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
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.
Biological psychiatry. Cognitive neuroscience and neuroimaging
May 1, 2024
Robin J Murphy, Suresh Muthukumaraswamy, Harriet de Wit
31 citations
Taking regular low doses of psychedelic drugs (microdosing) has drawn attention for potential psychotherapeutic effects, but controlled studies have lagged. A review of 14 rigorous double-blind placebo-controlled studies using investigator-supplied lysergic acid diethylamide (LSD) at 5-20 micrograms found that acute microdoses dose-dependently altered blood pressure, sleep, neural connectivity, social cognition, mood, and perception of pain and time. Perceptible drug effects occurred at 10-20 micrograms but not 5 micrograms. No serious adverse effects were reported. Repeated doses did not alter mood or cognition on any measures. Low doses of LSD appear safe and produce acute behavioral and neural effects in healthy adults, warranting further study in patient samples and with other psychedelics.
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.
Neuroscience and biobehavioral reviews
July 1, 2023
Manoj K Doss, Harriet de Wit, David A Gallo
30 citations
Psychoactive drugs affect emotional episodic memory at three stages: encoding, consolidation, and retrieval. Drugs given before encoding can impair (e.g., alcohol, benzodiazepines, THC, ketamine), enhance (e.g., dextroamphetamine), or both impair and enhance (e.g., MDMA) emotional memories compared to neutral ones. Sedatives given after encoding can preferentially boost emotional memories during consolidation, but this selectivity may weaken or reverse over time. Retrieving memories under THC, dextroamphetamine, MDMA, or sedatives can distort memory, especially for positive emotional content. The review proposes neural mechanisms and discusses how these effects might influence drug use and abuse.
Psychological review
March 1, 2024
Manoj K Doss, Jason Samaha, Frederick S Barrett et al.
24 citations
Psychoactive drugs produce unique subjective states, but their effects on episodic memory often overlap. This reanalysis of 10 data sets (28 drug conditions) used signal detection models to separate three memory processes: recollection (retrieving specific details), familiarity (recognizing without details), and metamemory (introspecting about memory accuracy). Sedatives impaired both recollection and familiarity during encoding but enhanced recollection during consolidation. Dissociatives and cannabinoids impaired recollection during encoding, and cannabinoids increased false recollections during retrieval. Psychedelics impaired recollection during encoding but tended to enhance familiarity. Stimulants enhanced metamemory during encoding and retrieval but impaired metamemory during consolidation. These distinct patterns help explain drug-specific phenomena like sedative-induced blackouts and psychedelic presque vu, and suggest that memory quantity and stability influence metamemory.
Psychopharmacology
July 1, 2017
Anya K. Bershad, Melissa A. Miller, Harriet de Wit
12 citations
MDMA (ecstasy) did not reduce stress responses during a public speaking task in healthy adults. In a randomized trial, 39 volunteers received placebo, 0.5 mg/kg, or 1.0 mg/kg MDMA before a stress and a no-stress session. The stress task increased heart rate, cortisol, and subjective stress in all groups. MDMA alone raised heart rate, cortisol, and subjective stress ratings, but it did not moderate reactions to the Trier Social Stress Test. The findings indicate that MDMA's therapeutic effects in PTSD may not extend to acute psychosocial stress.
Journal of psychopharmacology (Oxford, England)
March 1, 2022
Harriet de Wit, Anya K Bershad, Charles Grob
11 citations
The psychological processes by which mind-altering drugs improve mood or behavior remain poorly understood. Controlled laboratory studies using well-defined psychological constructs can help reveal how these drugs produce therapeutic benefits, but substantial methodological differences exist between clinical studies of therapeutic outcomes and laboratory studies of underlying mechanisms. Using MDMA as an example, this review examines differences in expectancies, social and physical context, participant characteristics, pharmacological factors, and outcome measures between studies with and without psychiatric participants. It describes challenges and opportunities in translating laboratory findings to clinical settings and identifies ways to bridge the gap between these research approaches.
Journal of psychopharmacology (Oxford, England)
March 1, 2024
Anya K Bershad, David T Hsu, Harriet de Wit
9 citations
MDMA, a compound being studied for treating PTSD, increases positive feelings in response to social feedback, such as receiving likes or rejections in a dating-app-like task. In a double-blind, placebo-controlled trial with 36 healthy adults aged 18-40, a high dose of MDMA (1.5 mg/kg) boosted positive affective responses to both positive and negative social feedback, compared to placebo and methamphetamine. This suggests MDMA may enhance social connection by making social interactions feel more rewarding, which could explain its therapeutic benefits. Further research is needed to test these effects in clinical populations and with different types of social feedback.
Biological psychiatry
May 15, 2025
Anya K. Bershad, Harriet de Wit
3 citations
Disrupted social homeostasis underlies many behavioral disorders, including problematic drug use. This narrative review examines whether single doses of psychoactive drugs can relieve the discomfort of social isolation and promote social connection. For opioid drugs, mu opioid agonists and kappa opioid antagonists reduce distress from social isolation, and mu opioid agonists enhance social reward. Amphetamine-like stimulant drugs, including MDMA, do not reduce the distress of social isolation but increase motivation for social contact and the pleasure derived from social interaction. Many questions remain, including whether these effects contribute to problematic drug use and the effects of drug withdrawal or dependence on social function.
Psychedelic medicine (New Rochelle, N.Y.)
December 1, 2024
Connor Haggarty, Hanna Molla, James Glazer et al.
2 citations
A low dose of LSD (26 µg) alters the brain's electrical response to neutral and happy faces, but not angry faces. In a double-blind, placebo-controlled experiment with 39 healthy adults, LSD reduced the amplitude of the N170 brain wave to neutral faces and reduced the P300 brain wave to neutral and happy faces, while angry faces were unaffected. These results suggest that low-dose LSD specifically changes how the brain processes non-threatening social cues, which may help explain reports of improved mood.
Psychopharmacology
February 1, 2026
Ana Deutsch, Connor J Haggarty, Gavin N Petrie et al.
1 citation
A single oral dose of methamphetamine (20 mg) reduced blood levels of the endocannabinoid 2-AG in healthy adults, while MDMA (100 mg) did not. Neither drug affected anandamide (AEA) levels. Under placebo, higher AEA concentrations were linked to disliking the drug effects, suggesting a connection between AEA and negative expectations. These findings show how stimulants act on the endocannabinoid system and may inform treatments for substance use disorders.
Scientific reports
December 28, 2024
Harriet de Wit, Evan Hahn, Shahd Smadi et al.
1 citation
Psychoactive drugs like alcohol and stimulants are often used in social settings, but little is known about how they alter social interactions. This study tested whether MDMA, methamphetamine, and alcohol increase feelings of connection between strangers having a conversation, and also compared conversations with deeper topics versus small talk without drugs. All four conditions—deeper conversations, MDMA, methamphetamine, and alcohol—significantly increased feelings of connection and closeness compared to control conditions (small talk or placebo). The authors suggest these feelings of connection may contribute to the rewarding effects of drugs when used socially.
The European journal of neuroscience
June 1, 2024
Connor J Haggarty, Anya K Bershad, Mahesh K Kumar et al.
1 citation
MDMA, but not methamphetamine, enhances the brain's early visual processing of happy and angry facial expressions, as measured by the N170 event-related potential in an EEG oddball paradigm. This effect was specific to emotional faces compared to neutral ones. Methamphetamine did not affect this neural measure, and neither drug altered other components of the response to emotional faces. The findings suggest a unique neural mechanism for MDMA's effects on socio-emotional processing, which may underlie its therapeutic potential for social anxiety and other psychiatric disorders.
BMJ open
May 11, 2026
Julia Colcott, Alexandre A Guerin, Olivia Carter et al.
A new tool, the MDMA-Assisted Psychotherapy Side Effects Tool (M-SET), was developed to systematically capture side effects during MDMA-assisted psychotherapy. Experts in MDMA-AP and neuropsychopharmacology participated in a two-round online Delphi process to refine a list of 165 items across four questionnaires covering screening, baseline, medication session days, and follow-up. The tool aims to improve safety monitoring and build a more robust evidence base on the tolerability of MDMA-AP for research and clinical use.
Biological psychiatry. Cognitive neuroscience and neuroimaging
May 1, 2026
Zachary Anderson, Matthew Gunn, Emily Jones et al.
A moderate oral dose of THC (7.5 mg) reduced resting-state functional connectivity within several brain networks, including corticostriatal circuits and networks involved in sensory processing, interoception, and spatial reasoning, in 33 healthy occasional young adult cannabis users. THC also decreased connectivity between two specific networks: one involving the anterior cingulate cortex and dorsal insula, and another involving the ventral insula and lingual gyrus. These connectivity changes were not related to subjective drug effects or recent cannabis use. The findings indicate that even a single moderate THC dose broadly disrupts intrinsic brain network connectivity.
Psychedelic medicine (New Rochelle, N.Y.)
March 1, 2026
Jonah Griffin-Stolbach, Hanna Molla, Donald Hedeker et al.
Questionnaires designed for high-dose psychedelic experiences fail to capture the subtle subjective effects of very low doses of LSD. Using data from 199 healthy volunteers given 6.5, 13, and 26 µg doses, a new 31-item questionnaire—the micro-dimensional Altered States of Consciousness (m-DASC)—was developed. It identifies four components: Transcendent Experience, Auditory Somatic Disturbance, Animated Intoxication, and Synesthesia, accounting for 44% of the variance. The m-DASC detected significant effects at 13 and 26 µg and correlated highly with longer questionnaires, offering a more sensitive tool for future low-dose psychedelic research.
Journal of psychopharmacology (Oxford, England)
January 13, 2026
James Glazer, Hanna Molla, Royce Lee et al.
A low dose of LSD (26 micrograms) altered brain responses to reward feedback in people with mild-to-moderate depression, compared to those without depression. In depressed participants, LSD increased a brain signal called the late positive potential (LPP) when they received loss feedback, suggesting enhanced emotional processing of rewards. This change was linked to immediate positive mood and lower depressed mood two days later. Across all participants, LSD reduced other reward-related brain signals. The findings cautiously support the idea that low-dose LSD may have antidepressant effects.
Imaging neuroscience (Cambridge, Mass.)
January 1, 2024
Hanna Molla, Giovanni Novembre, Anya Bershad et al.
MDMA increases the perceived pleasantness of touch, but the neural mechanisms are not well understood. In a double-blind, randomized, within-subject fMRI study with 18 healthy participants, MDMA (1.5 mg/kg) compared to placebo enhanced affective ratings of gentle touch at both a slower, more pleasant speed (3 cm/s) and a faster, less pleasant speed (30 cm/s). Plasma oxytocin levels also increased more during the MDMA session. On the neural level, primary sensorimotor areas showed greater hemodynamic changes during MDMA for both touch speeds, indicating an early influence within somatosensory pathways. Changes in oxytocin levels interacted with the drug in area MT+, associated with motion perception. However, the posterior insula did not show preferential activation for the slower stroking speed.