New psychoactive substances (NPSs) often emerge on the illicit drug market with limited pharmacological or toxicological data. Synthetic cathinones are the second largest NPS group, often mimicking the effects of classical stimulants such as cocaine and methylenedioxymethamphetamine (MDMA). Such stimulants primarily target dopamine (DAT), norepinephrine (NET) and serotonin (SERT) transporters,...
Fear-related psychiatric disorders such as phobias and anxiety are insufficiently treated by current therapies. Psychedelics targeting 5-HT₂A receptors show promise in modulating fear circuits, but their specific neurobiological substrates remain unclear. This study investigates the effects of 4-acetoxy-N,N-dimethyltryptamine (4-AcO-DMT), a psychedelic compound, on innate fear responses and...
Increasing interest in psychedelic and related drugs as potential therapies for a wide spectrum of difficult-to-treat conditions, that extend beyond neuropsychiatric disorders, provided the impetus for this themed issue. This collection of reviews and original articles includes the mechanistic basis of how these drugs act, the current status of preclinical research and progress in clinical...
Ketamine consists of two enantiomers, (R)-ketamine and (S)-ketamine, which exhibit distinct pharmacological properties. Currently, only the (S)-enantiomer has been approved for the treatment of major depressive disorder, whereas recent clinical studies have failed to demonstrate an antidepressant effect for (R)-ketamine. The quantitative electroencephalography (qEEG) gamma-enhancing effect of...
Abstract Background and Purpose New synthetic cannabinoid receptor agonists (SCRAs) are associated with severe adverse effects, including unexpected psychiatric symptoms. These compounds are mainly active through their potent agonism on the cannabinoid receptors CB 1 and CB 2 . Recently, evidence of the direct interaction of some SCRAs with the serotonergic 5‐HT receptors has emerged....
3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy, is a psychostimulant with entactogenic properties and known to induce arousal and euphoria. As an amphetamine derivate, MDMA acts on the monoamine systems in the brain and stimulates release of dopamine (DA), noradrenaline (NA) and serotonin (5-HT), yet their individual contributions in driving arousal and euphoria remain...
Chronic primary pain (CPP) persisting for more than 3 months, associated with significant emotional distress without any known underlying cause, is an unmet medical need. Traditional or adjuvant analgesics do not provide satisfactory pain relief for a great proportion of these patients. Therefore, identifying novel therapeutic targets and determining new treatments is important. In the present...
Legalisation of Cannabis use has led to considerable increases in the availability and potency of Cannabis products, as well as evolving patterns in methods of their consumption. Adolescent Cannabis use has increased, which can impair cognitive function during this critical developmental stage. The persistence of such effects into adulthood, however, is unclear. The present study examined...
The illicit drug 3,4-methylenedioxymethamphetamine (MDMA) has recently shown promising efficacy as an adjunct to psychotherapy for posttraumatic stress disorder (PTSD), although the underlying mechanisms are poorly defined. In this review, we contextualize the emergence of MDMA-assisted psychotherapy (MDMA-AT) within 20th century psychiatry and trace its journey from assisting with military...
Abstract Psychedelics have garnered great attention in recent years as treatments for major depressive disorder (MDD) and treatment‐resistant depression because of their ability to alter consciousness and afflicted cognitive processes with lasting effects. We aimed to characterise how psychedelics are currently being investigated to treat substance use disorders (SUDs). Additionally, we aimed...
Psychedelic drugs that activate 5-HT2A receptors have been long used for cultural, medicinal and recreational purposes. Interest in psychedelics for treating psychiatric disorders has resurged recently and is well documented; less well recognised are their anti-inflammatory properties. Growing evidence now demonstrates that psychedelics modulate immune responses, including inhibiting...
Serotonergic psychedelic drugs are under investigation as therapies for various psychiatric disorders, including major depression. Although serotonergic psychedelic drugs are 5-HT2A receptor agonists, some such agonists are not psychedelic, potentially due to differences in 5-HT2A receptor ligand bias or signalling efficacy. Here, we investigated 5-HT2A receptor signalling properties of...
Currently, the most actively investigated rapidly acting antidepressants, anxiolytics and/or anti PTSD agents, include psychedelics e.g. psilocybin, LSD, N , N ‐dimethyltryptamine, ayahuasca; non‐hallucinogenic entactogens, e.g. MDMA; psychoplastogens which rapidly promote neuroplasticity, e.g. ibogaine, ketamine and esketamine; and other atypicals e.g. dextromorphan/bupropion, esmethadone....
Psychedelic drugs such as LSD and psilocin were once relegated to the fringes of medical research because of their association with counterculture movements and a perceived concern about harm through recreational use, and their consequent legal prohibition in the early 1970s. However, these drugs are now experiencing a renaissance in the field of psychiatry based on increasing evidence that...
Non-selective NMDA receptor antagonism produces rapid symptom improvement in treatment-resistant depression; however, associated side effects necessitate medical oversight during administration. We hypothesised that selective GluN2A antagonism could provide similar efficacy with an improved side effect profile. Here, we report the pharmacology of JNJ-78911118, a brain-penetrant, GluN2A...
Abstract The past decade has seen a huge increase in clinical research with psychedelic drugs and 3,4‐methylenedioxymethamphetamine (MDMA), which have revealed great potential for treating mental health conditions. Given this progress in research, as well as the current unmet clinical need of millions of patients, in 2023, the Australian Therapeutic Goods Administration (TGA) approved the use...
The emerging antidepressant effects of ketamine have inspired tremendous interest in its underlying neurobiological mechanisms, although the involvement of 5-HT in the antidepressant effects of ketamine remains unclear. The chronic restraint stress procedure was performed to induce depression-like behaviours in mice. OFT, FST, TST, and NSFT tests were used to evaluate the antidepressant-like...
Abstract Psychedelic drugs are under active consideration for clinical use and have generated significant interest for their potential as anti‐nociceptive treatments for chronic pain, and for addressing conditions like depression, frequently co‐morbid with pain. This review primarily explores the utility of preclinical animal models in investigating the potential of psilocybin as an...
Psychedelic drugs have seen a resurgence in interest as a next generation of psychiatric medicines with potential as rapid-acting antidepressants (RAADs). Despite promising early clinical trials, the mechanisms which underlie the effects of psychedelics are poorly understood. For example, key questions such as whether antidepressant and psychedelic effects involve related or independent...
This brief review highlights some of the structure-activity relationships of classic serotonergic psychedelics. In particular, we discuss structural features of three chemotypes: phenethylamines, ergolines and certain tryptamines, which possess psychedelic activity in humans. Where they are known, we point out the underlying molecular mechanisms utilized by each of the three chemotypes of...
Background and Purpose Demand for new antidepressants has resulted in a re‐evaluation of the therapeutic potential of psychedelic drugs. Several tryptamines found in psilocybin‐containing “magic” mushrooms share chemical similarities with psilocybin. Early work suggests they may share biological targets. However, few studies have explored their pharmacological and behavioural effects....
Ayahuasca (AYA) is a botanical psychedelic with promising results in observational and small clinical trials for depression, trauma and drug use disorders. Its psychoactive effects primarily stem from N,N-dimethyltryptamine (DMT). However, there is a lack of research on how and where AYA acts in the brain. This study addressed these questions by examining the extinction of aversive memories in...
Abstract Substance use disorder (SUD) is a chronic condition, with maintained abuse of a substance leading to physiological and psychological alterations and often changes in cognitive and social behaviours. Current therapies include psychotherapy coupled with medication; however, high relapse rates reveal the shortcomings of these therapies. The signalling, expression profile, and neurological...
Background and purpose: Psychotic disorders have been reported in long-term users of synthetic cannabinoids. This study aims at investigating the long-lasting effects of repeated JWH-018 exposure. Experimental approach: Male CD-1 mice were injected with vehicle, JWH-018 (6 mg·kg-1 ), the CB1 -antagonist NESS-0327 (1 mg·kg-1 ) or co-administration of NESS-0327 and JWH-018, every day for 7 days....
British Journal of PharmacologyJune 1, 2023Mydirah Littlepage‐Saunders, Michael J. Hochstein, Doris S. Chang et al.5 citations
Dopamine transmission in the striatum is a critical mediator of the rewarding and reinforcing effects of commonly misused psychoactive drugs. G protein-coupled receptors (GPCRs) that bind a variety of neuromodulators including dopamine, endocannabinoids, acetylcholine and endogenous opioid peptides regulate dopamine release by acting on several components of dopaminergic circuitry. Striatal...