ACS Pharmacology & Translational Science
December 10, 2020
328 citations
Psychedelics are promising experimental medicines for neuropsychiatric disorders because they can rapidly and sustainably promote neural plasticity after a single dose. While peak mystical experiences are often considered essential to their therapeutic effects, the evidence is mostly correlational. New data suggest that subjective psychedelic effects may not be required for lasting changes in mood and behavior. Clarifying the role of these subjective effects will inform basic neuroscience and help expand patient access to future psychedelic-derived treatments.
ACS Pharmacology & Translational Science
August 31, 2020
Nadia R. P. W. Hutten, Natasha L. Mason, Patrick C. Dolder et al.
134 citations
Low doses of LSD (5, 10, and 20 μg) increase brain-derived neurotrophic factor (BDNF) levels in blood plasma, a marker of neuroplasticity. In a placebo-controlled within-subject study with healthy volunteers, BDNF levels rose at 4 hours after 5 μg and at 6 hours after both 5 and 20 μg, compared to placebo. This suggests that even low doses of LSD can acutely enhance neuroplasticity, supporting further research in patient populations for psychiatric conditions.
ACS Pharmacology & Translational Science
March 18, 2021
Stephen Ross, Gabrielle Agin-Liebes, Sharon L. Lo et al.
133 citations
People with advanced cancer face elevated risks of desire for hastened death, suicidal ideation, and completed suicide. Loss of meaning, a component of demoralization, predicts these outcomes. In a randomized controlled trial, psilocybin-assisted psychotherapy produced rapid and sustained improvements in depression, demoralization, and hopelessness. Secondary analyses showed that among participants with elevated suicidal ideation at baseline, reductions in suicidal ideation appeared as early as 8 hours and persisted for 6.5 months. Large reductions in loss of meaning emerged 2 weeks after treatment and remained significant at 6.5 months and at 3.2 and 4.5 year follow-ups. The findings suggest psilocybin-assisted psychotherapy may be an effective antisuicidal intervention for cancer patients due to its positive impact on hopelessness and meaning-making.
ACS Pharmacology & Translational Science
December 14, 2020
Adam K. Klein, Muhammad Chatha, Lauren J. Laskowski et al.
103 citations
The 5-HT2A receptor is the primary target for psilocybin and other serotonergic hallucinogens. Seventeen tryptamines with 4-hydroxy or 4-acetoxy groups and various N,N-dialkyl substituents were tested. All acted as full or partial agonists at 5-HT2 subtypes, with similar potencies at 5-HT2A and 5-HT2B receptors, though bulkier N-alkyl groups reduced potency at 5-HT2C receptors and increased 5-HT2B efficacy. O-acetylation reduced in vitro 5-HT2A potency by 10- to 20-fold without altering efficacy. All compounds induced head twitches in mice, consistent with LSD-like effects. Acetylation had little effect on head-twitch potency, suggesting O-acetylated tryptamines may act as prodrugs deacetylated in vivo. These derivatives have psilocybin-like properties, supporting their classification as psychedelic drugs.
ACS Pharmacology & Translational Science
May 4, 2021
James W. Sanders, Josjan Zijlmans
94 citations
The mysticism framework, often used to characterize psychedelic experiences and explain therapeutic outcomes, carries risks because it is tied to supernatural or nonempirical belief systems. The authors encourage researchers to adopt a demystified model of the psychedelic state to mitigate these risks.
ACS Pharmacology & Translational Science
November 2, 2022
Eline Pottie, Marilyn Naeem, Vamshikrishna Reddy Sammeta et al.
91 citations
Psilocybin is a prodrug for psilocin, which produces psychedelic effects by activating serotonin 5-HT2A receptors. This study examined three naturally occurring compounds from psilocybin-containing mushrooms—psilocybin, baeocystin, and aeruginascin—along with their synthetic 4-acetoxy and 4-hydroxy analogues. In cell-based assays, secondary and tertiary tryptamines with 4-acetoxy or 4-hydroxy substitutions showed nanomolar affinity for several human serotonin receptor subtypes, including 5-HT2A and 5-HT1A. In mice, only the tertiary amines psilocin, psilocybin, and psilacetin induced head twitch responses (ED50 0.11–0.29 mg/kg), indicating psychedelic-like activity, which was blocked by a 5-HT2A antagonist.
ACS Pharmacology & Translational Science
December 29, 2020
Justin C. Strickland, Albert Garcia‐romeu, Matthew W. Johnson
89 citations
The musical genre played during psilocybin sessions may influence mystical experiences and smoking cessation outcomes. In a small study of ten participants receiving psilocybin for tobacco smoking cessation, overtone-based music led to higher mystical experience scores than Western classical music. Six of ten participants chose overtone-based music for a third session. Biologically confirmed smoking abstinence was 66.7% for those choosing overtone-based playlists versus 50% for Western classical. These results question the assumed unique benefit of Western classical music typically used in psychedelic therapy and support further experimental examination of session components.
ACS Pharmacology & Translational Science
July 16, 2021
69 citations
The authors argue that the concept of mystical experience should remain central to psychedelic science, countering a recent call to abandon it. They emphasize the need to recognize the diversity and strangeness of psychedelic experiences, drawing on a rich tradition and scientific tools for studying mystical-type experiences. These experiences are relevant for understanding the therapeutic effects of psychedelics. The authors also call for greater diversity in both the types of experiences and the participants included in future research.
ACS Pharmacology & Translational Science
December 9, 2020
Christopher S. Stauffer, B. Anderson, Kile Ortigo et al.
65 citations
Attachment insecurity, measured as anxiety and avoidance, is an early-life risk factor for psychopathology. Psilocybin-assisted psychotherapy may reduce attachment anxiety. In a study of 18 male long-term AIDS survivors with moderate-severe demoralization, attachment anxiety decreased significantly from baseline to three months after a single psilocybin session embedded in group therapy. Attachment avoidance did not change. Higher baseline attachment anxiety predicted stronger mystical-type experiences during the psilocybin session, while higher baseline attachment avoidance predicted more challenging experiences. These results suggest that psilocybin-assisted psychotherapy could be optimized by considering individual attachment styles.
ACS Pharmacology & Translational Science
March 11, 2021
Richard J. Zeifman, Nikhita Singhal, Leah Breslow et al.
60 citations
Classic psychedelics such as psilocybin, ayahuasca, and LSD are being used more often and studied as a potential mental health treatment. Suicidality is a safety concern with these substances, yet they may also help reduce suicidal thoughts. A systematic review of 64 articles found mixed results for non-clinical use: some studies showed positive, negative, or no link between lifetime psychedelic use and suicidality. Early psychedelic therapy had some suicide cases, but it was unclear if therapy caused them. Recent clinical trials found no increased suicidality and preliminary evidence for acute and sustained decreases after treatment.
ACS Pharmacology & Translational Science
January 1, 2021
Konstantin Gerber, Inti García Flores, Angela Christina Ruiz et al.
54 citations
Since a 1957 Life Magazine article, chemical compounds from Psilocybe mushrooms have been the subject of many patent attempts, including recent ones for treating depression. The Mazatec indigenous communities, who have used these traditional medicines for millennia, are not included in any of these patents, despite international treaties that recognize indigenous rights to their intangible cultural heritage.
ACS Pharmacology & Translational Science
August 2, 2023
Zarmeen Zahid, Zhen Zheng, N. Jones et al.
50 citations
Psilocybin reduces anxiety-like behavior in male mice four hours after treatment, an effect that depends on a temporary spike in the stress hormone corticosterone. Blocking the corticosterone rise or the glucocorticoid receptor eliminated the short-term anxiolytic effect. A nonpsychedelic drug that also raised corticosterone produced similar anxiety reduction, as did stress-induced hormone release alone. The anxiolytic effect lasted seven days after a single psilocybin dose, but this long-term benefit was lost in mice with chronically elevated corticosterone. The findings suggest that an acute, resolvable glucocorticoid surge is necessary for psilocybin's postacute anxiety relief, while chronic stress hormone elevation undermines its lasting effects.
ACS Pharmacology & Translational Science
March 10, 2023
Marilyn Naeem, Grant C. Glatfelter, Duyen N. K. Pham et al.
25 citations
Tryptamine psychedelics structurally related to psilocybin, including those with variations at the 4-position (hydroxy, acetoxy, propionoxy) and N,N-dialkyl substitutions, primarily target multiple serotonin receptors, especially 5-HT2A and 5-HT1A. 4-Acetoxy and 4-propionoxy analogues show somewhat weaker binding affinities but similar target profiles across serotonin receptors. Variations in N,N-dialkyl groups produce differential binding at non-serotonin targets such as alpha and dopamine receptors, histamine receptors, and serotonin transporters. In mice, 4-PrO-DMT produces dose-related psilocybin-like effects: 5-HT2A-mediated head twitch response at 0.3-3 mg/kg and 5-HT1A-mediated hypothermia and reduced locomotion at 3-30 mg/kg. Data indicate that 5-HT2A-mediated head twitch response is attenuated by 5-HT1A agonist activity at high doses.
ACS Pharmacology & Translational Science
December 29, 2020
Michael B. Gatch, Adam C. Hoch, Theresa M. Carbonaro
13 citations
Eight novel substituted tryptamines produced hallucinogen-like effects in rats trained to discriminate the hallucinogen DOM from saline. All compounds fully substituted for DOM, with potencies equal to or less than DOM. Four compounds—4-OH-MET, 4-OH-DET, 4-OH-DMT, and 4-AcO-DMT—reduced response rates at fully substituting doses. Because these compounds mimic DOM's discriminative stimulus effects, they may carry similar abuse liability. 4-Acetoxy substituted compounds were less potent than 4-hydroxy ones, and N,N-diisopropyl compounds were less potent than those with dimethyl, diethyl, N-methyl-N-ethyl, or N-methyl-N-isopropyl groups.
ACS Pharmacology & Translational Science
March 7, 2025
Shuai Hu, Cong Lin, Hongshuang Wang et al.
8 citations
Psychedelics such as psilocybin and MDMA show promise for treating anorexia nervosa by disrupting maladaptive neural circuits, enhancing cognitive flexibility, and facilitating emotional processing. Early studies report reductions in symptoms and improvements in psychological well-being, particularly for patients unresponsive to conventional therapies like cognitive-behavioral therapy and pharmacotherapy. However, further research is needed to establish long-term safety, efficacy, and clinical integration, and to address legal, ethical, and safety challenges.
ACS Pharmacology & Translational Science
February 10, 2025
Xue Wang, Cong Lin, Xiaohui Wang
5 citations
Psychedelics like LSD, psilocybin, and MDMA may enhance pro-social behaviors in people with autism spectrum disorders by altering brain circuits involved in social cognition. The viewpoint discusses potential mechanisms underlying these effects, such as increased neuroplasticity and changes in serotonin receptor activity. While direct evidence in ASD populations is limited, the authors suggest that these compounds could offer new therapeutic avenues for improving social interaction and communication deficits. The paper calls for further research to explore the safety and efficacy of psychedelic-assisted therapy for autism, emphasizing the need for controlled clinical trials.
ACS Pharmacology & Translational Science
September 18, 2023
Richa Tyagi, Tanishka S. Saraf, Clinton E. Canal
5 citations
A psychedelic tryptamine, DPT, completely prevented sound-induced seizures in a mouse model of fragile X syndrome at a 10 mg/kg dose but not at lower doses. Although DPT activates several serotonin receptors in the lab, blocking those receptors did not stop its anti-seizure effect, nor did blocking sigma1 receptors. The anti-seizure action appears independent of DPT's psychedelic properties. However, high doses of DPT caused convulsions on their own, indicating complex, dose-dependent effects.
ACS Pharmacology & Translational Science
August 22, 2025
Devin P. Effinger, Serena S. Schalk, Jillian L. King et al.
3 citations
Microdosing involves taking psychedelics at doses too low to cause hallucinations, and is popular for supposed cognitive and emotional benefits. Psychedelics bind strongly to 5-HT 2B receptors, which can cause heart disease when chronically activated. In mice, researchers gave either serotonin or d-fenfluramine as positive controls, or low doses of LSD. Serotonin caused significant ventricular thickening at 4 and 8 weeks; d-fenfluramine caused aortic valve regurgitation at 4 weeks. No significant heart changes appeared in any LSD group. LSD, psilocybin, and norfenfluramine had similar affinity and potency at mouse and human 5-HT 2B receptors. Low-dose LSD produced substantial but short-lived receptor activation compared to d-fenfluramine. These data provide no evidence that prolonged low-dose LSD causes heart remodeling in mice.
ACS Pharmacology & Translational Science
July 16, 2025
Tobías Fernández‐borkel, Lucas F. Borkel, Jaime Rojas‐hernández et al.
3 citations
A proposed randomized controlled trial aims to determine whether the subjective psychedelic experience caused by psilocybin is necessary for its antidepressant effects in treatment-resistant depression, or whether neurobiological actions alone suffice. The protocol compares three groups: psilocybin while conscious, psilocybin under propofol-induced general anesthesia (which eliminates subjective experience), and anesthesia with placebo. Clinical assessments and fMRI measures of brain connectivity will be collected. The authors hypothesize that the conscious psilocybin group will show superior improvements in depression and anxiety, and that increased brain fractal complexity and entropy will correlate with therapeutic gains. The results could clarify the causal role of conscious experience in psychedelic therapy.
ACS Pharmacology & Translational Science
May 29, 2025
Meghan Hibicke, Erik Kaadt, Emil Märcher-Rørsted et al.
3 citations
A new compound, LPH-5, acts as a potent partial agonist at the 5-HT2A receptor with high selectivity over related 5-HT2B and 5-HT2C receptors. In rats, LPH-5 induced head-twitch responses and produced both acute and persistent antidepressant-like effects. These findings suggest that selective activation of the 5-HT2A receptor alone can produce antidepressant effects, indicating that this receptor is a key component in the therapeutic action of classical psychedelics like psilocybin and LSD.
ACS Pharmacology & Translational Science
May 15, 2025
Haojiang Zhai, Hongshuang Wang, Haohong Li et al.
3 citations
Psychedelics like psilocybin, LSD, and DMT may alter sleep architecture, particularly by influencing rapid eye movement (REM) sleep and vivid dreaming. This viewpoint suggests these substances could have therapeutic potential for sleep disorders, though their impact on sleep remains underexplored. The authors provide a perspective on how psychedelics might affect sleep phases and dreaming, opening an emerging area for sleep therapy.
ACS Pharmacology & Translational Science
September 11, 2025
Noelle Cataldo, John A. Razidlo, Cody J. Wenthur
2 citations
Psilocybin, a serotonergic psychedelic, enhanced fear extinction and improved extinction recall 24 hours later in male mice, regardless of whether they were stress-naïve or had been exposed to acute or chronic stress beforehand. Psilocybin transiently increased the stress hormone corticosterone in stress-naïve mice but not in previously stressed animals. The findings suggest psilocybin can promote fear extinction across different stress backgrounds, supporting its potential therapeutic relevance for disorders like PTSD where prior stress is a key factor.
ACS Pharmacology & Translational Science
July 8, 2025
Miyuan Zhang, Haiyan Zhai, Liu Yang et al.
1 citation
Psilocin, the active metabolite of psilocybin, induces psychedelic-like behavior in male mice by activating neurons in the medial prefrontal cortex (mPFC). Using c-Fos immunofluorescent labeling, the mPFC was the only brain region among several tested that was specifically associated with the head twitch response (HTR), a behavioral marker of psychedelic activity. A picomolar dose of psilocin directly into the mPFC triggered significant HTR. Optogenetic activation of these neurons increased spontaneous HTR, while acute inhibition suppressed drug-induced HTR. The findings establish the mPFC as a critical regulator of psilocin's psychedelic effects, offering insights for improving the clinical safety and therapeutic use of psychedelics.
ACS Pharmacology & Translational Science
April 14, 2026
Abhishek Gupta, Tuhin Bhattacharya, Subhamoy Pratihar et al.
Iboga alkaloids can reverse drug addiction and modulate drug tolerance, but their use is limited by severe psychedelic effects and cardiotoxicity from hERG potassium channel blockade. Researchers synthesized four modified ibogaine/ibogamine analogs (C1–C4) with a benzofuran moiety replacing the indole scaffold. Among these, the Endo-iboga analogs C2 and C4 showed notable anti-inflammatory and oxidative stress-relieving activity and improved restricted locomotor activity in a formalin-induced acute pain model in mice. C4 exhibited superior cytocompatibility (IC50 = 235 μM in C2C12 cells), no significant QTc prolongation in rat ECG tests, and the lowest hERG blockade risk (IC50 = 21.25 ± 4.89 μM). C4 acted as a potent KOR agonist and MOR antagonist, with weak 5HT2A agonist and σ1 antagonist activity, suggesting potential for acute pain management without notable cardiotoxicity.