Ketamine, a channel blocking NMDA receptor antagonist, is used off-label for its psychedelic effects, which may arise from a combination of several inter-related actions. Firstly, reductions of the contribution of NMDA receptors to afferent information from external and internal sensory inputs may distort sensations and their processing in higher brain centres. Secondly, reductions of NMDA receptor-mediated excitation of GABAergic interneurons can result in glutamatergic overactivity. Thirdly, limbic cortical disinhibition may indirectly enhance dopaminergic and serotonergic activity. Fourthly, inhibition of NMDA receptor mediated synaptic plasticity, such as short-term potentiation (STP) and long-term potentiation (LTP), could lead to distorted memories. Here, for the first time, we compared quantitatively the effects of ketamine on STP and LTP. We report that ketamine inhibits STP in a double sigmoidal fashion with low (40 nM) and high (5.6 μM) IC50 values. In contrast, ketamine inhibits LTP in a single sigmoidal manner (IC50 value ∼ 15 μM). A GluN2D-subunit preferring NMDA receptor antagonist, UBP145, has a similar pharmacological profile. We propose that the psychedelic effects of ketamine may involve the inhibition of STP and, potentially, associated forms of working memory. This article is part of the Special Issue entitled ‘Psychedelics: New Doors, Altered Perceptions’. Keywords: GluN2D subunit; Ketamine; LTP; Long-term potentiation; Memory; NMDA receptors; PCP; Phencyclidine; Psychedelics; STP; Short-term potentiation; Working memory.
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DMT Models the Near-Death Experience
Near-death experiences (NDEs) are complex subjective experiences, which have been previously associated with the psychedelic experience and more specifically with the experience induced by the potent serotonergic, N,N-Dimethyltryptamine (DMT). Potential similarities between both subjective states have been noted previously, including the subjective feeling of transcending one’s body and entering an alternative realm, perceiving and communicating with sentient ‘entities’ and themes related to death and dying. In this within-subjects placebo-controled study we aimed to test the similarities between the DMT state and NDEs, by administering DMT and placebo to 13 healthy participants, who then completed a validated and widely used measure of NDEs. Results revealed significant increases in phenomenological features associated with the NDE, following DMT administration compared to placebo. Also, we found significant relationships between the NDE scores and DMT-induced ego-dissolution and mystical-type experiences, as well as a significant association between NDE scores and baseline trait ‘absorption’ and delusional ideation measured at baseline. Furthermore, we found a significant overlap in nearly all of the NDE phenomenological features when comparing DMT-induced NDEs with a matched group of ‘actual’ NDE experiencers. These results reveal a striking similarity between these states that warrants further investigation. “I’d be scared”. “Scared of what?” “Scared of dying, I guess. Of falling into the void”. “They say you fly when you die”. (Feature film: ‘Enter the Void’).
A systematic study of microdosing psychedelics
The phenomenon of ‘microdosing’, that is, regular ingestion of very small quantities of psychedelic substances, has seen a rapid explosion of popularity in recent years. Individuals who microdose report minimal acute effects from these substances yet claim a range of long-term general health and wellbeing benefits. There have been no published empirical studies of microdosing and the current legal and bureaucratic climate makes direct empirical investigation of the effects of psychedelics difficult. In Study One we conducted a systematic, observational investigation of individuals who microdose. We tracked the experiences of 98 microdosing participants, who provided daily ratings of psychological functioning over a six week period. 63 of these additionally completed a battery of psychometric measures tapping mood, attention, wellbeing, mystical experiences, personality, creativity, and sense of agency, at baseline and at completion of the study. Analyses of daily ratings revealed a general increase in reported psychological functioning across all measures on dosing days but limited evidence of residual effects on following days. Analyses of pre and post study measures revealed reductions in reported levels of depression and stress; lower levels of distractibility; increased absorption; and increased neuroticism. To better understand these findings, in Study Two we investigated pre-existing beliefs and expectations about the effects of microdosing in a sample of 263 naïve and experienced microdosers, so as to gauge expectancy bias. All participants believed that microdosing would have large and wide-ranging benefits in contrast to the limited outcomes reported by actual microdosers. Notably, the effects believed most likely to change were unrelated to the observed pattern of reported outcomes. The current results suggest that dose controlled empirical research on the impacts of microdosing on mental health and attentional capabilities are needed.
Background Numerous anecdotal reports suggest that repeated use of very low doses of lysergic acid diethylamide (LSD), known as microdosing, improves mood and cognitive function. These effects are consistent both with the known actions of LSD on serotonin receptors and with limited evidence that higher doses of LSD (100–200 μg) positively bias emotion processing. Yet, the effects of such subthreshold doses of LSD have not been tested in a controlled laboratory setting. As a first step, we examined the effects of single very low doses of LSD (0–26 μg) on mood and behavior in healthy volunteers under double-blind conditions. Methods Healthy young adults (N = 20) attended 4 laboratory sessions during which they received 0 (placebo), 6.5, 13, or 26 μg of LSD in randomized order at 1-week intervals. During expected peak drug effect, they completed mood questionnaires and behavioral tasks assessing emotion processing and cognition. Cardiovascular measures and body temperature were also assessed. Results LSD produced dose-related subjective effects across the 3 doses (6.5, 13, and 26 μg). At the highest dose, the drug also increased ratings of vigor and slightly decreased positivity ratings of images with positive emotional content. Other mood measures, cognition, and physiological measures were unaffected. Conclusions Single microdoses of LSD produced orderly dose-related subjective effects in healthy volunteers. These findings indicate that a threshold dose of 13 μg of LSD might be used safely in an investigation of repeated administrations. It remains to be determined whether the drug improves mood or cognition in individuals with symptoms of depression.
The Anti-Addiction Drug Ibogaine and the Heart: A Delicate Relation
The plant indole alkaloid ibogaine has shown promising anti-addictive properties in animal studies. Ibogaine is also anti-addictive in humans as the drug alleviates drug craving and impedes relapse of drug use. Although not licensed as therapeutic drug and despite safety concerns, ibogaine is currently used as an anti-addiction medication in alternative medicine in dozens of clinics worldwide. In recent years, alarming reports of life-threatening complications and sudden death cases, temporally associated with the administration of ibogaine, have been accumulating. These adverse reactions were hypothesised to be associated with ibogaine’s propensity to induce cardiac arrhythmias. The aim of this review is to recapitulate the current knowledge about ibogaine’s effects on the heart and the cardiovascular system, and to assess the cardiac risks associated with the use of this drug in anti- addiction therapy. The actions of 18-methoxycoronaridine (18-MC), a less toxic ibogaine congener with anti-addictive properties, are also considered.
Increased global integration in the brain after psilocybin therapy for depression
Psilocybin therapy shows antidepressant potential, but its therapeutic actions are not well understood. We assessed the subacute impact of psilocybin on brain function in two clinical trials of depression. The first was an open-label trial of orally administered psilocybin (10 mg and 25 mg, 7 d apart) in patients with treatment-resistant depression. Functional magnetic resonance imaging (fMRI) was recorded at baseline and 1 d after the 25-mg dose. Beck’s depression inventory was the primary outcome measure ( MR/J00460X/1 ). The second trial was a double-blind phase II randomized controlled trial comparing psilocybin therapy with escitalopram. Patients with major depressive disorder received either 2 × 25 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily placebo (‘psilocybin arm’) or 2 × 1 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily escitalopram (10-20 mg) (‘escitalopram arm’). fMRI was recorded at baseline and 3 weeks after the second psilocybin dose ( NCT03429075 ). In both trials, the antidepressant response to psilocybin was rapid, sustained and correlated with decreases in fMRI brain network modularity, implying that psilocybin’s antidepressant action may depend on a global increase in brain network integration. Network cartography analyses indicated that 5-HT2A receptor-rich higher-order functional networks became more functionally interconnected and flexible after psilocybin treatment. The antidepressant response to escitalopram was milder and no changes in brain network organization were observed. Consistent efficacy-related brain changes, correlating with robust antidepressant effects across two studies, suggest an antidepressant mechanism for psilocybin therapy: global increases in brain network integration.
Abstract Aim of the study The aim of the present study is to determine in a procedurally uniform manner the mescaline concentrations in stem tissue of 14 taxa/cultivars of the subgenus Trichocereus of the genus Echinopsis (Cactaceae) and to evaluate the relationship (if any) between mescaline concentration and actual shamanic use of these plants. Materials and methods Columnar cacti of the genus Echinopsis, some of which are used for diagnostic and therapeutic purposes by South American shamans in traditional medicine, were selected for analysis because they were vegetative clones of plants of documented geographic origin and/or because they were known to be used by practitioners of shamanism. Mescaline content of the cortical stem chlorenchyma of each cactus was determined by Soxhlet extraction with methanol, followed by acid–base extraction with water and dichloromethane, and high-pressure liquid chromatography (HPLC). Results By virtue of the consistent analytical procedures used, comparable alkaloid concentrations were obtained that facilitated the ranking of the various selected species and cultivars of Echinopsis, all of which exhibited positive mescaline contents. The range of mescaline concentrations across the 14 taxa/cultivars spanned two orders of magnitude, from 0.053% to 4.7% by dry weight. Conclusions The mescaline concentrations reported here largely support the hypothesis that plants with the highest mescaline concentrations – particularly E. pachanoi from Peru – are most associated with documented shamanic use.
Aims: Ketamine remains an important medicine in both specialist anaesthesia and aspects of pain management. At the same time, its use as a recreational drug has spread in many parts of the world during the past few years. There are now increasing concerns about the harmful physical and psychological consequences of repeated misuse of this drug. The aim of this review was to survey and integrate the research literature on physical, psychological and social harms of both acute and chronic ketamine use. Method: The literature on ketamine was systematically searched and findings were classified into the matrix of Nutt et al.’s (2007) rational scale for assessing the harms of psychoactive substances. Results: A major physical harm is ketamine induced ulcerative cystitis which, although its aetiology is unclear, seems particularly associated with chronic, frequent use of the drug. Frequent, daily use is also associated with neurocognitive impairment and, most robustly, deficits in working and episodic memory. Recent studies suggest certain neurological abnormalities which may underpin these cognitive effects. Many frequent users are concerned about addiction and report trying but failing to stop using ketamine. Conclusions: The implications of these findings are drawn out for treatment of ketamine-induced ulcerative cystitis in which interventions from urologists and from addiction specialists should be coordinated. Neurocognitive impairment in frequent users can impact negatively upon achievement in education and at work, and also compound addiction problems. Prevention and harm minimization campaigns are needed to alert young people to these harmful and potentially chronic effects of ketamine.
Neuropharmacology of N,N-dimethyltryptamine
N,N-dimethyltryptamine (DMT) is an indole alkaloid widely found in plants and animals. It is best known for producing brief and intense psychedelic effects when ingested. Increasing evidence suggests that endogenous DMT plays important roles for a number of processes in the periphery and central nervous system, and may act as a neurotransmitter. This paper reviews the current literature of both the recreational use of DMT and its potential roles as an endogenous neurotransmitter. Pharmacokinetics, mechanisms of action in the periphery and central nervous system, clinical uses and adverse effects are also reviewed. DMT appears to have limited neurotoxicity and other adverse effects except for intense cardiovascular effects when administered intravenously in large doses. Because of its role in nervous system signaling, DMT may be a useful experimental tool in exploring how the brain works, and may also be a useful clinical tool for treatment of anxiety and psychosis.
Neural correlates of the DMT experience assessed with multivariate EEG
Studying transitions in and out of the altered state of consciousness caused by intravenous (IV) N,N-Dimethyltryptamine (DMT – a fast-acting tryptamine psychedelic) offers a safe and powerful means of advancing knowledge on the neurobiology of conscious states. Here we sought to investigate the effects of IV DMT on the power spectrum and signal diversity of human brain activity (6 female, 7 male) recorded via multivariate EEG, and plot relationships between subjective experience, brain activity and drug plasma concentrations across time. Compared with placebo, DMT markedly reduced oscillatory power in the alpha and beta bands and robustly increased spontaneous signal diversity. Time-referenced and neurophenomenological analyses revealed close relationships between changes in various aspects of subjective experience and changes in brain activity. Importantly, the emergence of oscillatory activity within the delta and theta frequency bands was found to correlate with the peak of the experience – particularly its eyes-closed visual component. These findings highlight marked changes in oscillatory activity and signal diversity with DMT that parallel broad and specific components of the subjective experience, thus advancing our understanding of the neurobiological underpinnings of immersive states of consciousness.