Frontiers in Pharmacology
July 13, 2022
Patrick Vizeli, Isabelle Straumann, Urs Duthaler et al.
43 citations
A single 125 mg dose of MDMA, given to 30 healthy men after fear conditioning and two hours before extinction learning, reduced skin conductance responses to a conditioned fear cue during both extinction learning and its recall the next day, compared with placebo. The drug did not affect fear-potentiated startle responses. Subjective feelings of trust and openness during extinction learning were linked to poorer discrimination between danger and safety cues during recall. MDMA raised oxytocin levels fourfold, but this increase did not correlate with fear extinction outcomes. The findings suggest MDMA can accelerate fear extinction learning and retention, at least for some physiological measures of fear, which may help explain its therapeutic benefit in PTSD.
Frontiers in Pharmacology
April 15, 2021
Meiying Cui, Wanlin Dai, Jing Kong et al.
43 citations
Major depressive disorder involves inflammation and immune processes, including alterations in cytokine levels and immune cell function. Th17 cells, a proinflammatory T cell subset, accumulate and disrupt the Th17/Treg balance, contributing to depression and depressive-like behaviors in animal models. Ketamine is an effective rapid-acting antidepressant, but its mechanisms are not fully understood. This review suggests that ketamine's antidepressant effects may involve immune modulation of Th17 cells and the Th17/Treg balance. Exploring these mechanisms could enhance ketamine's benefits and reduce side effects.
Frontiers in Pharmacology
October 7, 2020
Ilana Berlowitz, Ernesto García Torres, Heinrich Walt et al.
43 citations
In the Peruvian Amazon, tobacco—particularly Nicotiana rustica—is used as a potent medicinal plant, applied topically or ingested to treat conditions including mental health issues, respiratory problems, parasitic infections, gout, and spiritual-energetic ailments. A transdisciplinary field study interviewed a Maestro Tabaquero (traditional healer specializing in tobacco) to document preparation methods, indications, contraindications, effects, and risks. The most common remedy was a liquid taken orally, producing acute psychoactive effects and physiological responses like vomiting. Safe treatment requires a skilled healer knowledgeable in dosing and managing adverse effects. This work contributes to research on Amazonian medicine and psychedelic-assisted therapies.
Frontiers in Pharmacology
January 4, 2023
Kenneth Alper, Janelle Cange, Ria Sah et al.
39 citations
A single dose of psilocybin reduces voluntary ethanol consumption in male mice for three days afterward, but has no effect in female mice. The reduction is dose-related and occurs at 0.5 mg/kg or higher, but does not persist when ethanol is reintroduced after two days of withdrawal. The effect is not due to altered taste perception, motor effects, or nonspecific changes in drinking behavior. These findings suggest sex-dependent effects of psilocybin on alcohol drinking and indicate that the C57BL/6J mouse may be useful for studying sex differences in alcohol use disorder and the neurobiology of psychedelics.
Frontiers in Pharmacology
May 5, 2021
Débora González, Jordi Cantillo, Irene Hidalgo Pérez et al.
39 citations
People who took part in an Indigenous Shipibo healing program involving ayahuasca ceremonies showed significant increases in psychological well-being, happiness, and quality of life that lasted up to 12 months. A subgroup analysis indicated the improvements were due to the program rather than the passage of time. A relationship was found between decentering—the ability to observe thoughts and feelings objectively—and enhanced psychological well-being.
Frontiers in Pharmacology
December 3, 2020
Daniela Dudysová, Karolína Janků, Michal Šmotek et al.
37 citations
Psilocybin, a serotonergic psychedelic with antidepressant potential, altered sleep architecture in healthy volunteers the night after administration. In a randomized, double-blinded trial, 20 healthy adults (10 women, ages 28–53) received psilocybin or placebo. Psilocybin prolonged REM sleep latency and showed a trend toward reduced total REM sleep duration, with no changes in NREM sleep or whole-night EEG power spectra. Contrary to expectations, psilocybin suppressed slow-wave activity in the first sleep cycle, providing no evidence for sleep-related neuroplasticity. The findings suggest that psilocybin's antidepressant properties may involve sleep changes, possibly through different mechanisms than those of classical antidepressants.
Frontiers in Pharmacology
August 31, 2018
Kenneth Alper, Bin Dong, Relish Shah et al.
37 citations
A single high dose of LSD (50 μg/kg) reduced alcohol consumption by an average of 17.9% in adult male mice over 46 days, with no change in total fluid intake or activity. A lower dose (25 μg/kg) had no effect. The findings suggest classical hallucinogens warrant further animal research for addiction neurobiology and drug discovery.
Frontiers in Pharmacology
September 29, 2021
João Castelhano, Gisela Lima, Marta Teixeira et al.
34 citations
Tryptamine psychedelics such as LSD, psilocybin, DMT, and ayahuasca alter brain activation and connectivity in regions that match the distribution of 5HT2A and 5HT1A receptors, including visual cortex, cingulate cortex, medial prefrontal cortex, temporal cortex, and the right amygdala. These effects involve areas supporting mental imagery, theory of mind, and emotional regulation, suggesting potential therapeutic applications. The analysis confirms that changes occur in regions with high 5HT2A receptor density, but also in other areas like the dorsolateral prefrontal cortex. However, too few PET studies exist to meta-analyze receptor occupancy directly.
Frontiers in Pharmacology
July 11, 2017
Drew J. Puxty, Johannes G. Ramaekers, Rafael de la Torre et al.
33 citations
A single 75 mg dose of MDMA produces a dissociative state, marked by feelings of depersonalization and derealization, in healthy recreational users. Blocking the 5-HT2 receptor with ketanserin did not prevent this effect, indicating that the 5-HT2 receptor does not mediate MDMA-induced dissociation. Heart rate correlated with the dissociative state after MDMA alone, but not when ketanserin was given, suggesting heart rate changes do not directly cause dissociation. Cortisol levels and MDMA blood concentrations showed no clear relationship with dissociation. The exact neurobiological mechanism remains unknown and may be relevant to MDMA's therapeutic use.
Frontiers in Pharmacology
May 2, 2022
Ilana Berlowitz, Klemens Egger, Paul Cumming
32 citations
Monoamine oxidases (MAOs) are enzymes that break down biogenic amines like serotonin, dopamine, and tyramine in the brain and body. Beta-carboline alkaloids, such as harmine and harmane, are MAO inhibitors found in plants including tobacco and Banisteriopsis caapi, a key ingredient in the Amazonian ayahuasca brew. These beta-carbolines may boost the bioavailability of the hallucinogen DMT and might have antidepressant properties. However, the level of MAO inhibition needed to affect neurotransmitter signaling is not yet known. Unlike synthetic antidepressant MAO inhibitors that cause complete and irreversible inhibition, beta-carbolines are reversible and competitive, making complete inhibition unlikely. Many medicinal plants contain MAO inhibitors, but their pharmacological relevance often remains unclear.
Frontiers in Pharmacology
January 28, 2020
Esther Papaseit, Clara Pérez-mañá, Elizabeth B. de Sousa Fernandes Perna et al.
27 citations
Combining mephedrone with alcohol amplifies cardiovascular effects and intensifies euphoria and well-being compared to either drug alone, while mephedrone reduces the sedative effects of alcohol. In a double-blind, placebo-controlled trial with 11 male volunteers, the combination increased blood pressure, heart rate, and subjective feelings of euphoria. Mephedrone alone and alcohol alone were also tested. The results suggest that the abuse liability of mephedrone is greater when taken with alcohol, similar to other psychostimulants like amphetamines and MDMA.
Frontiers in Pharmacology
February 17, 2023
Lourdes Poyatos, Clara Pérez‐mañá, Olga Hladun et al.
26 citations
Methylone, a common synthetic cathinone used as a substitute for MDMA, produces similar acute effects in humans. In a controlled trial with 17 experienced psychostimulant users, a single 200 mg oral dose of methylone increased blood pressure and heart rate and induced pleasurable effects including stimulation, euphoria, wellbeing, enhanced empathy, and altered perception. Methylone's effect profile resembled MDMA's but with a faster onset and earlier disappearance of subjective effects. The findings suggest methylone's abuse potential is comparable to that of MDMA in humans.
Frontiers in Pharmacology
May 19, 2021
Brian Rush, Olivia Marcus, Sara Mallén García et al.
26 citations
This paper describes the protocol for the Ayahuasca Treatment Outcome Project (ATOP), which evaluates addiction treatment services at the Takiwasi Center in the Peruvian Amazon. The project aims to assess outcomes and understand therapeutic mechanisms of an ayahuasca-assisted, integrative treatment model for addiction rehabilitation. The protocol emphasizes the importance of treatment setting in designing and delivering a program involving the psychedelic tea ayahuasca. A mixed-methods approach to data collection and analysis is used to understand why, how, and for whom the treatment is effective across various outcomes.
Frontiers in Pharmacology
September 2, 2020
Jenessa N. Johnston, Jonathan S. Thacker, Charissa Desjardins et al.
25 citations
In adult male rats exposed to repeated corticosterone (a model of depression), ketamine restored the expression of reelin, a protein implicated in depression, and both reelin and ketamine rescued synaptic levels of mTOR and its activated form p-mTOR in the hippocampus and cerebellum, which had been reduced by corticosterone. Reelin, but not ketamine, also normalized serotonin transporter clustering on peripheral lymphocytes. These results suggest ketamine modulates reelin expression and support exploring reelin itself as a potential fast-acting antidepressant.
Frontiers in Pharmacology
January 20, 2021
Ole Jensen, Muhammad Rafehi, Lukas Gebauer et al.
24 citations
Several psychostimulants and hallucinogens are transported by organic cation transporters (OCTs), which may contribute to individual differences in their metabolism and toxicity. Mescaline is strongly transported by OCT1, with transport varying substantially across common genetic variants: reduced in variants *2, *3, *4, *5, *6, and moderately increased in *8. Other substances—methamphetamine, para-methoxymethamphetamine, (-)-ephedrine, cathine, and dimethyltryptamine—are substrates of OCT2, with affinities and transport capacities reduced by up to half in the A270S variant. Cathine also acts as a substrate for NET and DAT. These findings suggest that genetic variation in OCTs could underlie highly variable adverse reactions to mescaline and other psychostimulants.
Frontiers in Pharmacology
November 28, 2019
Karolina E. Kolaczynska, Dino Luethi, Daniel Trachsel et al.
24 citations
A series of 4-alkyloxy-substituted 2,5-dimethoxyamphetamines and their phenethylamine congeners (2C-O derivatives) were tested for binding and activation at serotonin, adrenergic, dopamine, and trace amine receptors, as well as monoamine transporters. Both amphetamine and phenethylamine derivatives bound with moderate to high affinity to the 5-HT2A receptor, with preference over 5-HT1A and 5-HT2C receptors. Extending the 4-alkoxy group generally increased binding affinities at 5-HT2A and 5-HT2C receptors but had mixed effects on activation. Phenethylamines bound more strongly to TAAR1 than their amphetamine analogs. The authors suggest that, based on high 5-HT2A binding, some compounds may produce psychedelic-like effects in humans.
Frontiers in Pharmacology
May 28, 2021
David M. O’shaughnessy, Ilana Berlowitz
21 citations
Plant diets (dietas) in Peruvian Amazonian medicine are flexible techniques used for healing, prevention, strength-building, rites of passage, and learning medicine. Many dieted plants are psychoactive, including Banisteriopsis caapi, the vine in ayahuasca. While ayahuasca has drawn clinical attention within psychedelic science, plant diets remain understudied. Interviews with eight extensively trained healers in San Martín, Peru (2015–2017) were analyzed thematically. The authors argue that the “set and setting” framework central to psychedelic research is insufficient for understanding diets, which should not be explained by pharmacology or psychology alone. Intercultural and interdisciplinary research is needed to better understand plant diets and traditional Amazonian medicine.
Frontiers in Pharmacology
October 2, 2023
Victor P Acero, Emily S Cribas, Kevin D Browne et al.
20 citations
Psychedelic compounds show promise for treating post-traumatic stress disorder, substance abuse, and treatment-resistant depression, but their full biological effects and mechanisms are not yet established. Most research has focused on psychological mechanisms, often overlooking non-psychological modes of action. Psychedelics may work through multiple mechanisms, including modulation of brain network activity, neuronal plasticity, neuroendocrine function, glial cell regulation, epigenetic processes, and the gut-brain axis. This review advocates for a multi-faceted approach using computational, cellular, and animal models to understand physiological effects and explore clinical applications beyond psychiatric disorders, such as brain injury, neurodegenerative diseases, and gut-brain axis dysfunction.
Frontiers in Pharmacology
March 22, 2022
Enzo Tagliazucchi
20 citations
Psychedelics profoundly alter subjective experience, sometimes with lasting effects, yet how they affect language production is understudied. This review examines two aspects: how acute psychedelic effects impact speech organization regardless of semantic content, and how analyzing semantic content of written retrospective reports can characterize subjective effects. Computational analysis of language production can partially predict therapeutic outcomes, relate psychedelic effects to other altered states and psychiatric disorder symptoms, and investigate neurochemical profiles and mechanisms of action. The authors conclude that analyzing brief interviews before, during, and after acute effects can expand scientific conclusions, and they list open questions for future research.
Frontiers in Pharmacology
March 18, 2020
Esther Papaseit, Marta Torrens, Mireia Ventura et al.
20 citations
2C-E, a psychedelic phenylethylamine similar to mescaline, acts as a partial agonist at serotonin 2A, 2B, and 2C receptors and inhibits norepinephrine and serotonin uptake. In an observational study, ten recreational psychedelic users self-administered single oral doses of 2C-E (6.5–25 mg). The drug induced alterations in perception, hallucinations, and euphoric mood, with saliva concentrations peaking 2 hours after administration. The effects resembled those of 2C-B and other serotonin-acting drugs.
Frontiers in Pharmacology
February 16, 2023
Yahong Chen, Junhong Liu, Yishan Yao et al.
19 citations
Psychedelics like DOM, mescaline, and psilocin reduce mouse locomotor activity at high doses and alter rearing behavior in an inverted U-shaped pattern. Blocking the 5-HT2A receptor with M100907 reversed changes in activity, rearings, and jumps from low-dose DOM, but not holepoking. The hallucinogenic 5-HT2A agonist 25CN-NBOH produced similar effects that were diminished by M100907, while nonhallucinogenic agonists TBG and lisuride did not increase rearing. Discriminant analysis distinguished all four psychedelics from nonhallucinogenic agonists based on behavior alone, suggesting increased rearing in mice may differentiate hallucinogenic from nonhallucinogenic 5-HT2A agonists.
Frontiers in Pharmacology
June 28, 2022
Nataliya S. Vorobyeva, Alena A. Kozlova
16 citations
Classic psychedelics, which resemble serotonin and bind to serotonin receptors, are being studied as treatments for psychiatric conditions such as post-traumatic stress disorder, major depressive disorder, anxiety, and substance use disorders. Mental health disorders are common and pose a major public health challenge; existing treatments often face issues with treatment resistance and high relapse rates. This review examines three naturally occurring psychedelics—psilocybin, ibogaine, and N,N-dimethyltryptamine—focusing on their pharmacological properties and clinical potential. The article aims to summarize key research on these substances and consider their possible use as alternatives or additions to current pharmacological and psychological therapies.
Frontiers in Pharmacology
February 9, 2022
Karolina E. Kolaczynska, Dino Luethi, Dino Luethi et al.
16 citations
Mescaline, a psychedelic found in peyote, belongs to a class of compounds called scalines and 3C-scalines, which may serve as novel therapeutics for psychedelic-assisted therapy. This in vitro study examined several previously uninvestigated scalines and 3C-scalines at key monoamine targets. These compounds bound to the 5-HT2A receptor with weak to moderately high affinity (Ki = 150–12,000 nM). 3C-scalines showed a marginal preference for 5-HT2A over 5-HT2C and 5-HT1A receptors, while scalines showed no preference. Extending the 4-alkoxy substituent increased binding affinities and activation potency at 5-HT2A but not 5-HT2B receptors.
Frontiers in Pharmacology
September 16, 2021
Lukas A. Basedow, Thomas Riemer, Simon Reiche et al.
16 citations
Repeated use of serotonergic psychedelics such as LSD, ayahuasca, and peyote is associated with distinct neuropsychological profiles rather than a uniform pattern of impairment. A systematic review of 13 studies (539 participants) found that LSD users performed worse on executive-functioning tasks, ayahuasca users showed better performance on the Stroop incongruent task, and peyote users showed no differences across domains. However, methodological quality varied widely, and most studies failed to fully control for confounding factors like other substance use. The evidence suggests that different psychedelics may have different long-term cognitive consequences.
Frontiers in Pharmacology
July 22, 2022
Leor Roseman, Katrin H. Preller, Evgenia Fotiou et al.
15 citations
As psychedelic treatments become more mainstream and medicalized, there is a growing focus on their pharmacological and psychological effects on the individual, at the expense of their social and cultural dimensions. Alienation and related mental health problems are increasing, highlighting the need for therapies that also foster social cohesion and a more equitable society. Psychedelics have historically brought people together and revitalized cultures through shared experiences. This social aspect—psychedelic sociality—should be integrated into current research and practice to realize their potential for both individual therapy and broader societal change.