Journal of Psychopharmacology
July 1, 2023
Oliver Rumle Hovmand, Emil Deleuran Poulsen, Sidse Arnfred et al.
52 citations
A systematic review of clinical trials on classical psychedelics (psilocybin, peyote, ayahuasca/DMT, and LSD) for psychiatric conditions found that all but one of the ten included trials were rated as high risk of bias. The trials predominantly enrolled white, highly educated participants, had small sample sizes, and experienced considerable dropout. Blinding was either unsuccessful or not reported regardless of the type of placebo used. Few trials published protocols, statistical analysis plans, or measures of psychotherapy fidelity. The authors suggest that future trials use parallel-group designs with active placebos in psychedelic-naïve populations, publish protocols and analysis plans, employ blinded clinician-rated outcomes, evaluate blinding, and measure expectancy and therapeutic fidelity.
Journal of Psychopharmacology
March 1, 2022
Gabrielle Agin-Liebes, Richard J. Zeifman, Jason B. Luoma et al.
51 citations
People who participated in ayahuasca retreats in Central and South America reported reduced negative mood and increased positive mood and psychological flexibility three months later. Acute experiences of cognitive reappraisal during the ceremony were the strongest predictor of improvements in positive mood and flexibility. Increases in psychological flexibility statistically accounted for the link between acute psychological factors, including reappraisal, and later mood improvements. The findings suggest that acute reappraisal and subsequent gains in psychological flexibility are key mechanisms behind psychedelic-assisted therapy's benefits, supporting the integration of mindfulness-based and third-wave therapy approaches with such interventions.
Journal of Psychopharmacology
March 30, 2021
Erich Studerus, Patrick Vizeli, Samuel Harder et al.
51 citations
The acute response to MDMA (ecstasy) is shaped by both drug concentration in the blood and personal characteristics. Pooling data from 10 placebo-controlled studies with 194 healthy adults, the strongest predictor of effects was MDMA plasma level. After adjusting for dose by body weight, higher activity of the enzyme CYP2D6 predicted lower MDMA concentrations. People scoring high in openness to experience reported more closeness, less general inactivation, and stronger altered states of consciousness. Those with high neuroticism or trait anxiety were more likely to have unpleasant or anxious reactions. These findings highlight that both pharmacological and non-pharmacological factors influence MDMA's effects, which may inform its therapeutic use.
Journal of Psychopharmacology
March 19, 2021
Rafael G. Dos Santos, Jaime Ec Hallak, Glen B. Baker et al.
51 citations
Major depressive disorder affects many people worldwide and current antidepressants often work slowly, have side effects, and fail about a third of patients. Psychedelics such as LSD, psilocybin, and ayahuasca are among the few compounds with recent human evidence of fast-acting antidepressant effects. Studies from the 1950s to 1970s reported antidepressive and anxiolytic effects, which modern trials are confirming (LSD, one trial; psilocybin, five trials; ayahuasca, two trials). These drugs appear to work primarily by activating serotonin receptors, especially the 5-HT2A receptor. The promising but limited evidence of safety and efficacy has encouraged further research into psychedelics for depression.
Journal of Psychopharmacology
May 1, 2007
Karsten Heekeren, Anna Neukirch, Jörg Daumann et al.
49 citations
Schizophrenia patients show reduced prepulse inhibition (PPI) of the startle reflex, but hallucinogen models of psychosis in healthy volunteers do not replicate this effect. In a double-blind crossover study with 15 healthy volunteers, the serotonergic hallucinogen DMT had no significant effect on PPI, while the NMDA antagonist S-ketamine increased PPI and decreased startle magnitude. Neither drug affected the attentional modulation of PPI. These results highlight differences between human hallucinogen models and both animal models and schizophrenia itself.
Journal of Psychopharmacology
June 30, 2023
Jordan Sloshower, Hamideh Safi-Aghdam, Surbhi Pathania et al.
47 citations
A single dose of psilocybin (0.3 mg/kg) doubled electroencephalographic theta power—a marker of neuroplasticity—in the auditory cortex of people with major depressive disorder two weeks later, while placebo produced no such change. Greater increases in theta power correlated with greater reductions in depression symptoms measured by the GRID-HAM-D-17 scale. These results provide evidence that psilocybin can induce sustained changes in human brain plasticity, and the theta-power increase may serve as an EEG biomarker for its antidepressant effects.
Journal of Psychopharmacology
December 20, 2020
Benjamin Illingworth, Declan J Lewis, Andrew T Lambarth et al.
47 citations
A meta-analysis of four randomized controlled trials found that MDMA-assisted psychotherapy can reduce symptoms of treatment-resistant post-traumatic stress disorder (PTSD), as measured by the Clinician Administered PTSD Scale (CAPS-IV). Doses of 75 mg and 125 mg of MDMA, but not 100 mg, produced significant decreases in CAPS-IV scores compared to active placebo. A significant reduction in Beck's Depression Inventory scores was only seen with the 75 mg dose. Participants reported more episodes of low mood, nausea, jaw-clenching during sessions, and lack of appetite within seven days. The authors conclude there is potential therapeutic benefit with minimal physical and neurocognitive risk, though better-powered trials are needed.
Journal of Psychopharmacology
August 22, 2007
Rüssel S. Falck, Jichuan Wang, Robert G. Carlson
45 citations
Among 402 young adult MDMA users followed for two years, depressive symptoms measured by the Beck Depression Inventory (BDI-II) declined from an average score of 9.8 at baseline to 7.7 at 24 months, decreasing by 0.36 points every six months. People with higher initial scores showed greater declines. Men and white participants had lower scores than women and non-whites; those with some university education had lower scores than those without. Current benzodiazepine or opioid users and people who had used MDMA more than 50 times had higher scores. The low and declining average scores suggest that for most people, MDMA use does not lead to long-term depressive symptoms.
Journal of Psychopharmacology
February 28, 2007
Ben Sessa
44 citations
While much has been written about the dangers of recreational MDMA/ecstasy use, the history of its apparently safe and effective therapeutic use in psychotherapy is less known. This paper explores that history and describes the recent re-emergence of scientific interest in MDMA and other psychedelic drugs, with several new double-blind randomized controlled trials underway. The author calls for the medical profession to engage in a dispassionate, open-minded debate about whether MDMA might have a legitimate place as an adjunct to psychotherapy, while acknowledging the limitations of new research and emphasizing appropriate but realistic caution.
Journal of Psychopharmacology
February 1, 2022
Isabel Wießner, Marcelo Falchi-Carvalho, Lucas Oliveira Maia et al.
43 citations
A randomized, double-blind, placebo-controlled crossover study gave 24 healthy volunteers 50 micrograms of LSD or an inactive placebo and tested creativity near the drug's peak using multiple tasks. LSD changed creativity in three ways: it increased novelty, surprise, originality, and semantic distances (pattern break); decreased utility, convergent thinking, and marginally elaboration (disorganization); and increased symbolic thinking and ambiguity (meaning). The findings suggest LSD shifts cognitive resources away from normal patterns toward new ones, and that LSD-induced symbolic thinking might aid psychedelic-assisted therapy.
Journal of Psychopharmacology
May 18, 2015
Sunjeev K. Kamboj, Emma J. Kilford, Stephanie Minchin et al.
43 citations
MDMA (ecstasy) and compassionate imagery both increase self-compassion and reduce self-criticism in recreational users. In a non-blind experiment, participants who consumed ecstasy showed similar pro-social effects to those produced by a contemplative compassion exercise, particularly in those with higher attachment-related avoidance. The findings suggest MDMA may enhance psychotherapy by fostering compassionate attitudes toward oneself. However, because the study was not blinded and drug purity was unknown, controlled trials with pharmaceutical-grade MDMA are needed to confirm these effects.
Journal of Psychopharmacology
June 19, 2013
Rl Carhart-Harris, Stefan Brugger, Dj Nutt et al.
43 citations
Five drugs—cannabis, psilocybin, amphetamine, ketamine, and alcohol—were compared for how well they model psychiatric symptoms. Mental health professionals rated how specific certain experiences were to symptom clusters like depression or psychosis. People with personal drug experience then reported how reliably each drug produced those experiences. No experiences were specific to negative or cognitive psychotic symptoms over depression. Psilocybin best modeled positive psychotic symptoms, while acute alcohol and amphetamine best modeled mania. These findings challenge current assumptions about drug models and point to an understudied area needing more research.
Journal of Psychopharmacology
November 20, 2023
Andreas Halman, Geraldine Kong, Jerome Sarris et al.
42 citations
A systematic review of 52 studies published before September 2023 examined how classic psychedelics (LSD, psilocybin, mescaline, DMT, 5-MeO-DMT, and ayahuasca) interact with other drugs in humans. When combined with antidepressants, antipsychotics, anxiolytics, mood stabilizers, or recreational drugs, the psychedelics' effects were sometimes weakened, sometimes strengthened, and sometimes unchanged. Except for a few case reports, no serious adverse events were reported. The review maps the potential molecular pathways that may explain these interactions, highlighting a critical gap in knowledge about the safety and outcomes of combining psychedelics with other substances.
Journal of Psychopharmacology
June 7, 2022
Emma I Kopra, Jason Ferris, James Rucker et al.
42 citations
Among 10,293 people who used LSD in the past year, 1.0% sought emergency medical treatment, with a per-event risk of 0.2%. Younger age, mental health conditions, and more frequent use increased that risk. Most adverse reactions were psychological—anxiety, panic, confusion—often linked to poor setting or mindset. Symptoms usually resolved within 24 hours, though 11 people had issues lasting beyond 4 weeks. LSD appears relatively safe in recreational settings; adverse effects are typically short-lived and psychological. In clinical contexts, screening, preparation, and supervision should further reduce risks.
Journal of Psychopharmacology
March 1, 2021
A. Inserra, D. de Gregorio, Tamim Rezai et al.
42 citations
LSD alters the firing patterns of neurons in the reticular thalamus, which controls information flow to the cortex. In anesthetized mice, low doses of LSD decreased activity in half of these neurons, while higher doses increased activity in the other half. This was accompanied by increased firing in the mediodorsal thalamus, a relay station to the cortex. LSD only excited neurons in the prefrontal cortex at the highest dose. A dopamine D2 receptor blocker reversed some effects, suggesting LSD acts partly through this receptor. These changes in thalamocortical gating may explain how LSD alters consciousness in humans.
Journal of Psychopharmacology
September 10, 2020
H. Oeri
42 citations
A review examines entactogenic drugs as potential alternatives to MDMA for psychotherapy, particularly for post-traumatic stress disorder. While MDMA shows promising clinical results and may soon be approved, patients with cardiovascular conditions or stimulant use histories may not respond well to its mechanism. The review analyzes substances from 1,3-benzodioxole, cathinone, benzofuran, aminoindane, indole, and amphetamine classes, focusing on neurotoxic risks, neuropharmacological mechanisms, and entactogenic commonalities with MDMA. Several compounds are identified as potential alternatives.
Journal of Psychopharmacology
October 17, 2012
Daniel I. Brierley, Colin Davidson
42 citations
Harmine, a key component of the psychoactive tea ayahuasca, increases dopamine efflux in a specific region of the rat brain's nucleus accumbens (the shell) through a novel mechanism independent of its known monoamine oxidase inhibition. Using fast cyclic voltammetry in rat brain slices, harmine (300 nM) boosted dopamine efflux to 148% of baseline in the shell, and this effect was additive with cocaine (260% of baseline). The increase was blocked by the 5-HT2A/2C antagonist ketanserin, while the MAO inhibitor moclobemide had no effect. Harmine did not alter dopamine efflux in the accumbens core or reuptake in either subregion. These findings suggest harmine acts via a presynaptic 5-HT2A receptor-dependent mechanism, potentially supporting an agonist therapy approach for cocaine dependence.
Journal of Psychopharmacology
August 1, 2022
Paweł Orłowski, Anastasia Ruban, Jan Szczypiński et al.
40 citations
People who have used psychedelics more times over their lifetime tend to show greater positive emotional reactions and lower negative emotional reactions, along with more reflection and internal self-awareness, and less rumination and concern about how others see them. These associations were explained largely by the intensity of past ego-dissolution and mystical experiences during psychedelic use. The findings suggest that regular naturalistic use of psychedelics is linked to adaptive, lasting changes in emotional reactivity and self-consciousness, which may underlie previously observed increases in well-being among users.
Journal of Psychopharmacology
January 1, 2022
Grant M Jones, Matthew K Nock
40 citations
Lifetime use of MDMA/ecstasy was associated with 16% lower odds of a major depressive episode (MDE) over a person's lifetime, the past year, and severe past-year MDE. Psilocybin use was linked to 10% lower odds of a past-year MDE and 13% lower odds of a severe past-year MDE. Other illegal or misused substances either showed no association with MDE or were linked to increased odds. The findings come from a large US sample and suggest a potential protective relationship, but experimental studies are needed to test causality.
Journal of Psychopharmacology
August 12, 2023
Michael Tagen, Daniel Mantuani, Alex Holstein et al.
39 citations
Taking very low, repeated doses of psychedelics like LSD, psilocybin, mescaline, DMT, or MDMA may pose a risk of valvular heart disease because these substances activate the serotonin 5-HT2B receptor, which is linked to heart valve damage. All five compounds and some of their metabolites bind to this receptor with potency equal to or greater than their binding to the 5-HT2A receptor. Safety margins based on typical microdose blood levels are higher than those of known valvulopathogens, but risk is not absent. No animal or clinical studies properly designed to assess this risk exist for the psychedelics, though chronic full-dose MDMA use is associated with valvular heart disease. Further research is needed.
Journal of Psychopharmacology
April 30, 2019
Dino Luethi, Karolina E. Kolaczynska, Melanie Walter et al.
39 citations
Metabolites of the popular illicit drugs MDMA, methylone, and MDPV can interact with human monoamine transporters and receptors at concentrations relevant to their pharmacological effects. MDMA and methylone inhibited norepinephrine uptake more potently than dopamine or serotonin uptake. N-demethylation of MDMA did not change its uptake inhibition profile, but N-demethylation of methylone reduced overall potency. Opening the methylenedioxy ring produced catechol metabolites that maintained norepinephrine and dopamine uptake inhibition but had much weaker effects on serotonin uptake. Further O-methylation of these catechols reduced norepinephrine uptake inhibition, yielding metabolites without significant stimulant properties. N-demethylated metabolites of MDMA and methylone circulate unconjugated and may contribute to the drugs' effects in human users.
Journal of Psychopharmacology
November 1, 2007
Ben Sessa, David Nutt
39 citations
MDMA, originally used as a clinical tool in couples therapy on the West Coast of America after LSD was banned, leaked into recreational use and was prohibited in the mid-1980s. Despite its growing recreational use in rave and party scenes, medical research on MDMA stopped, and the drug became demonized by politicians. Doctors and pharmacologists debated its short-, medium-, and long-term dangers, while its therapeutic potential was forgotten. The paper argues that political restrictions, such as MDMA's classification as a class A schedule 1 drug in the UK, severely limit human research and threaten scientific objectivity and evidence-based clinical excellence. It calls for exploring MDMA's potential medical and research uses without political influence.
Journal of Psychopharmacology
November 26, 2022
Melissa Shukuroglou, Leor Roseman, David Nutt et al.
38 citations
Listening to music after psilocybin therapy for treatment-resistant depression increases the pleasure people feel from music, and this increase correlates with a reduction in anhedonia (loss of pleasure). Nineteen patients received a low dose (10 mg) and then a high dose (25 mg) of psilocybin one week apart. Functional MRI scans before and after treatment showed that during music listening, functional connectivity between the nucleus accumbens (a brain reward region) and areas resembling the default mode network decreased after treatment. The findings suggest psilocybin therapy enhances music-evoked pleasure and point to a possible brain mechanism involving reduced connectivity in the default mode network.
Journal of Psychopharmacology
September 3, 2010
Gjh Dumont, J. G. Coen van Hasselt, M. de Kam et al.
38 citations
Combining MDMA and THC does not worsen cognitive impairment beyond that caused by THC alone, but it does increase the desired subjective drug effects and perceived drug strength, which may explain why many young people use them together. In a placebo-controlled crossover trial with 16 healthy volunteers aged 18–27, THC alone produced more robust cognitive impairment than MDMA alone, and co-administration did not exacerbate single-drug effects on cognitive function. However, the combination enhanced subjective experiences compared with MDMA alone.
Journal of Psychopharmacology
January 22, 2009
Gjh Dumont, Rik C. Schoemaker, Daan J. Touw et al.
37 citations
Combining MDMA (ecstasy) with alcohol impairs psychomotor accuracy even though it increases feelings of arousal and psychomotor speed. In a double-blind, placebo-controlled crossover study with 16 healthy young adults, MDMA alone boosted speed without affecting accuracy and caused arousal, while alcohol alone slowed both speed and accuracy and induced sedation. When taken together, the combination reversed alcohol-induced sedation and improved speed, but accuracy remained significantly impaired. The effects peaked 90–150 minutes after MDMA administration and then declined, except for alcohol sedation, which emerged fully after the infusion stopped. This mismatch between perceived performance and actual impairment may affect neuropsychological functioning.