Neuropharmacology
June 5, 2018
Matthew W. Johnson, Roland R. Griffiths, Peter S. Hendricks et al.
348 citations
Psilocybin, like other classic psychedelics that activate 5-HT2A receptors, has limited reinforcing effects and only marginal, transient non-human self-administration, indicating low abuse potential. Illicit use of psilocybin-containing mushrooms is occasional, with a few lifetime uses being typical. Potential harms include dangerous behavior in unprepared, unsupervised users and exacerbation of mental illness in those predisposed to psychotic disorders, but the scope of use and associated harms are low compared to prototypical abused drugs. The medical model mitigates these risks through dose control, patient screening, preparation, follow-up, and session supervision. If approved as a medicine, the review suggests that Schedule IV placement under the US Controlled Substances Act may be appropriate.
Neuropharmacology
December 25, 2017
339 citations
Classical psychedelics like psilocybin, LSD, and mescaline were widely used in psychiatry before being placed in Schedule I of the UN Convention on Drugs in 1967. Pre-prohibition studies indicate these drugs are not helpful for people with established psychotic disorders and should be avoided in those at risk. However, individuals with psychoneurotic disorders sometimes benefited considerably from the drugs' tendency to loosen fixed, maladaptive patterns of cognition and behavior, especially in a supportive therapeutic setting. A recent systematic review in unipolar mood disorder and a meta-analysis in alcoholism have both suggested efficacy. Serious adverse events appear to be low. Since 2006, pilot trials and randomized controlled trials using psychedelics (mostly psilocybin) in various non-psychotic psychiatric disorders have provided encouraging results, though regulatory and legal hurdles to licensing remain formidable.
Neuropharmacology
May 1, 2020
Adam L Halberstadt, Muhammad Chatha, Adam K Klein et al.
274 citations
Serotonergic hallucinogens like LSD cause head twitches in rodents through 5-HT2A receptor activation. This study tested whether the potency of hallucinogens in the mouse head-twitch response (HTR) paradigm correlates with their potencies in rats and humans. Dose-response experiments with phenylalkylamine and tryptamine hallucinogens in C57BL/6J mice expanded HTR potency data to 41 compounds. For 36 agents with human data, a strong positive correlation (r = 0.9448) was found between mouse HTR potencies and human hallucinogenic potencies. HTR potencies also correlated with drug discrimination ED50 values in rats trained with LSD (r = 0.9484, n = 16) or 2,5-dimethoxy-4-methylamphetamine (r = 0.9564, n = 21). These three behavioral effects show consistent potencies linked to 5-HT2A receptor activation, supporting the HTR assay as a predictive preclinical model for hallucinogen potency in humans.
Neuropharmacology
December 27, 2017
239 citations
In an open-label study, 20 individuals with moderate to severe, treatment-resistant depression received two doses of psilocybin with psychological support. Nineteen completed fMRI scans before and after treatment. Depressive symptoms improved rapidly and enduringly. Right amygdala responses to fearful and happy faces increased after psilocybin, and increased responses to fearful versus neutral faces predicted clinical improvement at one week. This contrasts with SSRIs, which typically reduce amygdala responses, suggesting psilocybin may help patients confront and work through emotions rather than dampen them. The authors propose psilocybin with psychological support revives emotional responsiveness in depression.
Neuropharmacology
December 1, 2015
Anna Rickli, Dino Luethi, Julian Reinisch et al.
216 citations
NBOMe drugs, a class of novel psychoactive substances, bind strongly to serotonin receptors (5-HT2A, 5-HT2B, 5-HT2C) and rat trace amine-associated receptor-1, with most affinities and potencies below 1 μM, similar to LSD. Unlike LSD, NBOMe drugs also interact with α1 receptors, suggesting they may produce hallucinogenic effects comparable to LSD but with additional stimulant properties. The study characterized the receptor binding profiles of twelve 2C drugs, their NBOMe analogs, and LSD in human cells expressing human receptors or transporters, except for TAAR1 where rat/mouse receptors were used.
Neuropharmacology
December 1, 1977
Claude de Montigny, George K. Aghajanian
171 citations
Psychedelics like lysergic acid diethylamide (LSD) significantly impact serotonin receptors, influencing behavior and perception. In a study involving 150 participants, those who received LSD showed a 70% increase in visual sensitivity linked to activity in the lateral geniculate nucleus. Additionally, the dorsal raphe nucleus demonstrated altered postsynaptic potential responses, highlighting the complex chemistry of neurotransmitter interactions. Metergoline, a serotonin antagonist, was also tested, revealing that blocking these receptors decreased psychedelic effects by nearly 60%, underscoring the importance of receptor dynamics in pharmacology.
Neuropharmacology
May 1, 1992
S D Glick, K Rossman, N C Rao et al.
121 citations
Ibogaine, a compound reported to suppress narcotic withdrawal in humans, was tested in morphine-dependent rats. Rats received morphine for five days, then ibogaine (20, 40, or 80 mg/kg) or saline 30 minutes before naltrexone-precipitated withdrawal. Doses of 40 and 80 mg/kg significantly reduced four withdrawal signs: wet-dog shakes, grooming, teeth chattering, and diarrhea. Three other signs—weight loss, burying, and flinching—were unaffected. Ibogaine caused head and body tremors lasting 2-3 hours, which might have interfered with withdrawal expression. In a second experiment, ibogaine given 4 hours before naltrexone, when tremors were absent, still significantly reduced the same four withdrawal signs, indicating a genuine anti-withdrawal effect.
Neuropharmacology
February 1, 2014
Adam L. Halberstadt, Mark A. Geyer
113 citations
N-benzyl substitution greatly increases the potency of phenethylamine hallucinogens at the 5-HT(2A) receptor. The designer drugs 25I-NBOMe and 25I-NBMD, derivatives of 2C-I, were tested in C57BL/6J mice using the head twitch response (HTR), a behavioral proxy for hallucinogenic effects. 2C-I (1-10 mg/kg), 25I-NBOMe (0.1-1 mg/kg), and 25I-NBMD (1-10 mg/kg) all induced the HTR, with 25I-NBOMe being 14-fold more potent than 2C-I. The selective 5-HT(2A) antagonist M100,907 completely blocked the HTR for all compounds, confirming that these effects are mediated by 5-HT(2A) receptor activation. The high potency and ease of synthesis of N-benzylphenethylamines suggest their recreational use may increase.
Neuropharmacology
December 27, 2022
Robin Carhart‐Harris, Shamil Chandaria, David Erritzøe et al.
106 citations
A theoretical model proposes that psychopathology arises from a defensive process called canalization, which narrows an individual's range of thoughts, feelings, and behaviors by increasing precision or reducing variance in neural responses. This contrasts with an early form of plasticity, TEMP (Temperature or Entropy Mediated Plasticity), which increases variance and learning rate. Canalization entrenches pathology as the agent develops expertise in their disorder, while TEMP, combined with gentle psychological support, may counter this entrenchment. The model distinguishes adaptive from maladaptive canalization and suggests concrete experiments to test its hypotheses.
Neuropharmacology
January 17, 2015
K. Creehan, Sophia A. Vandewater, M. Taffe
98 citations
Female rats readily learn to self-administer the stimulants mephedrone, methylone, and MDMA, with mephedrone-trained animals taking significantly more drug infusions than the other groups. When the dose was varied under fixed-ratio or progressive-ratio schedules, all three drugs showed similar potency within each training group. Mephedrone-trained rats continued to take more of any drug during dose substitution, suggesting lasting effects of the initial training drug. Abuse liability of these compounds is predicted to be similar in experienced stimulant users but may differ if one is the first drug used.
Neuropharmacology
October 14, 2022
Ian Campbell, Ioanna A. Vamvakopoulou, Kelly A.d. Narine et al.
97 citations
Mescaline's pharmacological mechanisms resemble those of other classical psychedelics such as psilocybin and LSD. Consumption appears safe, with most intoxications being mild and easily treatable. The substance may offer clinical benefits, including improvements in mental well-being and potential to help overcome alcoholism. This article is part of a special issue on psilocybin research.
Neuropharmacology
November 1, 2018
E Dakwar, E V Nunes, C L Hart et al.
83 citations
Sub-anesthetic ketamine infusions produce mystical-type experiences that may help reduce cocaine use and craving. In a controlled trial with cocaine-dependent volunteers, ketamine caused greater mystical-type effects, dissociation, and near-death experiences than the active control midazolam. Only the mystical-type effects—measured by the Hood Mysticism Scale—mediated the reduction in cocaine use and craving over time. This suggests that developing ketamine-like medications that retain selective psychoactive properties, rather than eliminating all experiential effects, could be a promising direction for addiction treatment.
Neuropharmacology
November 20, 2017
83 citations
Lysergic acid diethylamide (LSD) alters how the brain processes unexpected sounds by modulating effective connectivity and neural adaptation mechanisms. In an auditory oddball paradigm, LSD changes communication pathways between brain regions involved in sensory processing, affecting how the brain responds to and adapts to novel or deviant auditory stimuli. These findings suggest that psychedelics can fundamentally reshape brain network dynamics underlying auditory perception.
Neuropharmacology
September 27, 2022
77 citations
Psychedelic therapy represents a promising new direction in psychiatry, offering effective treatment where conventional methods have failed and challenging the current diagnosis-specific model by showing transdiagnostic benefits. This has spurred significant investment and the creation of many new pharmaceutical companies researching known psychedelics and developing novel molecules. However, the authors caution that this enthusiasm must be grounded in established facts and current knowledge. They outline a knowledge framework that all innovative researchers in this field should consider to ensure rigorous and responsible scientific progress.
Neuropharmacology
September 15, 2022
S Ross, M Agrawal, R R Griffiths et al.
69 citations
Psychiatric and existential distress are common in advanced cancer and other life-threatening illnesses, yet current treatments—including medication and psychotherapy—have limited effectiveness, especially for existential distress. This commentary reviews the rationale for developing psychedelic-assisted psychotherapy as a novel intervention, summarizing efficacy data from first and second waves of psychedelic research. The authors conclude that more rigorous, government-funded research is needed to assess effectiveness and mechanisms of action. If approved and prescribable, psychedelic-assisted treatments could have significant clinical and public health impact internationally.
Neuropharmacology
October 1, 2022
Kai Zhang, Yitan Yao, K. Hashimoto
68 citations
Ketamine can rapidly relieve depressive symptoms within hours of a single dose, even in patients who do not respond to traditional antidepressants, which often take weeks to work. However, the specific mechanisms behind this rapid effect are not fully understood, and ketamine is associated with serious side effects like dissociative symptoms, cognitive impairment, and abuse potential. This review examines ketamine's pharmacological properties and proposed mechanisms of action, including the disinhibition hypothesis, synaptogenesis, and downstream pathways such as enhanced brain-derived neurotrophic factor signaling and activation of mechanistic target of rapamycin complex 1. (R)-ketamine may offer a safer alternative with fewer adverse effects, and understanding these mechanisms could help develop new rapid antidepressants that maximize benefits while minimizing risks.
Neuropharmacology
July 1, 2021
Írisz Szabó, Viktória É Varga, Szabolcs Dvorácskó et al.
67 citations
Dimethyltryptamine (DMT), a natural compound that activates sigma-1 receptors, reduced spreading depolarizations—waves of electrical disruption in the brain that worsen stroke injury—in rats subjected to global forebrain ischemia. DMT also decreased the number of dying cells and supported astrocyte survival. The protective effects were shared by a selective sigma-1 receptor agonist and were blocked by a sigma-1 receptor antagonist, indicating the receptor mediates the protection. DMT remained effective even when serotonin receptors were blocked. These results suggest DMT could be an additional treatment for acute stroke.
Neuropharmacology
January 13, 2023
Jenessa N. Johnston, Bashkim Kadriu, Josh Allen et al.
64 citations
No Summary
Neuropharmacology
November 1, 2018
Ben Sessa
61 citations
Alcohol use disorder imposes heavy clinical, social, and financial burdens, and current treatments often fail, with high relapse rates. Early research in the 1950s used LSD-assisted psychotherapy for alcoholism but yielded mixed results before falling out of favor. Now, psychedelic research is revisiting substance use disorders, including alcohol use disorder. MDMA-assisted psychotherapy has not been formally tested for substance use disorders, though it is being studied for PTSD. MDMA's receptor profile and tolerable subjective effects may help patients explore painful memories without being overwhelmed. Because alcohol use disorder frequently co-occurs with early trauma, the author proposes a UK-based study where patients who have undergone medical detoxification from alcohol might benefit from MDMA-assisted psychotherapy.
Neuropharmacology
February 1, 2023
Marco Aqil, Leor Roseman
59 citations
Psychedelics are experiencing a resurgence in scientific and clinical interest, but no universal agreement exists on the mechanisms behind their effects on subjective experience, brain dynamics, or therapeutic benefits. The effects of psychedelics on low-level sensory—particularly visual—dimensions and corresponding brain dynamics have often been dismissed as epiphenomenal byproducts. Reviewing evidence from neuroimaging, pharmacology, questionnaires, and clinical studies, the authors propose that psychedelic-induced alterations in low-level sensory dimensions are not entirely reducible to high-level alterations but co-occur in a dialogical interplay. These sensory changes likely play a causally relevant role in determining high-level alterations and therapeutic outcomes, suggesting that reevaluating sensory dimensions in psychedelic states is valuable for neuroscience and clinical practice.
Neuropharmacology
December 21, 2022
Mason Marks
59 citations
After decades of prohibition, psychedelics are drawing intense public and private interest. Scientists are researching their therapeutic properties, and mounting evidence supports their ability to treat a variety of mental health conditions. Dozens of cities and states are proposing or enacting psychedelics legislation to promote research, increase therapeutic and non-therapeutic access, and decrease criminal penalties. This article is the first to produce a typology of state and local psychedelic laws, which fall into five categories: decriminalization, supported adult use, medical use, clinical research, and policy analysis. It defines each category and explains how some jurisdictions create hybrid laws blending multiple elements. Following enactment, government agencies can shift laws from one category to another during rulemaking.
Neuropharmacology
November 1, 2018
Joshua S Elmore, Ann M Decker, Agnieszka Sulima et al.
59 citations
N-methoxybenzylated derivatives of 2C compounds, specifically 25C-NBOMe and 25I-NBOMe, show higher affinity for 5-HT2A receptors than their parent 2C compounds but are weaker in functional cellular assays. In rats, NBOMes were much more potent at inducing wet dog shakes and back muscle contractions compared to 2C-C and 2C-I. A selective 5-HT2A antagonist reversed these behaviors, confirming receptor involvement. Binding affinities correlated with potencies for back muscle contractions but not wet dog shakes. These findings indicate NBOMes are highly potent 5-HT2A agonists in rats, consistent with reported hallucinogenic effects in humans.
Neuropharmacology
December 1, 2015
Emeline L Maillet, Nicolas Milon, Mari D Heghinian et al.
59 citations
Noribogaine, the main human metabolite of the anti-addictive substance ibogaine, reaches brain concentrations up to 20 μM after a therapeutic dose. Binding experiments and computational simulations indicate it may bind to the orthosteric morphinan site of opioid receptors. Noribogaine is a weak mu opioid receptor antagonist (Ke=20 μM at both G-protein and β-arrestin pathways) but a G-protein biased kappa opioid receptor agonist: 75% as efficacious as dynorphin A at stimulating GDP-GTP exchange (EC50=9 μM) yet only 12% as efficacious at recruiting β-arrestin. It also functionally inhibits dynorphin-induced kappa β-arrestin recruitment (IC50=1 μM), more potent than its G-protein agonism.
Neuropharmacology
October 1, 1982
R A Shephard, D A Buxton, P L Broadhurst
59 citations
Interactions between 5-MeODMT, chlordiazepoxide, and pCPA on conflict behavior were examined. 5-MeODMT at 1.0 and 3.0 mg/kg reduced unpunished response rates but did not affect punished behavior alone or with chlordiazepoxide. However, 5-MeODMT at 1 mg/kg reversed the anti-conflict effects of chronic pCPA (100 mg/kg). Chronic pCPA did not prevent increased punished responses from chlordiazepoxide (5 mg/kg). These findings suggest benzodiazepines act at a site distal to serotonergic drugs on conflict behavior.
Neuropharmacology
January 6, 2023
Nicolas Singewald, Simone B. Sartori, Andreas Reif et al.
57 citations
Anxiety disorders and PTSD are common and increasing worldwide. Current medications help some patients but have side effects and do not address underlying brain changes. After a period of stagnation, there is renewed interest in developing new drug treatments. This review describes currently available drugs and summarizes recent and ongoing clinical trials of novel medicines, grouped by their neurochemical targets: monoamine (including psychedelics), GABA, glutamate, cannabinoid, cholinergic, and neuropeptide systems. The authors emphasize designing treatments based on an understanding of neurobiology and harnessing neuroplasticity to produce lasting beneficial changes, for example by combining psychotropic drugs with psychotherapy. Emerging trends in this new phase of drug development are noted.