American Journal of Psychiatry
August 29, 2018
Nolan Williams, Boris D. Heifets, Christine Blasey et al.
510 citations
Blocking opioid receptors with naltrexone dramatically reduced the antidepressant effect of ketamine in adults with treatment-resistant depression, while leaving ketamine's dissociative effects unchanged. In a double-blind crossover trial, 12 participants received either placebo or 50 mg of naltrexone before a ketamine infusion. Seven of 12 met the response criterion (≥50% reduction in depression scores) after ketamine plus placebo, but depression score reductions were significantly smaller when naltrexone was given. The trial was halted at an interim analysis because naltrexone blocked the antidepressant effect. The findings indicate that ketamine's acute antidepressant effect requires opioid system activation, while its dissociative effects do not.
Journal of Neuroscience
November 30, 2020
Danilo de Gregorio, Argel Aguilar-Valles, Katrin H. Preller et al.
258 citations
A renewed interest in hallucinogens for treating psychiatric disorders has emerged. Preclinical and clinical studies have confirmed ketamine's efficacy for depression. Emerging evidence points to psilocybin and LSD's therapeutic properties and their ability to modulate functional brain connectivity. MDMA, an entactogen, has shown usefulness for post-traumatic stress disorder. This review summarizes the pharmacology of hallucinogenic compounds, highlighting differences between psychedelic and nonpsychedelic hallucinogens and entactogens, and describes their behavioral effects in animals and humans. Together, these data substantiate the potential of these compounds for treating mental diseases.
Psychopharmacology
April 1, 2022
Jacob S. Aday, Boris D. Heifets, Steven D. Pratscher et al.
214 citations
Psychedelic research faces unique methodological challenges beyond those typical of psychotherapy and pharmacology trials. The pronounced subjective effects of high-dose psychedelics make it difficult to mask participants to their treatment condition. Positive media coverage inflates participants' expectations for benefit, and unmasking combined with expectations can produce large placebo and nocebo effects. Recommendations to improve masking and reduce expectancy bias include careful study development, participant recruitment and selection, incomplete disclosure of study design, choice of active placebo, and measurement of expectations and masking efficacy. Incorporating these design elements aims to reduce bias and improve the ability to discern treatment-specific effects.
Science Translational Medicine
December 11, 2019
Boris D. Heifets, Juliana S Salgado, Madison Taylor et al.
119 citations
MDMA's prosocial effects can be separated from its addictive properties by using fenfluramine, a selective serotonin-releasing compound. This finding reveals a conserved neuronal pathway that could be targeted to develop new therapeutics with limited abuse liability, offering a potential strategy for creating safer treatments that promote social connection without the risks of addiction.
Neuropsychopharmacology
July 24, 2023
Boris D. Heifets, David E. Olson
66 citations
Psychedelics and entactogens can produce rapid and lasting therapeutic effects, but there is a disconnect between how they are used in human clinics and how they are studied in animals. Human research emphasizes extra-pharmacological factors like set, setting, and integration, which are poorly modeled in animal experiments. Animal studies focus on neuronal activation and structural plasticity, which are hard to measure in humans. The paper proposes bridging this gap by focusing on the circuits these compounds modulate rather than single molecular targets, suggesting that selective circuit modulation of behavioral phenotypes may be more fruitful for identifying novel compounds with similar therapeutic effects.
Biological psychiatry. Cognitive neuroscience and neuroimaging
May 1, 2024
Balázs Szigeti, Boris D. Heifets
62 citations
Clinical trials of psychedelics such as psilocybin, LSD, and DMT have challenged how nondrug factors like participant expectations are measured and controlled in mental health research. Higher doses of these psychoactive substances make it harder to conceal treatment conditions in double-blind, placebo-controlled designs. Growing public enthusiasm for psychedelic therapy raises questions about whether trial results are biased by positive expectancy. This review covers key concepts of expectancy and its measurement, examines expectancy effects reported in modern microdose and macrodose trials, and considers expectancy as a physiological process that can be independent of or interact with drug effects. Expectancy can be harnessed to improve outcomes and managed to enhance trial rigor.
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.
Cell
July 1, 2016
Boris D. Heifets, Robert C. Malenka
41 citations
MDMA (ecstasy) is known for inducing feelings of closeness and empathy. Examining how it works may lead to new treatments for psychiatric disorders involving social behavior deficits.
Science Advances
April 26, 2024
Ben Rein, Kendall Raymond, Cali Boustani et al.
37 citations
MDMA, a psychoactive drug known for its prosocial effects, enhances empathy-like behaviors in mice by increasing serotonin signaling in the nucleus accumbens. The drug, whether given systemically or infused directly into this brain region, strengthens the social transfer of pain and analgesia, a behavioral test of empathy. Optogenetically stimulating serotonin release in the nucleus accumbens mimics MDMA's effects, confirming serotonin's role. MDMA also restores deficits in empathy-like behaviors in a mouse model of autism lacking the Shank3 gene. The findings indicate that serotonin signaling in the nucleus accumbens is a core mechanism underlying MDMA's empathogenic effects.
medRxiv Preprint Server
April 28, 2023
Theresa R. Lii, Ashleigh E. Smith, Josephine R. Flohr et al.
28 citations
preprint
A single dose of intravenous ketamine (0.5 mg/kg) delivered during surgical anesthesia did not reduce depressive symptoms more than placebo in adults with major depressive disorder. In a triple-masked, randomized trial of 40 patients, depression severity scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) did not differ between the ketamine and placebo groups at 1, 2, or 3 days after infusion. Clinical response rates were similar (60% versus 50% on day 1). Only 36.8% of participants correctly guessed their treatment assignment, indicating successful masking. One serious adverse event occurred in each group, unrelated to ketamine. The findings suggest that ketamine's acute psychoactive effects may contribute to previously reported antidepressant results through subject-expectancy bias.
JAMA Psychiatry
June 26, 2019
Boris D. Heifets, Robert C. Malenka
28 citations
Methylenedioxy-methamphetamine (MDMA) and psilocybin may offer therapeutic benefits for mental health conditions, but their approval for treatment would require establishing appropriate mental health care infrastructures. This includes trained therapists, treatment protocols, and regulatory frameworks to ensure safe and effective use. The authors outline the necessary preparations for integrating these substances into clinical practice.
December 1, 2021
Jacob S. Aday, Boris D. Heifets, Steven D. Pratscher et al.
20 citations
preprint
Clinical trials of psychedelic therapy face unique methodological challenges that threaten the interpretability of results. The intense subjective effects of high-dose psychedelics make it difficult to mask participants to their treatment condition, and widespread positive media coverage inflates participants' expectations for benefit. Participant unmasking and treatment expectations can interact, making psychedelic therapy highly susceptible to large placebo and nocebo effects. Recommendations to improve rigor include careful study development, participant recruitment and selection, incomplete disclosure of the study design, choice of active placebo condition, and measurement of participant expectations and masking efficacy. Incorporating these design elements is intended to reduce bias and increase the ability to discern treatment-specific effects.
bioRxiv (Cold Spring Harbor Laboratory)
April 9, 2025
Odilia D Lu, Katrina White, Kendall Raymond et al.
18 citations
preprint
Psilocybin, the active compound in magic mushrooms, had several clear and repeatable immediate effects on mouse behavior, including increased anxiety and avoidance and reduced fear expression. However, its effects one day later were not consistent across five different laboratories, and no reliable changes were seen in depression-like behavior, fear extinction learning, social preference, or social reward learning. Using about 200 mice per experiment across five independent labs, the findings show that psilocybin's lasting behavioral effects in mice are more modest and less reliable than previously claimed. This coordinated multi-lab approach highlights the importance of replication for producing trustworthy results.
Biological Psychiatry
May 5, 2025
Matthew B Pomrenze, Sam Vaillancourt, Pierre Llorach et al.
11 citations
Ketamine produces a rapid increase in movement (locomotor activation) in mice by acting on mu opioid receptors (MORs) in the central amygdala (CeA). This effect is blocked by the opioid receptor antagonist naltrexone, and the same blockade occurs with a MOR-selective antagonist. Whole-brain imaging showed that naltrexone most strongly altered ketamine-induced cFos expression in the CeA, particularly in neurons that co-express MOR and PKCδ. Interrupting MOR function specifically in the CeA, either with a drug or genetic manipulation, prevented ketamine's locomotor effects. This indicates that ketamine's acute behavioral effects involve opioid signaling in the CeA, which may relate to its antidepressant mechanism in humans.
JAMA Network Open
April 1, 2025
Xue Zhang, Laura M Hack, Claire Bertrand et al.
10 citations
In a double-blind, placebo-controlled trial, 16 adults with subthreshold PTSD symptoms and early life trauma but no current psychiatric disorders were given 120 mg of MDMA or placebo. Participants were split into two groups based on baseline brain activity in the amygdala in response to nonconscious threat cues: those with high amygdala reactivity (NTNA+) and those with low reactivity (NTNA-). MDMA, compared with placebo, reduced activity in the amygdala and subgenual anterior cingulate cortex (sgACC), increased connectivity between the sgACC and amygdala, and increased liking of threatening facial expressions, but only in the NTNA+ subgroup. These findings suggest that baseline neural circuit profiles can identify who may benefit most from MDMA therapy and point to possible biomarkers for personalized treatment.
bioRxiv (Cold Spring Harbor Laboratory)
February 21, 2023
Daniel Ryskamp Rijsketic, Austen B Casey, Daniel A. N. Barbosa et al.
10 citations
preprint
Psilocybin, given to mice in either their home cage or an enriched environment, increased neural activity in brain regions including the neocortex, caudoputamen, central amygdala, and parasubthalamic nucleus while decreasing activity in the hypothalamus, cortical amygdala, striatum, and pallidum. The effects of both the drug and the environment were strong and widespread but largely independent, with very few interactions between context and psilocybin treatment. This suggests that the brain's response to psilocybin is not strongly modulated by environmental setting at the level of immediate early gene expression.
The American journal of psychiatry
June 1, 2026
Jason M Tucciarone, Igor D. Bandeira, Christine Blasey et al.
5 citations
Ketamine rapidly reduces suicidal thoughts in major depressive disorder, but the effect is short-lived. In this trial, adults with major depression and active suicidal ideation received a single ketamine infusion, then were randomly assigned to take either low-dose buprenorphine or a placebo daily for four weeks. Suicidal thoughts dropped significantly more in the buprenorphine group (average decrease of 11.6 points on the Scale for Suicide Ideation) than in the placebo group (average decrease of 6.3 points). Depression scores did not differ between groups. No serious side effects occurred. Buprenorphine appears to sustain and boost ketamine's antisuicidal effects, offering a potentially safe, scalable option for suicide prevention.
Nature Communications
January 22, 2026
Nicholas Gregory, Tyler E. Girard, Akila Ram et al.
5 citations
Psilocybin, a psychedelic compound, was tested for direct pain-relieving effects in mice with inflammatory, nerve injury, and muscle pain. Across a range of doses (0.3, 2, and 10 mg/kg) in both sexes, using multiple sensory and functional pain tests, psilocybin showed no analgesic effect except for reduced cold sensitivity. That reduction likely resulted from psilocybin-induced hypothermia rather than true pain relief. The findings suggest that any lasting therapeutic benefits of psilocybin for chronic pain are not due to direct analgesic action.
British Journal of Pharmacology
October 21, 2025
Austen B Casey, Boris D. Heifets
3 citations
MDMA, known as the illicit drug ecstasy, shows promise when used alongside psychotherapy for posttraumatic stress disorder (PTSD), though how it works remains unclear. This review traces MDMA's path from military interrogation aid to prohibited substance and now to clinical use. The authors identify three core subjective effects—prosocial behavior, reduced threat perception, and euphoria—and examine how each may contribute to both therapeutic benefits and abuse potential. They emphasize serotonin's central role in MDMA's effects while noting gaps in understanding its mechanism. The review also critiques preclinical models, highlights limitations like sex biases and assumptions about therapeutic alliance, and calls for clarifying mechanisms to develop safer, more effective MDMA-like treatments.
bioRxiv (Cold Spring Harbor Laboratory)
July 7, 2025
Akila Ram, Austen B Casey, Robert C. Malenka et al.
2 citations
preprint
Psilocybin does not produce direct analgesic effects in mice, despite suggestions from clinical and preclinical data that it might help chronic pain. Across multiple pain assays and models of acute and chronic inflammatory, neuropathic, and musculoskeletal pain, no dose of psilocybin was analgesic. The finding indicates that any therapeutic benefits for chronic pain syndromes are unlikely to come from direct pain relief.
Journal of Psychoactive Drugs
November 22, 2024
Wesley C Ryan, Boris D. Heifets
2 citations
In an addiction psychiatry practice offering intramuscular ketamine with psychotherapy for depression, 70 patients received 1,114 sessions over nearly seven years. Induction produced an 82% response, and improvement remained above 80% after six months of maintenance sessions given every 21 days at a mean dose of 1.13 mg/kg. Many patients (38%) stayed in treatment for at least a year. Dropouts were mostly due to logistical reasons (50%); side effects accounted for only 9.7%. One case of ketamine use disorder required residential treatment. Nausea was the main side effect managed with medication. Maintenance ketamine-assisted psychotherapy extended benefits for mood, anxiety, and substance use and was generally well tolerated.
bioRxiv Preprint Server
September 20, 2021
Laura M Hack, Katherine G. Warthen, Xue Zhang et al.
2 citations
preprint
Ketamine, a drug used for depression and anesthesia, causes dose-dependent increases in dissociation and intoxication, reduces emotional insensitivity, and raises stress as measured by cortisol. It alters brain connectivity, particularly between reward and negative affect circuits and thalamic sub-regions. Increased coupling between the amygdala and anteroventral thalamus correlates with greater dissociation and intoxication, while decreased coupling of anteromedial and posterior parietal thalamus correlates with increased sensory reward responsiveness. Drug-altered connectivity involving the nucleus accumbens and thalamic sub-regions shows negative associations with anxiety. These findings help disentangle the brain states underlying ketamine's acute effects, informing its therapeutic use and abuse risk.
JAMA Psychiatry
June 1, 2026
Ben Deverett, Duan Li, Theresa R. Lii et al.
1 citation
Ketamine produces distinct brain-wave patterns that may be linked to its therapeutic effects. General anesthesia selectively blocks one of these patterns—theta oscillations—while leaving another pattern, beta-gamma oscillations, intact. In 52 participants, ketamine given during anesthesia preserved beta-gamma power increases but eliminated the characteristic theta augmentation seen during awake administration. This suggests that different neurophysiologic effects of ketamine can be separated, offering a way to investigate which brain-wave changes underlie its antidepressant, analgesic, or dissociative properties.
Anesthesiology
February 3, 2026
Pilleriin Sikka, May Ching Ngo, Sherry Hu et al.
1 citation
A standardized propofol-based anesthesia protocol with EEG monitoring and verbal priming about dreaming led 69% of 452 surgical patients to report dreaming, and 93% of those who received all protocol elements did so. Most dreams were positive (86%), and dreamers reported higher subjective sleep quality than nondreamers. The protocol was safe, with no intraoperative awareness, and recovery times and medication use did not differ between groups. Adherence was high for most elements but low for the no-stimulation emergence period. The approach is feasible in routine clinical care and aligns with Enhanced Recovery After Surgery principles.
Journal of Affective Disorders
July 15, 2025
Theresa R. Lii, Josephine R. Flohr, Robin L. Okada et al.
1 citation
The endogenous opioid system may influence the placebo antidepressant response. A post hoc analysis of a randomized, placebo-controlled trial of intravenous ketamine in depressed patients undergoing routine surgery tested whether baseline opioid use affected antidepressant responses. The analysis found that baseline opioid use significantly reduced post-treatment depression severity in patients who received placebo, but not in those who received ketamine. This reduction was independent of baseline depression severity, pain intensity, and ethnicity. The findings, based on a small sample, require confirmation by prospective controlled studies. Opioid use at baseline attenuated the placebo antidepressant response independently of pain, while the antidepressant response was preserved in opioid users who received ketamine.