Biological Psychiatry
June 3, 2019
Anya K. Bershad, Scott T. Schepers, Michael P. Bremmer et al.
176 citations
Single very low doses of LSD (6.5, 13, and 26 micrograms) produce dose-related subjective effects in healthy young adults. The highest dose (26 μg) increased ratings of vigor and slightly decreased positivity ratings of images with positive emotional content. Other mood measures, cognition, and physiological measures were unaffected. A threshold dose of 13 μg might be used safely in an investigation of repeated administrations. It remains to be determined whether the drug improves mood or cognition in individuals with symptoms of depression.
Behavioural Pharmacology
September 1, 2005
A. B. Ilan, Alan Gevins, Michael J. Coleman et al.
165 citations
Smoking marijuana with delta9-tetrahydrocannabinol (THC) produces expected effects on mood, behavior, and brain activity, but varying the concentrations of other cannabinoids like cannabichromene (CBC) and cannabidiol (CBD) does not change responses. Twenty-three healthy marijuana users (12 men, 11 women) participated in four sessions, randomly assigned to low or high THC groups (1.8% versus 3.6%). Under blinded conditions, they smoked placebo or THC cigarettes with low or high levels of CBC (0.1% versus 0.5%) and CBD (0.2% versus 1.0%). Active THC cigarettes decreased performance, reduced EEG power, and attenuated ERP components reflecting attentional processes during working and episodic memory tests, mostly without dose dependence. CBC and CBD concentrations did not alter any outcomes, consistent with THC being the primary active constituent.
Psychoneuroendocrinology
April 19, 2014
M. Kirkpatrick, Sunday M. Francis, Royce Lee et al.
106 citations
MDMA (ecstasy) increases feelings of sociability and closeness. This study tested whether those effects come from a rise in the hormone oxytocin. In 14 healthy MDMA users given MDMA, oxytocin nasal spray, or placebo, only the higher MDMA dose (1.5 mg/kg) raised blood oxytocin levels to a peak of 83.7 pg/ml around 90–120 minutes, versus 18.6 pg/ml after placebo. The higher oxytocin spray (40 IU) raised levels to 48.0 pg/ml. MDMA increased heart rate, blood pressure, and feelings of euphoria and sociability, but oxytocin spray did not. The subjective effects of MDMA were not linked to oxytocin levels, suggesting oxytocin may not be the main cause of MDMA's prosocial effects.
Journal of Psychopharmacology
August 26, 2016
Anya K. Bershad, Melissa A. Miller, Matthew J. Baggott et al.
104 citations
MDMA, a recreational drug, enhances sociability and feelings of closeness more than other stimulants like dextroamphetamine, methamphetamine, and methylphenidate. This review compares human laboratory studies on the social effects of MDMA versus other stimulants, from simple ratings of sociability to complex social behaviors, and examines the neurochemical mechanisms involved. The findings suggest that MDMA's distinct prosocial effects may underlie its recreational use and potential as a psychotherapy aid, distinguishing it from typical stimulants.
Biol Psychiatry Cogn Neurosci Neuroimaging
December 20, 2019
Anya K. Bershad, Katrin H. Preller, Royce Lee et al.
95 citations
A very low dose of LSD (13 μg) alters brain connectivity in circuits involved in emotion, even though it produces negligible subjective changes. In healthy young adults, the dose increased amygdala connectivity with the right angular gyrus, right middle frontal gyrus, and cerebellum, while decreasing connectivity with the postcentral and superior temporal gyri. Effects on positive mood were weak and variable, but increases in positive mood correlated with stronger amygdala–middle frontal gyrus connectivity. These preliminary findings suggest that sub-perceptual doses of LSD can modulate limbic brain networks, though further research with repeated dosing is needed to clarify any potential antidepressant effects.
Journal of Psychopharmacology
March 4, 2015
Matthew G. Kirkpatrick, Andrew W. Delton, Theresa E. Robertson et al.
86 citations
MDMA increases generosity, but the effect depends on the recipient's social closeness. In two studies, participants decided whether they or another person would receive money. Without MDMA, people were more generous toward close friends than acquaintances or strangers; generosity was linked to household income and the personality trait Agreeableness. After a high dose of MDMA (1.0 mg/kg), generosity increased only toward a friend. A lower dose (0.5 mg/kg) slightly increased generosity toward a stranger, especially among women. The findings suggest MDMA's prosocial effects are selective, similar to oxytocin, and depend on relationship proximity.
Addict Biol
February 1, 2022
Harriet de Wit, Hanna Molla, Anya K. Bershad et al.
82 citations
Repeated low doses of LSD (13 or 26 μg) taken every 3–4 days by healthy adults produced modest subjective effects, such as feeling a drug effect and stimulant-like or LSD-like sensations, but did not improve mood or cognitive performance on psychomotor or most emotional tasks. No lingering effects on mood or task performance were detected at a drug-free follow-up session 3–4 days later. The study concludes that, in a controlled setting with a limited number of administrations, repeated low-dose LSD is safe but yields negligible changes in mood or cognition in healthy volunteers.
Psychopharmacology
March 15, 2014
M. Kirkpatrick, M. Baggott, J. Mendelson et al.
78 citations
Across three independent laboratories in Basel, San Francisco, and Chicago, 220 healthy volunteers received either placebo or MDMA (1.5 mg/kg or a 125-mg fixed dose) under double-blind conditions. Despite differences in study methods and participants' prior drug use, MDMA produced very similar cardiovascular and subjective effects at all sites. Prior MDMA use was inversely related to feeling "Any Drug Effect" only at sites testing more experienced users. The pharmacological effects of MDMA are robust and highly reproducible across settings, with modest evidence for tolerance in regular users.
Journal of Psychopharmacology
April 29, 2015
Matthew J. Baggott, Matthew G. Kirkpatrick, Gillinder Bedi et al.
69 citations
MDMA increases the use of social, sexual, and emotional words during conversation. In a double-blind, within-subjects study, 35 healthy volunteers who had previously used MDMA received either 1.5 mg/kg oral MDMA or a placebo and then discussed a close personal relationship for five minutes. Both a standard dictionary method and a machine learning analysis showed that MDMA altered speech content: it boosted social and sexual words, and also increased words related to both positive and negative emotions. These changes in speech content may help explain how MDMA enhances sociability and emotional connection during social interactions.
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.
Social Cognitive and Affective Neuroscience
March 27, 2014
Margaret C. Wardle, Matthew G. Kirkpatrick, Harriet de Wit
52 citations
MDMA (ecstasy) increases positive emotional responses specifically to pictures containing people, while reducing positive responses to non-social positive pictures. In two studies with 101 healthy occasional MDMA users, participants rated their reactions to positive, negative, and neutral images with and without social content after receiving different doses of MDMA. The drug did not simply amplify all positive feelings; instead, it selectively enhanced the appeal of social scenes. This suggests MDMA's prosocial effects—such as increased closeness and sociability—may arise from making social contact feel more valuable relative to non-social rewards, which could explain its recreational appeal and potential therapeutic use in psychotherapy.
Journal of Psychopharmacology
May 13, 2012
Michael E. Ballard, Gillinder Bedi, Harriet de Wit
52 citations
Acute oral doses of Δ⁹-tetrahydrocannabinol (THC) impair recognition of fearful and angry facial expressions but have only marginal effects on recognition of sadness and happiness. THC does not consistently alter ratings of emotional scenes, nor does its effect on emotional evaluation relate to its mood-altering properties. The findings indicate that THC specifically reduces perception of facial threat without positively biasing the evaluation of emotional stimuli more broadly.
The International Journal of Neuropsychopharmacology
December 28, 2014
Stephanie M. Gorka, Daniel A. Fitzgerald, Harriet de Wit et al.
43 citations
Δ(9)-Tetrahydrocannabinol (THC) enhances functional connectivity between specific amygdala subregions (basolateral and superficial) and the rostral anterior cingulate/medial prefrontal cortex during social threat processing in healthy adults. This effect may help reduce threat perception or improve socio-emotional regulation, shedding light on the neurocircuitry underlying affective processes. The findings come from a double-blind, placebo-controlled, within-subjects study with 16 participants using functional magnetic resonance imaging.
Psychopharmacology (Berl)
October 5, 2014
Matthew G. Kirkpatrick, Harriet de Wit
43 citations
MDMA increased heart rate, blood pressure, and positive subjective effects whether people were alone, with a research assistant, or with another participant who also took the drug. It also increased ratings of another person's attractiveness and social interaction when others were present. The drug's effects were stronger on some measures—feeling the drug, dizziness, and cardiovascular responses—when taken with another drug user, but social behavior and other effects did not differ across conditions. The social context had only a modest influence on MDMA's effects.
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.
Social Neuroscience
January 20, 2016
Anya K. Bershad, Jessica Weafer, Matthew G. Kirkpatrick et al.
35 citations
MDMA (ecstasy) increases sociability and empathy, likely through the release of oxytocin. A single-letter variation in the oxytocin receptor gene (OXTR rs53576) influences how people respond to the drug. In a double-blind, within-subjects study, 68 healthy volunteers with past MDMA experience received placebo, 0.75 mg/kg, or 1.5 mg/kg of MDMA. At the higher dose, individuals with the A/A genotype did not show the increase in sociability seen in G allele carriers. No genotypic differences appeared at the lower dose or in cardiovascular or other subjective effects. The results suggest MDMA-induced sociability depends on oxytocin signaling and that genetic variation in the oxytocin receptor modulates the drug's social effects.
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.
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.
PLoS One
October 25, 2021
Annie Regan, Seth Margolis, Harriet de Wit et al.
18 citations
MDMA produces a moderate-to-large increase in self-reported feelings of sociability—such as feeling loving, talkative, and friendly—according to a meta-analysis of 27 placebo-controlled studies involving 592 participants. The overall effect size was d = 0.86, indicating a substantial boost in sociability-related outcomes. This finding suggests MDMA could have powerful implications for social interactions and clinical settings, such as in psychotherapy. The analysis highlights the need for larger experimental studies and further investigation into the mechanisms linking MDMA to enhanced social connection.
Psychopharmacology (Berl)
February 1, 2018
H. Valerie Curran, David Nutt, Harriet de Wit
17 citations
Psychedelics and related drugs show therapeutic possibilities for mental health conditions, with research exploring their mechanisms, including brain modulation and neuroplasticity. The work discusses how these compounds may alter brain pathways and states of consciousness to produce therapeutic benefits. It also addresses the regulatory landscape for these substances in medical research and mental healthcare. The authors suggest that understanding the neurobiology and therapeutic mechanisms is crucial for advancing treatment research and medical innovation.
Schizophrenia Bulletin
June 26, 2023
Anya K. Bershad, Harriet de Wit
12 citations
No effective medications exist for diminished social motivation in schizophrenia, a negative symptom with severe functional consequences. This review synthesizes pharmacologic challenge studies in healthy volunteers to identify novel directions for drug development. Amphetamines, MDMA, and some opioid medications enhance social motivation in healthy adults and may represent promising avenues for investigation in schizophrenia. Given their acute effects on behavioral and performance-based measures, these drugs may be particularly beneficial as an adjunct to psychosocial training programs. It remains to be determined how these medications affect patients with deficits in social motivation and in which contexts they may be most effectively administered.
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.