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
January 1, 2025
Agnieszka Zelek-Molik, Ewa Litwa
19 citations
Mood disorders like major depressive disorder and bipolar disorder are leading causes of disability worldwide, characterized by depressed mood, anhedonia, sleep disturbances, appetite changes, fatigue, cognitive impairment, and feelings of worthlessness. A growing number of patients experience treatment resistance, even with long-term therapy, creating an urgent need for rapid-acting and safe antidepressants. This review summarizes trends in novel antidepressant research, focusing on drugs with multi-directional mechanisms and high efficacy for treatment-resistant depression. Animal models of depression remain essential for predicting therapeutic strategies and understanding the physiological effects of new compounds, guiding the development of innovative treatments.
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
July 6, 2018
Elizabeth B. de Sousa Fernandes Perna, Eef L. Theunissen, Patrick C. Dolder et al.
18 citations
A single 100 mg dose of 4-fluoroamphetamine (4-FA), a phenethylamine novel psychoactive substance, produced strong elevation in blood pressure for 4-5 hours followed by sustained increased heart rate in healthy volunteers. Effects on mood and neurocognitive function peaked at 1 hour, including significant elevations of vigor, friendliness, elation, arousal, and positive mood, along with improvements in attention and motor performance. Negative affect also increased during the acute and subacute phases. The 150 mg dose was canceled after an interim safety review. The findings confirm clinical observations of acute toxicity and warrant warnings about health risks.
Frontiers in Pharmacology
January 1, 2023
Klemens Egger, Frederik Gudmundsen, Naja Støckel Jessen et al.
17 citations
Co-administration of harmine with DMT in rats increased brain DMT levels by inhibiting its metabolism to indole-3-acetic acid, yet no significant occupancy of serotonin 5-HT2A receptors by DMT was detected, even at brain DMT concentrations up to 11.3 µM. Low doses of DMT and/or harmine did not significantly alter brain glucose metabolism as measured by [18F]FDG-PET. These preliminary findings suggest that the role of MAO-A inhibition in potentiating DMT's psychedelic effects may be more complex than previously assumed, and further dose-response studies are needed.
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.
Frontiers in Pharmacology
January 1, 2025
Jing Wang, Yulei Hao, Di Ma et al.
14 citations
Recreational abuse of six addictive drugs—methamphetamine, cocaine, synthetic cathinones, ketamine, nitrous oxide, and heroin—damages the nervous system through shared toxic pathways, including oxidative stress, mitochondrial dysfunction, excitotoxicity, and neuroinflammation. Psychostimulants disrupt monoaminergic signaling, causing cognitive impairment and neurovascular damage. Dissociative anesthetics impair glutamatergic transmission and mitochondrial function, worsening excitotoxicity and neuronal death. Opioids target the brain's reward system, inducing oxidative stress and neuroinflammation. Current treatments focus on symptom management and behavioral therapy; emerging options like antioxidants and NMDA receptor modulators need further validation.
Frontiers in Pharmacology
April 18, 2024
Elad Lerer, Alexander Botvinnik, Orr Shahar et al.
14 citations
Psilocybin and a psilocybin-containing mushroom extract, but not the serotonin precursor 5-hydroxytryptophan, increased expression of immediate early genes cfos and egr1 in the somatosensory cortex of male mice. The head twitch response, a behavioral measure, did not correlate with gene expression changes. Blocking the 5-HT2C receptor enhanced psilocybin-induced egr2 expression, but other serotonergic modulators had no effect. These findings suggest that cfos and egr1 expression may be linked to psychedelic effects.
Frontiers in Pharmacology
January 1, 2023
Leah M Salinsky, Christina R Merritt, Joshua C Zamora et al.
14 citations
Opioid misuse and overdose deaths are a major public health problem involving prescription opioids and potent fentanyl derivatives. Repeated overdose events indicate opioid use disorder (OUD). Opioids reduce pain by activating µ-opioid receptors (MOR) in the central nervous system, and dysregulation of reward circuitry underlies OUD. Serotonin (5-HT) contributes to opioid pharmacology and OUD. There is renewed interest in psychedelic compounds acting through the 5-HT2A receptor (5-HT2AR) for treating substance use disorders. Emerging data suggest MOR and 5-HT2AR crosstalk at cellular levels and in OUD circuitry, offering opportunities for novel pharmacological intervention. This review discusses the opportunities and challenges of using 5-HT2AR agonists as therapeutics for OUD.
Frontiers in Pharmacology
January 1, 2024
Carla Soares, Gisela Lima, Marta Lapo Pais et al.
13 citations
A pharmacoimaging study in eleven healthy experienced users found that inhaled DMT increases functional connectivity between brain regions involved in social cognition and emotional processing. Specifically, DMT strengthened connections between the supramarginal gyrus and the precuneus, posterior cingulate gyrus, amygdala, and orbitofrontal cortex, as well as between the amygdala and orbitofrontal cortex. These changes occurred in socio-emotional and affective-value circuits, offering insight into how psychedelics may alter brain function and potentially contribute to therapeutic effects in disorders involving social and reward processing deficits.
Frontiers in Pharmacology
December 3, 2020
Lauri Elsilä, Nuppu Korhonen, Petri Hyytiä et al.
13 citations
Acute doses of LSD at 0.025, 0.1, and 0.2 mg/kg did not alter reward-driven decision making in mice performing a touch-screen version of the Iowa Gambling Task, nor did the serotonin 2A receptor agonist 25CN-NBOH. The highest LSD dose (0.4 mg/kg) reduced premature responses and increased omission rates without affecting option selection. Amphetamine decreased correct responses and premature responding while increasing omission rates. Mice can perform previously learned decision-making tasks under LSD at commonly used doses.
Frontiers in Pharmacology
February 2, 2024
Joachim Neumann, Stefan Dhein, Uwe Kirchhefer et al.
12 citations
Hallucinogenic drugs like LSD, psilocybin, and DMT affect the brain by stimulating serotonin receptors, particularly 5-HT2A receptors, which likely causes their hallucinogenic effects. However, these drugs also act on the heart, potentially increasing the force of contraction and heart rate, and may lead to arrhythmias. This review examines the inotropic and chronotropic actions of bufotenin, psilocin, psilocybin, LSD, ergotamine, ergometrine, N,N-dimethyltryptamine, and 5-methoxy-N,N-dimethyltryptamine in the human heart.
Frontiers in Pharmacology
January 1, 2024
Senbing Zhang, Yanzhu Pu, Jianning Liu et al.
12 citations
(R)-ketamine shows promise for treatment-resistant depression with fewer psychomimetic and dissociative side effects than (R,S)- or (S)-ketamine, but a recent small randomized controlled trial found its antidepressant efficacy did not surpass placebo in adults. The compound may also have applications in cognitive disorders, stroke, Parkinson's disease, multiple sclerosis, osteoporosis, substance use disorders, inflammatory diseases, COVID-19, and organophosphate poisoning. This review covers (R)-ketamine's mechanisms and antidepressant research, highlighting its potential and need for further verification.
Frontiers in Pharmacology
June 28, 2017
Patrick C. Dolder, Edna Grünblatt, Felix Müller et al.
12 citations
A single 100 μg dose of LSD did not change the expression of the serotonin 5-HT2A receptor gene (HTR2A) or the early growth response genes EGR1, EGR2, and EGR3 in the whole blood of 15 healthy subjects, measured 1.5 and 24 hours after administration. This null finding contrasts with rodent studies showing that LSD acutely increases EGR1 and EGR2 expression in the brain and that repeated use reduces 5-HT2A receptor binding. Whether chronic LSD administration alters gene expression in humans remains unknown.
Frontiers in Pharmacology
January 12, 2024
Ninon Freidel, Liliane Kreuder, Brenden Samuel Rabinovitch et al.
11 citations
Clinical trials of psychedelics for neurological and psychiatric disorders have systematically excluded people with past or current seizures, despite a lack of evidence that supervised psychedelic use causes or worsens seizures. No clinical trial or preclinical seizure model has shown that psychedelics induce seizures. This review presents cases where individuals experienced either seizures or seizure remission after psychedelic use, with the overall trend indicating safety in controlled clinical settings. The authors propose future research directions to include this population.
Frontiers in Pharmacology
January 1, 2013
Wendy K. Adams, Adam L. Halberstadt, Maarten Van den Buuse
11 citations
Blocking NMDA receptors with phencyclidine (PCP) can produce schizophrenia-like symptoms in humans, but PCP also affects other systems. Rats with serotonin-depleting lesions in the dorsal hippocampus showed increased hyperactivity from PCP but not from the more selective NMDA blocker MK-801. Lesions in the ventral hippocampus had no effect. PCP and MK-801 both made the rats' movement paths smoother and less predictable, but the dorsal hippocampus lesions did not alter these qualitative effects for PCP, though they slightly reduced MK-801's effect on unpredictability. The results reveal a functional difference between PCP and MK-801 related to serotonin in the dorsal hippocampus, relevant to schizophrenia research.