ACS Pharmacology & Translational Science
December 10, 2020
David E. Olson
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
September 11, 2020
Calvin Ly, Alexandra C. Greb, Maxemiliano V. Vargas et al.
127 citations
Cortical neuron atrophy, including neurite retraction and spine loss, is a hallmark of depression. Psychoplastogens are small molecules hypothesized to reverse these changes. Ketamine and LSD, from two structurally distinct chemical classes, promote sustained growth of cortical neurons after brief stimulation. This growth occurs in two phases: an initial stimulation phase requiring TrkB activation, followed by a growth period needing sustained mTOR and AMPA receptor activation. These temporal details suggest that rapidly excreted psychoplastogens could be effective neurotherapeutics with advantages over ketamine and LSD.
ACS Pharmacology & Translational Science
April 9, 2021
Gabrielle Agin-Liebes, Trevor F Haas, Rafael Lancelotta et al.
121 citations
Most people who used mescaline in natural settings reported lasting improvements in depression, anxiety, PTSD, and substance use disorders, with 68–86% of those with a history of these conditions noting subjective improvement after their most memorable experience. Those who improved reported stronger acute mystical-type, psychological insight, and ego dissolution effects (Cohen's d 0.7–1.5). For 35–50% of respondents, the mescaline experience ranked among the top five most spiritually significant or meaningful events of their lives. Psychological insight during the experience was linked to higher odds of improvement in depression, anxiety, and alcohol and drug use disorders. The authors call for controlled clinical trials to confirm these preliminary findings.
ACS Pharmacology & Translational Science
April 9, 2021
Matthew W. Johnson
109 citations
A viewpoint article outlines three major pitfalls in psychedelic research that could hinder their medical use: imprecise use of the term "consciousness," the inappropriate introduction of investigators' or clinicians' religious or spiritual beliefs, and ethical challenges related to clinical boundaries in psychedelic treatments.
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
Joost J. Breeksema, Michiel van Elk
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
April 9, 2021
Thomas W. Flanagan, Gerald Billac, Alexus N. Landry et al.
50 citations
Psychedelic drugs can reduce inflammation, but this effect does not depend on their mind-altering properties. By testing 21 different 5-HT2A receptor agonists in a rat model of allergic asthma, the drug 2,5-dimethoxyphenethylamine (2C-H) was identified as the key structure for anti-inflammatory activity. Specific chemical modifications either enabled or blocked this effect. No link was found between a drug's ability to trigger calcium signaling (a standard measure of receptor activation) and its ability to prevent asthma symptoms or produce behavioral effects. This suggests that anti-inflammatory benefits arise from distinct receptor pathways, not the canonical signaling pathway. These findings could guide development of non-psychoactive anti-inflammatory drugs targeting the 5-HT2A receptor.
ACS Pharmacology & Translational Science
April 9, 2021
Shreyas Bhat, Daryl A. Guthrie, Ameya Kasture et al.
37 citations
Protein misfolding caused by missense mutations is rare but collectively leads to serious folding diseases. Ibogaine and noribogaine can correct folding defects in the dopamine transporter (DAT) but rescue only a limited number of DAT mutants linked to infantile Parkinsonism and dystonia. By reconfiguring the ibogaine ring system, a series of analogs were generated and tested for binding to wild-type transporters and for rescuing two synthetic folding-deficient mutants. The most active tropane-based analog (9b) acted as an effective pharmacochaperone in vivo in Drosophila carrying a DAT mutation and rescued 6 out of 13 disease-associated human DAT mutant proteins in vitro, identifying a novel lead compound with potential for medication development for patients with DAT mutations.
ACS Pharmacology & Translational Science
March 8, 2024
Grant C. Glatfelter, Eline Pottie, John S. Partilla et al.
28 citations
Lisuride, a non-psychedelic analogue of LSD, lacks psychedelic effects because it acts as a partial agonist at the 5-HT2A receptor and a potent agonist at the 5-HT1A receptor, which counteracts psychedelic activity. In vitro, LSD strongly activated 5-HT2A signaling, while lisuride showed only partial efficacy (6-52% of maximum) and blocked LSD's effects. In male mice, LSD caused head twitch responses (a behavioral marker of psychedelic action), whereas lisuride suppressed these responses and induced hypothermia and reduced movement. Blocking the 5-HT1A receptor restored baseline head twitches but did not increase them above normal, indicating that lisuride's lack of psychedelic effects stems from its partial agonist-antagonist activity at 5-HT2A, not solely from 5-HT1A activation.
ACS Pharmacology & Translational Science
April 9, 2021
Joaquín González, Matías Cavelli, Santiago Castro-Zaballa et al.
26 citations
Ibogaine, a psychedelic alkaloid with anti-addictive potential, produces vivid, dream-like experiences while awake. Analyzing intracranial electroencephalograms in rats, ibogaine-induced wakefulness showed gamma oscillations with greater power than control levels but reduced coherence and complexity. This gamma activity profile resembled that of natural REM sleep, providing biological evidence linking the psychedelic state to REM sleep and advancing understanding of ibogaine's oneirogenic 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
June 14, 2024
Richard A Glennon, Małgorzata Dukat
21 citations
The compound DOI, first synthesized in 1973, is a serotonin receptor agonist, specifically acting at 5-HT2 receptors in rat and human brain. It emerged from research on hallucinogenic agents and is now studied for potential therapeutic use in neuropsychiatric disorders such as treatment-resistant depression. This review traces the historical and current developments that made DOI a landmark agent in 5-HT2 receptor research.
ACS Pharmacology & Translational Science
January 25, 2024
Thomas W. Flanagan, Timothy P. Foster, Thomas E. Galbato et al.
18 citations
Two psychedelic compounds, (R)-DOI and (R)-DOTFM, both activate the serotonin 2A receptor with comparable in vitro activity and behavioral potency, yet only (R)-DOI prevents inflammation and airway hyperresponsiveness in a mouse model of asthma. The compounds produce distinct differences in protein expression and inflammatory-related gene expression in lung tissue. The anti-inflammatory effects of certain psychedelics involve suppression of arginase 1 expression, revealing key mechanistic components of their anti-inflammatory action.
ACS Pharmacology & Translational Science
April 8, 2022
Grant C. Glatfelter, Michael R. Chojnacki, Shelby A. McGriff et al.
18 citations
A simple, noninvasive method using computer analysis of video recordings accurately measures the head twitch response (HTR) in mice, a behavioral proxy for psychedelic drug effects in humans. Male mice injected with the 5-HT2 receptor agonist DOI showed dose-related increases in HTRs (0.03–3 mg/kg), which were blocked by the 5-HT2A antagonist M100907. Computer scoring closely matched visual scoring by trained observers, captured nearly all HTRs, and produced few false positives from behaviors like grooming. Optimizing lighting improved results. This method offers a reliable, surgery-free alternative for studying psychedelic-like activity.
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
July 11, 2025
Zahira Ziva Cohen, Grace Blest‐hopley
9 citations
Ovarian hormone fluctuations, particularly estradiol and progesterone, modulate neurotransmitter systems involved in psychedelic pharmacology, including serotonin, dopamine, GABA, and glutamate. These hormonal changes across the menstrual cycle influence 5-HT2A receptor expression and functional connectivity, potentially affecting both the subjective intensity and therapeutic efficacy of psychedelics. The paper argues that incorporating menstrual phase tracking and hormonal assays into clinical trials and observational studies can reduce data variability, support individualized care, and improve informed consent practices for women. A better understanding of the interplay between female-specific biology and psychedelic pharmacodynamics is needed to advance safe, ethical, and effective therapies.