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.
Journal of Psychopharmacology
January 12, 2024
Antonin Rouaud, Gregor Hasler, Abigail E. Calder
36 citations
Microdosing psychedelics like LSD and psilocybin has become popular, but its long-term effects on heart health are unknown. These drugs share structural similarities with medications that raise the risk of cardiac fibrosis and valvulopathy when taken regularly. This review evaluates the evidence that microdosing for months or more could increase the risk of cardiac fibrosis, discusses the role of the 5-HT2B receptor in drug-induced cardiac fibrosis, and recommends safety evaluations for future studies.
Journal of Psychopharmacology
March 28, 2021
Mitch Earleywine, Luna F. Ueno, Maha N. Mian et al.
36 citations
High doses of cannabis can produce subjective effects similar to those of the psychedelic psilocybin, but at a lower rate. In a survey, 17–19% of cannabis users reported a “breakthrough” experience, compared to 59% in psilocybin clinical trials. Heavier cannabis users reported lower scores. These effects may parallel the therapeutic benefits seen with psilocybin, suggesting potential for cannabis-assisted psychotherapy.
Journal of Psychopharmacology
September 1, 2005
Alex Gamma, Daniel Brandeis, Ruven Brandeis et al.
36 citations
People who use ecstasy (MDMA) along with other drugs show reduced P3 brain-wave amplitudes during a task that requires inhibiting a prepared response, compared with non-users. This lower amplitude is consistent with greater neural disinhibition. However, the normal pattern of brain activity shifting forward when inhibiting a response, and the less frontal location of the inhibition-related brain signal, do not point to a fundamental disruption of inhibitory brain mechanisms. The differences became weaker after accounting for age, education, and lifetime cannabis use.
Journal of Psychopharmacology
May 1, 2024
Max Wolff, Ricarda Evens, Lea J. Mertens et al.
34 citations
A new questionnaire, the General Change Mechanisms Questionnaire (GCMQ), reliably measures five psychotherapy processes—resource activation, therapeutic relationship, problem actuation, clarification, and mastery—during psychedelic experiences. Validated in 1153 English-speaking and 714 German-speaking users, the GCMQ showed good internal consistency and convergent validity. Experiences varied with setting and use motives (therapeutic, hedonic, escapist). Resource activation, clarification, and mastery moderated the link between stressful life events and well-being, suggesting potential therapeutic benefits. Five distinct user profiles emerged, which may inform clinical use and harm reduction.
Journal of Psychopharmacology
August 1, 2022
Javier Hidalgo Jiménez, José Carlos Bouso
34 citations
DMT, a potent psychedelic naturally produced by many plants and animals including humans, may play significant roles in mammalian physiology. This review integrates historical and recent evidence to address ongoing debates about DMT's relevance. Arguments dismissing endogenous DMT are often based on obsolete data or misleading assumptions. Evidence strongly suggests DMT functions as a neurotransmitter, neuromodulator, hormone, and immunomodulator, and is important in pregnancy and development. Key experiments are proposed to definitively determine DMT's specific physiological roles.
Journal of Psychopharmacology
July 17, 2020
Carl Roberts, Isaac Osborne-Miller, Jon C. Cole et al.
33 citations
Both people who have used magic mushrooms and those who have not perceive mushrooms as less dangerous than heroin, cocaine, prescription painkillers, GHB, ecstasy, tobacco, and alcohol. However, those without experience rate mushrooms as significantly more dangerous than users do, and they expect more negative intoxication effects. Users expect greater entactogenic, prosocial, aesthetic, and mood effects, as well as perceptual alterations. Motivations for use predict expected effects—for example, using mushrooms for personal psychotherapy is linked to expecting increased entactogenic and decreased negative effects. The findings align with data on low actual harm but conflict with legal classifications.
Journal of Psychopharmacology
January 24, 2011
Jéssica Ruiz‐medina, Catherine Ledent, Olga Carretón et al.
33 citations
Adenosine A2a receptors are crucial for the rewarding and neuroinflammatory effects of MDMA. In mice lacking these receptors, MDMA failed to support self-administration, indicating a complete loss of its reinforcing properties. Additionally, the neurotoxic regimen of MDMA caused increased glial activation in the striatum of normal mice, but this inflammatory response was attenuated in mice without A2a receptors. Acute effects on body temperature, locomotion, and anxiety were similar in both genotypes. This work identifies the A2a adenosine receptor as a key mediator of MDMA's addictive potential and neurotoxicity.
Journal of Psychopharmacology
July 31, 2024
Roman Palitsky, Deanna M. Kaplan, John Perna et al.
32 citations
A multidisciplinary working group identified 54 potential adverse events that warrant systematic assessment in psychedelic-assisted therapies, finding that existing measurement tools substantially fail to cover these constructs. The group developed recommendations for when and how to assess these adverse events across preparation, dosing, integration, and follow-up phases, and demonstrated a preliminary assessment protocol. The framework addresses the need to capture post-acute dosing adverse events, accounting for both the pharmacotherapy and psychotherapy components of psychedelic-assisted therapy, as well as documented impacts on worldviews and spirituality.
Journal of Psychopharmacology
August 31, 2023
Pravesh Sharma, Quang Anh Nguyen, Erin Carpenter et al.
32 citations
Psilocybin, the psychoactive compound in hallucinogenic mushrooms, shows modest evidence for treating depression and anxiety disorders, and early data suggest it may reduce harmful drinking in alcohol use disorder. When administered under supervision, side effects are mild and transient, and severe adverse events are uncommon. However, a recent clinical trial found increased suicidal ideations and non-suicidal self-injurious behaviors in the psilocybin arm. Further investigation is needed to identify which patient subgroups benefit most and which are at risk for adverse outcomes.
Journal of Psychopharmacology
November 16, 2023
Oliver Rumle Hovmand, Emil Deleuran Poulsen, Sidse Arnfred
31 citations
Classical psychedelics such as psilocybin, peyote, ayahuasca, and LSD can temporarily alter consciousness, affecting perception, mood, and sense of self. Reliable measurement tools are needed because the acute subjective experience may influence treatment outcomes. A review of 93 trials identified 17 different rating scales used to assess these altered states. The five most common instruments were the Five-Dimensional Altered States of Consciousness Questionnaire, visual analog or Likert scales developed for specific trials, the Hallucinogen Rating Scale, the States of Consciousness Questionnaire, and the Abnormer Psychischer Zustand. The authors recommend developing a core set of outcome measures to allow comparisons across different psychedelics, participants, and settings, and suggest designing instruments that assess the setting of the experience.
Journal of Psychopharmacology
October 2, 2008
Sj Kish, Paul S. Fitzmaurice, Lj Chang et al.
31 citations
A post-mortem analysis of a high-dose MDMA user's brain found that protein levels of the serotonin transporter (SERT) were markedly reduced in the striatum and occipital cortex (by 48–58%) and less affected in frontal and temporal cortices (by 25%), while tryptophan hydroxylase (TPH), the enzyme that synthesizes serotonin, was severely decreased in the caudate and putamen (by 68% and 95%, respectively). The reduction in striatal SERT protein was larger than the binding decreases typically reported in imaging studies. These results suggest high-dose MDMA exposure may cause loss of two key protein markers of serotonin neurons, possibly indicating physical damage or downregulation of neuronal components.
Journal of Psychopharmacology
January 21, 2008
Christopher D. Verrico, Laurie J. Lynch, Michele A. Fahey et al.
31 citations
Oral MDMA impairs executive function in monkeys for several days, a finding potentially relevant to human MDMA users. The cognitive deficits were reversed by inhibitors of the serotonin transporter (citalopram) and the norepinephrine transporter (desipramine), but not by a dopamine/norepinephrine transporter inhibitor (methylphenidate). MDMA also altered sleep latency. The results implicate the norepinephrine transporter and norepinephrine in MDMA-induced cognitive impairment, suggesting that serotonin deficits alone may not explain the cognitive effects. The study used cynomolgus monkeys trained in a reversal learning task and tested with oral or intramuscular MDMA, with or without transporter inhibitor pretreatments.