis in vulnerable individuals, though the risk magnitude is not well quantified. The authors suggest potential therapeutic applications for carefully selected symptoms in stable patients using low-dose, controlled approaches and provide recommendations for managing psychosis-related risk.
Psychopharmacology • June 20, 2026 • E. C. H. M. Haijen-bongers, P.p.m. Hurks, J. Schepers et al.
In adults with attention-deficit hyperactivity disorder, six weeks of biweekly low-dose lysergic acid diethylamide (20 µg) produced a limited effect on temporal processing, specifically on a time reproduction task, but did not improve performance on other neuropsychological measures of attention, inhibition, or motivational processing. The finding was observed in a secondary analysis of a double-blind, placebo-controlled trial with 46 completers. Baseline performance predicted some treatment outcomes differently between the LSD and placebo groups. The authors caution that the single positive result should be interpreted cautiously, especially because the parent trial showed no corresponding improvements in clinical symptoms.
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.
Translational Psychiatry • June 13, 2026 • Jillian L. King, Devin P. Effinger, Cameron Basquez-pfeifer et al.
The head-twitch response (HTR) in mice, a standard test for hallucinogenic potential, fails to reliably indicate overall psychoactivity. Lisuride, which did not produce HTR, caused impaired movement, coordination, stress, cognitive disruption, and reduced prefrontal cortex EEG power. LSD, which triggered strong HTR, had minimal effects on these measures. Neither compound's effects beyond HTR depended on 5-HT₂A receptors. The HTR alone is insufficient and should be combined with other assessments.
Acta neuropsychiatrica • June 10, 2026 • Helerin Raikkerus, Andrea Bujour, Mark Kennedy et al.
A systematic review of research on psychedelics for ADHD identified only six studies meeting inclusion criteria. One randomized controlled trial found no statistically important difference compared to placebo. Three cross-sectional studies reported positive effects of psychedelics, and one found statistically important improvement measured by the Child Bipolar Questionnaire. A case study showed improvement in depressive symptoms and functioning with ketamine. The evidence is insufficient to recommend psychedelics for ADHD, and it remains unknown whether patients whose depression responds to ketamine also have ADHD. No research examined how psychedelics affect patient subgroups with different causes of symptoms.
International journal of methods in psychiatric research • June 1, 2026 • Kurt Stocker, Matthias Hartmann, Frederick S Barrett et al.
The eight-factor structure of the Psychedelic Experience Scale (PES48), which includes the Mystical Experience Questionnaire (MEQ30) and additional factors for paradoxicality, connectedness, visual experience, and distressing experience, is valid for use in English. Analysis of 280 measurements from 145 healthy participants in four placebo-controlled psilocybin studies found that six subscales have high internal consistency, one good, and one acceptable. Both the MEQ30 and MEQ40 models show acceptable to good model fits, with better fits in English than in German. All six MEQ40 scale means were higher in English data, suggesting that the PES48 provides a broader conceptualization of mystical and non-mystical psychedelic experiences, and that setting may influence mystical experience.
Psychedelic medicine (New Rochelle, N.Y.) • June 1, 2026 • Brian S Barnett, Akhil Anand, Jeremy Weleff et al.
Among US adults who first used LSD at least 5 years ago, only 4.2% reported using it in the past year. Past-year use dropped sharply with time since first use, from 14.4% among those who started 5 years ago to 0.1% among those who started 46–50 years ago. Factors linked to past-year use included being male, never married, living in poverty, higher education, lifetime stimulant use, recent contact with drug sellers, having sold illegal drugs, perceiving LSD as lower risk and more available, and a past-year suicide attempt. Having children at home, living in a small metro area, and more years since first use were linked to lower odds. Perceived risk and availability showed the strongest associations.
Neuroscience and biobehavioral reviews • June 1, 2026 • Javier Hidalgo Jiménez, Karl Kristjan Kaup, Jaan Aru • 1 citation
Psychedelics such as LSD and NBOH produce complex, heterogeneous effects on brain cells, challenging the idea that they simply increase cortical excitability. A systematic review of 23 in vitro and 26 in vivo electrophysiological studies found that these compounds modulate both excitatory and inhibitory processes in a cell-type- and compartment-specific manner, with biphasic, dose-dependent, and context-sensitive responses. Activation of 5-HT2A receptors triggers intricate calcium signaling, downregulating excitatory currents and firing rates in many neurons while enhancing glutamate release and activating a subset of projection fibers. Modulation of presynaptic and extrasynaptic GluN2B-containing NMDA receptors appears central to these effects.
Pharmacology & therapeutics • May 1, 2019 • Matthew W Johnson, Peter S Hendricks, Frederick S Barrett et al. • 520 citations
Classic psychedelics like LSD, mescaline, and psilocybin are serotonin 2A receptor agonists with a long history of sacramental use and a resurgence in research. Epidemiological studies suggest naturalistic nonmedical use may be linked to positive mental health and prosocial outcomes, though some individuals are harmed in unsupervised settings. Recent therapeutic studies indicate efficacy in treating psychological distress from life-threatening diseases, depression, and nicotine and alcohol addictions. These compounds fairly reliably occasion mystical experiences, which are associated with improved psychological outcomes in healthy volunteers and patients. Neuroimaging studies reveal neurobiological mechanisms, broadening understanding of the brain, serotonin system, and consciousness. Overall, classic psychedelics show strong therapeutic potential and as tools for investigating mystical experiences and brain function.
eLife • October 25, 2018 • Katrin H. Preller, Joshua B. Burt, Jie Lisa Ji et al. • 416 citations
Lysergic acid diethylamide (LSD) reduces associative brain connectivity while increasing sensory-somatomotor and thalamic connectivity. These neural effects, along with the subjective experience, are fully blocked by ketanserin, a selective 5-HT2A receptor antagonist. The spatial pattern of LSD's effects across the brain matches the distribution of 5-HT2A receptor gene expression in humans. These results strongly implicate the 5-HT2A receptor in LSD's neuropharmacology, informing the neurobiology of psychedelics and guiding development of psychedelic-based therapeutics.
Scientific Reports • April 19, 2017 • Michael Schartner, Robin Carhart‐Harris, Adam B. Barrett et al. • 450 citations
Measures of neural signal diversity, such as entropy and Lempel-Ziv complexity, are higher during wakeful rest than during anesthesia. In this study, these measures were computed for spontaneous magnetoencephalographic signals from humans under psilocybin, ketamine, and LSD. All three psychedelics produced reliably higher signal diversity, even after controlling for spectral changes, with the most pronounced increase in temporal (single-channel LZ complexity) rather than spatial diversity. Selective correlations emerged between changes in signal diversity and the intensity of psychedelic experience. This is the first time these measures have been applied to the psychedelic state and have yielded values exceeding normal waking consciousness, suggesting that psychedelic phenomenology constitutes an elevated level of consciousness.
Cell • January 26, 2017 • Daniel Wacker, Sheng Wang, J. Mccorvy et al. • 466 citations
The hallucinogen LSD binds to the human serotonin receptor 5-HT2B, and its crystal structure reveals conformational rearrangements that accommodate LSD, explaining the selectivity of its diethylamide group. LSD dissociates very slowly from both 5-HT2BR and 5-HT2AR, a key receptor for its psychoactive effects. Molecular dynamics simulations suggest that a 'lid' formed by extracellular loop 2 (EL2) at the binding pocket entrance may cause LSD's slow binding kinetics. A mutation that increases this lid's mobility greatly speeds up LSD's binding and selectively reduces LSD-mediated β-arrestin2 recruitment, providing a molecular explanation for LSD's actions at human serotonin receptors.
Curr Biol • April 13, 2016 • 531 citations
Lysergic acid diethylamide (LSD) increases global functional connectivity in the brain, and this neural change correlates with the experience of ego dissolution—a temporary loss of the sense of self. The more the brain's networks became globally interconnected under LSD, the more participants reported a diminished or dissolved sense of self. This suggests that the subjective feeling of ego dissolution is linked to a breakdown of the normal modular organization of brain connectivity.
Proc Natl Acad Sci U S A • April 11, 2016 • 887 citations
LSD produces marked changes in brain activity that correlate with its psychological effects. Increased blood flow in the visual cortex, decreased alpha power there, and an expanded functional connectivity profile of the primary visual cortex strongly correlated with visual hallucinations, suggesting that intrinsic brain activity influences visual processing more during the psychedelic state. Decreased connectivity between the parahippocampus and retrosplenial cortex correlated strongly with ego-dissolution and altered meaning, indicating this circuit's role in maintaining the self and processing meaning. Different imaging metrics showed strong relationships, allowing firmer inferences about their functional significance.
Journal of psychopharmacology (Oxford, England) • March 1, 2015 • Peter S Hendricks, Christopher B Thorne, C Brendan Clark et al. • 377 citations
Among over 190,000 US adults surveyed from 2008 to 2012, those who had ever used classic psychedelics (such as LSD or psilocybin) showed lower odds of past-month psychological distress, past-year suicidal thinking, past-year suicidal planning, and past-year suicide attempt compared with those who had not. The reduced odds ranged from 14% lower for suicidal thinking to 36% lower for suicide attempt. In contrast, use of other illicit drugs was generally linked to higher odds of these outcomes. The findings suggest that classic psychedelics might help prevent suicide and that their strict legal status should be reconsidered to allow more research.
Journal of Psychopharmacology • November 11, 2014 • Peter Gasser, Katharina Kirchner, Torsten Passie • 458 citations
In patients with anxiety linked to life-threatening diseases, LSD-assisted psychotherapy produced lasting benefits. Twelve months after treatment, none of the ten participants reported adverse reactions, and significant reductions in anxiety (measured by the STAI) were sustained. Qualitative interviews revealed that most participants experienced insightful, cathartic, and interpersonal encounters; 77.8% reported reduced anxiety and 66.7% reported improved quality of life. Subjective accounts pointed to facilitated access to emotions, confrontation of unknown anxieties and resources, and intense peak experiences as key psychological mechanisms. These experiences helped restructure emotional trust, situational understanding, habits, and worldview. The findings suggest that medically supervised LSD therapy can be safe and yield enduring benefits.
The Journal of Nervous and Mental Disease • March 4, 2014 • Peter Gasser, Dominique Holstein, Yvonne Michel et al. • 752 citations
In a small pilot study, 12 patients with anxiety related to life-threatening diseases underwent two sessions of LSD-assisted psychotherapy, receiving either a full 200-microgram dose or a low 20-microgram active placebo, with the placebo group later crossing over to the full dose. At a 2-month follow-up, trait anxiety decreased with a large effect size, and state anxiety also dropped significantly. These anxiety reductions persisted for 12 months. No serious adverse effects occurred beyond one day after treatment. The findings suggest that, under careful medical supervision, LSD can reduce anxiety, supporting the need for larger controlled trials.
Science • March 21, 2013 • Daniel Wacker, Chong Wang, Vsevolod Katritch et al. • 689 citations
Serotonin receptors are targets for drugs treating depression, obesity, and migraine headaches. Crystal structures of two serotonin receptor subtypes bound to antimigraine medications or a precursor of LSD reveal how subtle differences in ligand binding cause substantial differences in receptor signaling and biological responses. The structures show that the same ligand can activate one or both of the two main serotonin receptor signaling mechanisms, depending on which receptor it binds.
Journal of Psychopharmacology • March 8, 2012 • Teri Suzanne Krebs, Pål-ørjan Johansen • 580 citations
A meta-analysis of six randomized controlled trials involving 536 participants found that a single dose of LSD, given alongside various alcoholism treatment programs, was associated with a decrease in alcohol misuse. The odds ratio for a beneficial effect was 1.96 (95% confidence interval 1.36–2.84), indicating a statistically significant reduction in alcohol misuse. Heterogeneity between trials was negligible. The analysis discusses secondary outcomes, risk of bias, and limitations of the included studies.
CNS Neuroscience & Therapeutics • November 11, 2008 • Torsten Passie, John H. Halpern, Dirk O. Stichtenoth et al. • 459 citations
Lysergic acid diethylamide (LSD) was synthesized in 1938 and its psychoactive effects discovered in 1943. It was used in psychiatric research during the 1950s and 1960s to produce experimental psychosis and in psycholytic and psychedelic therapy. After becoming an illegal drug of abuse from the mid-1960s, scientific interest has resumed with new methods and oversight. This review covers all aspects of LSD's pharmacology and psychopharmacology, based on nearly 10,000 scientific papers. LSD is physiologically well tolerated and psychological reactions can be controlled in a medical setting, but uncontrolled use risks complications. New interest focuses on LSD as a tool for studying consciousness and potential treatments for cluster headache and terminally ill patients.
Archives of General Psychiatry • February 1, 1994 • Ruck J. Strassman • 454 citations
Intravenous DMT produces rapid, intense hallucinogenic effects that peak within two minutes and resolve within half an hour, closely tracking blood levels. At higher doses (0.2 and 0.4 mg/kg), volunteers experienced brightly colored, rapidly moving visual images, a dissociative state with alternating euphoria and anxiety, and a complete replacement of ongoing mental experience. Lower doses (0.05–0.1 mg/kg) primarily caused emotional and bodily sensations, with 0.1 mg/kg producing the least desirable effects. A new Hallucinogen Rating Scale captured dose-related differences better than biological measures, offering a tool for comparing DMT with other agents affecting brain receptors.
Science • August 16, 1968 • George K. Aghajanian, Warren E. Foote, Michael Sheard • 406 citations
Injections of d-lysergic acid diethylamide (LSD) into the midbrain cause a reversible halt in the spontaneous firing of neurons that contain serotonin. The dose needed is at or below the level that produces noticeable behavioral changes. This inhibition of serotonin-containing neurons may explain the drug's effect of reducing serotonin metabolism.