Psychedelics and Neuroscience

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Papers

In our literature study we came across the following studies of note. Browse the meta, review, commentary articles for an overview. Check out the individual studies for specific experiments and observations.

The Effects of Hallucinogens on Gene Expression

2017 | Martin, D. A., Nichols, C. D.

This book chapter/review (2017) discusses the current state of knowledge on the molecular genetic responses to psychedelics within the brain in order to contribute to our understanding of how even single doses of psychedelics can have longer-term effects on brain and behavior.

Self unbound: ego dissolution in psychedelic experience

2017 | Gerrans, P., Letheby, C.

This opinion paper (2017) argues that ego dissolution experiences induced by psychedelic substances offer insight into the nature of the "self." The authors argue that self-awareness is the result of hierarchical predictive models tied to an unchanging entity and, ultimately, that the "self" is merely a useful fiction.

Neuroimaging in moderate MDMA use: A systematic review

2015 | Borgwardt, S., Dolder, P. C., Lang, U. E., Lenz, C., Liechti, M. E., Mueller, F., Steiner, M., Walter, M.

This systematic review (2015; 19 studies) found no convincing evidence that moderate use of MDMA is associated with significant brain alterations. However, the authors point out that the included studies were very heterogeneous and often of low quality.

Antidepressant actions of ketamine: from molecular mechanisms to clinical practice

2015 | Monteggia, L. M., Zarate, C. A.

This review (2015) provides an overview of the antidepressant mechanism of ketamine, clinical studies with ketamine, and its use in shaping the development of next-generation treatments, which include better tolerated non-ketamine NMDA antagonists and other non-NMDA glutamatergic modulators.

Amanita muscaria: chemistry, biology, toxicology, and ethnomycology

2003 | Melendez-Howell, L. M., Michelot, D.

This review (2003) examines the chemical, biological, and toxicological properties of the alkaloids contained in Amanita Muscaria (Fly Agaric) alongside the sociocultural context of its etymology. The principal substrates ibotenic acid and muscimol exert their psychotropic effects through stimulation of inhibitory glutamatergic and GABAergic neurotransmission.

When the endogenous hallucinogenic trace amine N, N-dimethyltryptamine meets the sigma-1 receptor

2009 | Hayashi, T., Su, T. P., Vaupel, D. B.

This theory building study (2009) presents a hypothetical signaling scheme involving the sigma-1 receptor to explain the psychedelic effects of DMT.

The pharmacology of psilocybin

2002 | Emrich, H. M., Passie, T., Schneider, U., Seifert, J.

This study (2002) details the pharmacology of psilocybin.

Amanita muscaria (fly agaric): from a shamanistic hallucinogen to the search for acetylcholine

2018 | Dukan, E., Lee, M. R., Milne, I.

This review (2018) examines the cultural context of the Amanita Muscaria (Fly Agaric) mushroom, from its early shamanistic use in Siberia and the investigation of its pharmacology. The identification of its hallucinogenic alkaloids, muscarine, muscazole, muscazone, and ibotenic acid/muscimole led to the identification of acetylcholine as the mediator of their parasympathetic activity, and the development of anticholinergic medicines for treating asthma and COPD.

Anti-inflammatory activity of ayahuasca and its implications for the treatment of neurological and psychiatric diseases

2021 | Daros, G. C., da Silva, M. G., de Bitencourt, R. M.

This review (2021) examines the antioxidant, anxiolytic (anxiety), and antidepressant effects of ayahuasca, with a particular emphasis on its anti-inflammatory action yielding therapeutic benefits for disorders related to neuroinflammatory factors.

Serotonin research: contributions to understanding psychoses

2008 | Geyer, M. A., Vollenweider, F. X.

This review (2008) summarizes convergent evidence in support of the serotonergic model of psychedelics, schizophrenia, and psychosis, and concludes that the serotonergic system contributes to psychotic states only by interacting with other neurotransmitter systems in the brain.

Serotonergic Hallucinogen-Induced Visual Perceptual Alterations

2016 | Kometer, M., Vollenweider, F. X.

This book chapter (2018) examines the most common attributes of psychedelic-induced visual hallucinations, which entails visual intensification of brightness, contrast, and color saturation, alterations in object size, and changed perception of meaning and self-relevance. Other common features of visual distortions include recurrent patterns influenced by audiovisual synesthesia or even complex visual imagery that entails visions of people, animals, or landscapes. The authors discuss the underlying mechanisms of these phenomena, such as the role of 5-HT2A receptor activation which leads to the cortical excitation of regions that encode specific contents of hallucinations, and the effects of reduced alpha oscillations that amplify internally driven excitation signal to the point that they outweigh incoming sensory information.

The Varieties of the Psychedelic Experience: A Preliminary Study of the Association Between the Reported Subjective Effects and the Binding Affinity Profiles of Substituted Phenethylamines and Tryptamines

2018 | Erowid, F., Erowid, E., Pallavicini, C., Sanz, C., Tagliazucchi, E., Zamberlan, F.

This data-analytic study compared the similarity between several different psychedelic compounds, in terms of their reported subjective effects, binding affinity profiles, and molecular structures. Through the application of a novel machine-learning algorithm to the experience reports sampled from Erowid, the authors found that differences in subjective experience could be predicted by target binding site affinity and/or their conformational receptor states of the respective molecules. Notabely, the 5-HT receptor subtypes yielded relatively poor predictions by themself in contrast to dopamine receptors (D1–5), which highlights that the dopaminergic action of LSD (in contrast to psilocybin) may elicit different types of subjective experiences.

NMDAR inhibition-independent antidepressant actions of ketamine metabolites

2016 | Albuquerque, E. X., Alkondon, M., Dossou, K. S. S., Elmer, G. I., Fang, Y., Fischell, J., Georgiou, P., Gould, T. D., Huang, X., Mayo, C. L., Moaddel, P. J., Morris, P. J., Pribut, H. J., Singh, N. S., Thompson, S. M., Thomas, C. J., Wainer, I. W., Yuan, P., Zanos, P., Zarate, C. A.

This review highlights findings from animal studies that examined whether a ketamine-metabolite (HNK) with fewer side effects is sufficient to induce antidepressant effects, as measured via behavioral, electroencephalographic, electrophysiological, and cellular measures which compared it to the effects of ketamine in mice. Results indicated that the metabolite can exert antidepressant effects through early activation of glutaminergic AMPA-receptors, independent of NMDA receptor inhibition that is typically induced by ketamine.

The neurobiology of depression, ketamine and rapid-acting antidepressants: Is it glutamate inhibition or activation?

2018 | Abdallah, C. G., Duman, R. S., Krystal, J. H., Sanacora, G.

This review (2018) examines the neurobiology of depression in light of the rapid fast-acting antidepressant properties of ketamine, with particular regard for the role of inhibitory and excitatory glutamate transmission. It is evident that the primary mechanism of ketamine is the induction of transient (minutes-to-hours) postsynaptic glutamate activation, which ultimately leads to a sustained (days-to-weeks) increase in synaptic formation and strength in the prefrontal cortex. However, it is unclear whether ketamine's effects on glutaminergic inhibition via extrasynaptic NMDA) receptors exert rapid or even slow antidepressant effects.

A Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics

2021 | Kwan, A. C., Savalia, N., Shao, L-X,

This opinion article (2021) postulates that ketamine and psychedelics substances enact their rapid fast-acting antidepressant effects by means of promoting neuroplasticity in a heterogeneous manner, by enhancing or suppressing dendritic excitability across different parts of the cellular membrane. Although precise measurements of this pharmacological effect across the entire dendritic tree are currently still lacking, the authors hypothesize that the spatial mismatches in the opposing effects of these drugs drive neuroplasticity at specific dendritic hotspots, depending on the microcircuitry of their respective target neurons.

Targeting glutamate signalling in depression: progress and prospects

2021 | Abdallah, C. G., Mathew, S. J., Murrough, J. W.

This review (2017) examines the history, rationale, and efficacy of glutamate-modulating agents in treating depression. Ketamine has emerged as the prototypical fast-acting antidepressant and has yielded compelling hypotheses about the role of glutamate, although the role of its effects on NMDA receptor inhibition still remains unclear as to whether it alleviates depression. Preliminary evidence also suggests that ketamine-like drugs exert antidepressant properties by regulating monoamine signaling, opioid signaling, inflammatory systems, or even epigenetic mechanisms.

Glutamate and gamma-aminobutyric acid systems in the pathophysiology of major depression and antidepressant response to ketamine

2016 | Ballard, E. D., Lener, M. S., Niciu, M. J., Nugent, A. C., Park, L. T., Park, M., Zarate, C. A.

This review (2017) examines ketamine's rapid antidepressant efficacy with respect to evidence that it can neurochemical/physiological disturbances, such as abnormalities in excitatory and/or inhibitory neurotransmission in association with altered brain levels of glutamate and gamma-aminobutyric acid. It highlights neuroimaging studies to support the notion that glutamatergic modulation may be a viable biomarker for investigating depression in future studies.

Treating Addiction: Perspectives from EEG and Imaging Studies on Psychedelics

2016 | de Araujo, D. B., Tófoli, L.F.

This book chapter (2016) reviews the evidence regarding the effects of psychedelics on the brain and their potential as treatments for psychiatric and addictive disorders.

Mechanisms of ketamine action as an antidepressant

2018 | Gould, T. D., Zanos, P.

This review (2018) examines the neurobiological mechanisms underlying the antidepressant effects of ketamine. Whereas previous presumed that NMDA receptor inhibition is the principal mechanism, new evidence suggests that additional receptor-pathways that are specific to its downstream metabolite hydroxynorketamine are sufficient to improve depression (in animal studies) without blocking NMDA.

Ketamine-Associated Brain Changes: A Review of the Neuroimaging Literature

2018 | Cusin, C., Deckersbach, T., Felicione, J. M., Gosai, A., Ionescu, D. F., Shapero, B. G., Shin, P.

This review (2018) examines the neural correlates of ketamine-associated brain changes in patients with depression. Although ketamine affects different areas of the brain in various ways, its most notable effects were found in the subgenual anterior cingulate cortex, posterior cingulate cortex, prefrontal cortex, and hippocampus. Ketamine affects emotional blunting, which may be associated with reduced limbic responses to emotional stimuli, and increase neural activity in reward processing. It also reduces brain activation in regions, such as the Default Mode Network (DMN), associated with self-monitoring, which may be linked to its dissociative effects.

Meta-analysis of executive functioning in ecstasy/polydrug users

2016 | Jones, A., Montgomery, C., Roberts, C. A.

This meta-analysis (2016) compared cognition between current MDMA (n=1221) users and poly-drug users (n=1224) with regard to executive functions, such as updating, switching, inhibition, and access to long-term memory. Current ecstasy users exhibited significant but small-size deficits in executive functioning, with regard to access to long-term memory, task-switching, and memory updating, which was independent of their accumulated lifetime ecstasy dose.

Classical hallucinogens as antidepressants? A review of pharmacodynamics and putative clinical roles

2014 | Barnes, G., Baumeister, D., Giaroli, G., Tracy, D.

This review (2014) examines the effects of psychedelic drugs with regard to their pharmacodynamics and molecular biology, their electrophysiological and neuroimaging profile, and summarizes the evidence for potential therapeutic mechanisms of action, including effects on neurogenesis, cortical networks, and the immune system. It also examines the clinical profile of psychedelic substances with regard to risks for healthy individuals, as well as the potential to treat clinical conditions such as depression, notwithstanding the criminalized status of psychedelics, despite negligible risk and a lack of evidence for its alleged adverse effects.

Reviewing the ketamine model for schizophrenia

2013 | Frohlich, J, Van Horn, J. D.

This review (2013) examines the psychotomimetic model of ketamine, with regard to its inhibitory glutaminergic transmission that causes similar abnormalities in cortical oscillations as observed in patients with schizophrenia. This similarity may be indicative of an early developmental stage leading up to acute schizophrenia, given that the hallucinatory profile of ketamine entails visual hallucinations, whereas chronic schizophrenia is marked almost exclusively by auditory hallucinations.

Serotonergic hyperactivity as a potential factor in developmental, acquired and drug-induced synesthesia

2013 | Brogaard, B.

This literature review (2013) evaluates synaesthesia and proposes that the role of excessive serotonin (genetic or drug induced) plays a role through increasing excitability and connectedness of brain regions.

The induction of synaesthesia with chemical agents: a systematic review

2013 | Luke, D. P., Terhune, D. B.

This review (2013) investigates how psychedelics (serotonin agonists) elicit synaesthesia (merging of senses) and what neurological mechanisms may underlie these effects.

Increased spontaneous MEG signal diversity for psychoactive doses of ketamine, LSD and psilocybin

2017 | Barrett, A. B., Carhart-Harris, R. L., Muthukumaraswamy, S., Schartner, M.

This computational modeling study re-analyzed data of multidimensional spontaneous MEG recordings collected during the administration of LSD, psilocybin, and ketamine during resting-state compared to the placebo condition. Results indicate that the intensity of psychedelic states corresponds to increased brain-wide signal diversity, as compared to placebo, across a range of measures and three different psychedelic compounds.

Short term changes in the proteome of human cerebral organoids induced by 5-MeO-DMT

2017| Dakic, V., de Araujo, D. B., de Moraes Maciel, R., Martins-de-Souza, D., Nascimento, J. M., Rehen, S. K., Ribeiro, S., Sartore, R. C.

This study (2017) investigated the molecular alterations caused by 5-MeO-DMT in human cerebral organoids. The authors found evidence for a good number of proteins that seem to be differentially expressed after drug exposure.

The serotonin hallucinogen 5-MeO-DMT alters cortico-thalamic activity in freely moving mice: Regionally-selective involvement of 5-HT1A and 5-HT2A receptors

2017| Artigas, F., Celada, P., Llado-Pelfort, L., Riga, M. S.

This rodent study (2017) suggests that the hallucinatory effects of 5-MeO-DMT may be due to simultaneous alteration of prefrontal and visual brain activities. The authors point to 5-HT1A receptor antagonists as a potential treatment for visual hallucinations.

Ketamine’s antidepressant effect is mediated by energy metabolism and antioxidant defense system

2017| Asara, J. M., Deery, M. J., Dethloff, F., Feret, R., Filiou, M. D., Howard, J. A., Iannace, J., Labermaier, C., Lilley, K., Maccarrone, G., Müller, M. B., Teplytska, L., Turck, C. W., Webhofer, C., Weckmann, K.

This study (2017) examined the hippocampi of mice treated with ketamine in order to ascertain which pathways the drug affected. The researchers found, among other things, that ketamine tended to downregulate the ATP/ADP metabolite ratio.

A Single Dose of LSD Does Not Alter Gene Expression of the Serotonin 2A Receptor Gene (HTR2A) or Early Growth Response Genes (EGR1-3) in Healthy Subjects

2017| Borgwardt, S., Dolder, P. C., Grünblatt, E., Liechti, M. E., Müller, F.

Regarding the phenomenon of rapid tolerance after repeated use of LSD, this double-blind study (2017, n=15) found that a single dose of LSD (100 μg) did not alter gene expression of the serotonin (5-HT) 2A receptor gene.

Two dose investigation of the 5-HT-agonist psilocybin on relative and global cerebral blood flow

2017| Kraehenmann, R., Lewis, C. R., Michels, L., Preller, K. H., Stämpfli, P., Vollenweider, F. X.

This double-blind, placebo-controlled study (n=58) investigated the effect of two different doses of psilocybin (11mg-15mg/70kg) on cerebral blood flow. The larger dose led to significant higher rating on 4 of 11 scales of altered consciousness. It also showed which specific brain regions became more, and less, active.

The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitro

2017| Alonso-Gil, S., de la Fuente Revenga, M., Feilding, A., Morales-García, J. A., Perez-Castillo, A., Riba, J., Rodrigues, M.

Regarding the reportedly anti-depressant effect of ayahuasca, this study (2017) found that the three main alkaloids contained in B. caapi (one of the two main ingredients of ayahuasca) stimulate adult neurogenesis/plasticity in vitro (new neuronal cells in a dish).

Acute and subacute psychoactive effects of Kambô, the secretion of the Amazonian Giant Maki Frog (Phyllomedusa bicolor): retrospective reports

2020| Bermpohl, F., Hage, L. T., Majic, T., Reiche, S., Schmidt, T. T.

This retrospective survey study (n=22) investigated the (sub)acute effects of Kambô, the secretion of the Amazonian Giant Leaf Frog (Phyllomedusa bicolor), using the Altered States of Consciousness Rating Scale (5D/11D-ASC), the Phenomenology of Consciousness Inventory (PCI), the Mystical Experience Questionnaire (MEQ), the Challenging Experience Questionnaire (CEQ), and the Persisting Effects Questionnaire (PEQ). While persistent effects were described as pleasant and bared personal and spiritual significance, the acute effects exhibited no resemblance to psychedelic-type distortions in perception and thinking.

MDMA-Induced Dissociative State not Mediated by the 5-HT2A Receptor

2017| de la Torre, R., Farré, M., Kuypers, K. P. C., Pizarro, N., Pujadas, M., Puxty, D. J., Ramaekers, J. G.

This placebo-controlled study (n=20) argues, against usual assumptions, that the serotonin (5-HT) 2a receptor is not involved in the induction of a dissociative state after MDMA administration.

Effects of the South American psychoactive beverage ayahuasca on regional brain electrical activity in humans: a functional neuroimaging study using low-resolution electromagnetic tomography

2004| Anderer, P., Barbanoj, M. J., Jané, F., Riba, J., Saletu, B.

This double-blind placebo-controlled, randomized, within-subjects clinical study (n=18) investigated the effects of ayahuasca (59.5mg DMT/70kg) on brain electrical activity with low-resolution electromagnetic tomography and found a decrease of the delta, alpha-2, and beta-1 frequency rhythms over the temporo-parieto-occipital junction, and a decrease of theta rhythm in the temporomedial and frontomedial cortices.

The Effects of Daytime Psilocybin Administration on Sleep: Implications for Antidepressant Action

2020| Andrashko, V., Bravermanová, A., Brunovský, M., Bušková, J., Dudysová, D., Froese, T., Horacek, J., Janků, K., Kopřivová, J., Korčák, J., Mander,B. A., Páleníček, T., Saifutdinova, E., Šmotek, M., Tylš, F., Viktorinová, M., Zach, P.

This randomized, double-blind, placebo-controlled, within-subjects study (n=17) investigated the effects of psilocybin (18.2mg/70kg) on brain rhythms during sleep and found that it increased the transition period from wakefulness to REM sleep and reduced the duration of the REM period. These results are in line with the effects of other antidepressants and diametrically opposed to biomarkers of depression that include shortened wakefulness to REM transitions and increased REM duration and density.

Psychedelic-inspired drug discovery using an engineered biosensor

2021| Azinfar, A., Dong, C., Dunlap, L. E., Hwang, I., Ly, C., Oh, W. C., Olsen, D. E., Sun, J., Tian, L., Vargas, M. V., Wetsel, W. C.

This study describes the development and use of an engineered biosensor (PsychLight) that detects relevant serotonin release to predict the hallucinogenic behavioral effects of psychedelics. This tool is used to identify non-hallucinogenic psychedelic compounds that still elicit antidepressant-like effects.

Gas chromatographic analysis of dimethyltryptamine and beta-carboline alkaloids in ayahuasca, an Amazonian psychoactive plant beverages

2009| De Oliveira, C. D. R., Dörr, F. A., Moura, S., Pires, A. P. S., Silva, W. A. E., Yonamine, M.

This biochemical methods development study (2008) describes a simple gas chromatographic assay for quantifying the composition of ayahuasca's active alkaloids.

Ketamine has distinct electrophysiological and behavioral effects in depressed and healthy subjects

2018| Ballard, E. D., Brutsche, N. E., Gould, T. D., Moaddel, P. J., Nugent, A. C., Park, L. T., Zarate, C. A.

This double-blind, placebo-controlled, brain imaging study (MEG; n=60) found that ketamine (35mg/70kg) produced different effects in healthy (n=25) and depressed (MDD; n=35) subjects. Both had significant improvement in scores of depression, increases in resting gamma power, those with MDD and lower initial gamma scores and higher scores after ketamine improved most.

Topographic pharmaco-EEG mapping of the effects of the South American psychoactive beverage ayahuasca in healthy volunteers

2002| Anderer, P., Barbanoj, M. J., Jané, F., Morte, A., Riba, J., Saletu, B., Urbano, G.

This double-blind crossover placebo-controlled clinical study (n=18) investigated the effects of ayahuasca (42 & 59.5mg/70kg) on temporal brain activity in healthy volunteers and found an absolute power decreased in all frequency bands measured with EEG which paralleled the time course of its subjective effects.

Mental changes experimentally produced by d-lysergic acid diethylamide tartrate

1988| Deshon, H. J., Rinkel. M., Solomon, H. C.

This early open-label investigation (1952) reports observations of mental changes in normal adults (n=15) produced by LSD (70μg/70kg) across 17 repeated experiments. Alterations were observed in the areas of thinking and speech, emotion, mood and affect, sensory and time perception, behavior, morbid ideas, and sensory experiences, and neurological signs, which were taken to reflect a schizophrenic-like state.

Effects of varied doses of psilocybin on time interval reproduction in human subjects

2008| Hasler, F., Vollenweider, F. X., Wittmann, M.

This double-blind, placebo-controlled, within-subjects study (n=21) investigated the effects of psilocybin (0.84, 8.05, & 17.5mg/70kg) on time perception and found that it increased the loss rate of internal time representation even within the microdose range. This may be indicative of psilocybin's subjective effects, such as the experience of ‘time standing still'.

Effects of Ayahuasca on the Recognition of Facial Expressions of Emotions in Naive Healthy Volunteers: A Pilot, Proof-of-Concept, Randomized Controlled Trial

2021| Bertozi, G., Bouso, J. C., Campos Braga, I., Cecílio, H. J. E., de Lima Osório, F., De Oliveira Silveira, G., Dos Santos, R. G., Rocha, J. M., Rossi, G. N., Yonamine, M.

This randomized, double-blind, placebo-controlled, pilot study (n=22) investigated the acute and prolonged effects of ayahuasca (9.36mg of DMT, 79.62mg of harmine, 50.71mg of tetrahydroharmine, 7.38mg of harmaline) on social cognition amongst healthy volunteers. Contrary to previous studies which indicate that psychedelics reduce the recognition of fearful face stimuli, this study yielded null results in the absence of ayahuasca-induced effects on the recognition of emotions in facial expressions.

The effects of the preferential 5-HT2A agonist psilocybin on prepulse inhibition of startle in healthy human volunteers depend on interstimulus interval

2007| Csomor, P. A., Geyer, M. A., Knappe, B., Quednow, B. B., Vollenweider, F. X.

This double-blind, placebo-controlled, randomized, counterbalanced, within-subjects study (n=16) investigated the effects of psilocybin (8, 15, & 22mg/70kg) on prepulse inhibition, and found that it inhibited this startle reflex at short interstimulus intervals in a dose-dependent manner. Results indicated the impairment of attention and an inability to filter out unnecessary sensory information under the influence of psilocybin that is similar to patients with schizophrenia.

Effects of ayahuasca on sensory and sensorimotor gating in humans as measured by P50 suppression and prepulse inhibition of the startle reflex, respectively

2002| Barbanoj, M. J., Riba, J., Rodríguez-Fornells, A.

This placebo-controlled, double-blind, cross-over, within-subjects study (n=18) investigated whether ayahuasca (42mg & 56mg/70kg DMT) impairs the ability to filter out unnecessary sensory information in healthy volunteers. This yielded mixed results, with evidence to support that ayahuasca impairs sensorimotor gating in the domain of auditory suppression, but not within the domain of visual-induced prepulse inhibition of the startle reflex.

Serotonergic psychedelic drugs LSD and psilocybin reduce the hierarchical differentiation of unimodal and transmodal cortex

2021| Bernhardt, B., Carhart-Harris, R. L., Girn, M., Roseman, L., Smallwood, J., Spreng, R. N.

This pre-print tested the hypothesis that LSD and psilocybin reduce whole-brain hierarchical (top-down) organization. The results of a model that looks at fMRI data confirms this hypothesis.

Salvinorin-A induces intense dissociative effects, blocking external sensory perception and modulating interoception and sense of body ownership in humans

2015| Addy, P. H., Balleste, M. R., Barker, S., Claramunt, J., Coimbra, J., Garrido, M., Gonzales, M., Johnson, M. W., Maqueda, A. E., Puntes, M., Riba, J., Valle, M.

This double-blind, randomized placebo-controlled, within-subjects study (n=8) investigated the effects of vaporized salvinorin-A (0.25, 0.50, & 1 mg) on interoception and the sense of body-ownership in healthy volunteers, who reported an increase of bodily sensations at moderate doses, and an almost complete loss of body ownership and out-of-body experiences at the highest. These effects were rapid and intense but short-lived and included perceptual modifications in the visual domain and commonly entailed auditory hallucinations that are not typical for serotonergic hallucinogens by contrast. This implicates that the Kappa opioid system plays a significant role in the regulation of sensory perception, interoception, and the sense of body ownership.

Ketamine induces a robust whole-brain connectivity pattern that can be differentially modulated by drugs of different mechanism and clinical profile

2015| Brammer, M., Doyle, O. M., Joules, R., Mehta, M. A., O’daly, O. G., Schwarz, A. J., Williams, S. C.

This double-blind, placebo-controlled, cross-over, within-subjects study (n=22) investigated the effects of ketamine (30mg/70kg) on whole-brain functional connectivity in healthy male participants while attenuating pre-synaptic glutamate release directly via pretreatments with the sodium-channel modulator lamotrigine (300 mg), and indirectly via pretreatment with the 5-HT2A receptor antagonist risperidone (2mg). Ketamine induced robust changes in the functional connectivity pattern and produced a shift from a cortically-centered to a sub-cortically-centered brain state. Pre-treatment with risperidone, but not lamotrigine, resulted in a strong modulation of the ketamine-induced hub changes, which suggests that these changes are likely a result of NMDA blockade and possible serotonergic modulation rather than purely modulation of glutamate release.

EEG Gamma Band Alterations and REM-like Traits Underpin the Acute Effect of the Atypical Psychedelic Ibogaine in the Rat

2021| Carrera, I., Castro-Zaballa, S., Cavelli, M., González, J., Mondino, A., Rubido, N., Tort, A. B. L., Torterolo, P.

This rat study (n=54) investigated the acute effects of ibogaine (12mg/0.3kg) with intracranial electroencephalography and computational assessment of brain states related to sleep and wakefulness. Results indicated that ibogaine induces REM sleep traits during wakefulness and NREM sleep, which are driven by local power increases of gamma oscillations. This provides evidence that ibogaine's effects are psychedelic in so far that it enhances dream-like states of waking consciousness.

Crystal Structure of an LSD-Bound Human Serotonin Receptor

2017| Betz, R. M., Che, T., Dror, R. O., Lansu, K., Levit, A., McCorvy, J. D., Nichols, D. E., Roth, B. L., Schools, Z. L., Shoichet, B. K., Venkatakrishnan, A. J., Wacker, D., Wang, S.

This crystallography study analyzed the structure of LSD bound to a serotonin receptor and found that a branch of the receptor folds over the molecule while it is lodged into the binding pocket, and this lid-like structure secures LSD in place. This contributes to a slow dissociation rate of LSD, which forms the basis for its long-lasting effect. The authors suggest ways of introducing molecular mutations to selectively alter receptor signaling by increasing the mobility of this lid structure.

The Endogenous Hallucinogen and Trace Amine N,N-Dimethyltryptamine (DMT) Displays Potent Protective Effects against Hypoxia via Sigma-1 Receptor Activation in Human Primary iPSC-Derived Cortical Neurons and Microglia-Like Immune Cells

2016| Djurovic, S., Frecska, E., Kovacs, A., Rajnavolgyi, E., Riba, J., Szabo, A.

This in vitro study investigated whether DMT acts neuroprotective against oxidative stress within cultured neurons and immune cells derived from human precursor cells. Results indicate that DMT robustly increases the survival of these cells in response to severe oxygen deprivation, through activation of the Sig-1 receptor, a key modulator of cellular oxidative stress. The authors postulate that DMT may be endogenously generated to mitigate oxidative stress occasioned by adverse brain injuries such as ischemic infarcts.

A Model for the Application of Target-Controlled Intravenous Infusion for a Prolonged Immersive DMT Psychedelic Experience

2016| Gallimore, A. R., Strassman, R. J.

This methodological paper (2016) outlines the development of a target-controlled intravenous infusion protocol for administering DMT within the context of neuroimaging research. Whereas a single dose does not exert effects beyond 20 minutes, this method maintains a stable brain concentration that enables the investigation of a stable and prolonged DMT experience over an indefinite period.

Time course of pharmacokinetic and hormonal effects of inhaled high-dose salvinorin A in humans

2016| Caspers, M. J., Griffiths, R. R., Johnson, M. W., MacLean, K. A., Prisinzano, T. E.

This open-label study (n=6) investigated the effects of vaporized Salvinorin A (1.26mg or 1.47mg/70kg) with regard to the pharmacokinetic time course of its availability in plasma concentration, subjective intensity ratings, and downstream hormonal effects. Results indicated that is plasma concentration and intensity of drug effects peaked at 2 minutes after inhalation. Salvinorin A increased prolactin (a hormone) 5 minutes after inhalation, whereas cortisol (another hormone) concentration was inconsistent and not well correlated with drug levels.

Oxytocin receptor gene variation predicts subjective responses to MDMA

2016| Bershad, A. K., de Wit, H., Kirkpatrick, M. G., Miller, M. A., Wardle, M. C., Weafer, J. J.

This double-blind, placebo-controlled within-subjects study (n=68) investigated the subjective effects of MDMA (52.5mg and 105 mg/70kg) in relation to genetic variation of oxytocin receptors of healthy participants. Results indicated that a single nucleotide polymorphism in the oxytocin receptor gene-mediated differences in sociability and euphoria in response to the higher dose, thus providing further evidence that oxytocin mediates the distinct social effects of MDMA.

Behavioral and pharmacokinetic interactions between monoamine oxidase inhibitors and the hallucinogen 5-methoxy-NN-dimethyltryptamine

2016| Halberstadt, A. L.

This rat study (n=180) investigated the pharmacokinetic interactions between 5-MeO-DMT (0.25mg/0.25kg) and the MAO-A inhibitor clorgyline and the MAO-A/B inhibitor pargyline, and their effects on prepulse inhibition (PPI), a phenomenon related to the ability to filter out unnecessary information. Results confirmed that the MAO inhibitors increase the accumulation of 5-MeO-DMT in the nervous system, and boost its disruptive effects on PPI by activating the 5-HT2a receptor pathway.

Modulatory effect of the 5-HT1A agonist buspirone and the mixed non-hallucinogenic 5-HT1A/2A agonist ergotamine on psilocybin-induced psychedelic experience

2016| Kraehenmann, R., Pokorny, T., Preller, K. H., Vollenweider, F. X.

This double-blind, placebo-controlled, randomized, within-subject study (n=36) with four experimental drug conditions, investigated the effects of psilocybin (11.9mg/70kg) in combination with the selective 5-HT1A agonist buspirone (20mg/70kg) and non-hallucinogenic 5-HT2A/1A agonist ergotamine (3mg/70kg), to investigate how the interaction of these serotonin receptor subtypes affect altered states of consciousness. While ergotamine exerted no effect, buspirone selectively inhibited psilocybin-induced visual hallucinations, affective changes, derealization, and depersonalization via activation of 5 -HT1A and/or an interaction between 5-HT1A and 5-HT2A receptors.

LSD alters eyes-closed functional connectivity within the early visual cortex in a retinotopic fashion

2016| Carhart-Harris, R. L., Feilding, A., Kaelen, M., Leech, R., McGonigle, J., Nutt, D. J., Orban, C., Roseman, L., Sereno, M. I.

This placebo-controlled within-subjects study (n=10) investigated the effects of LSD (75μg) on brain activity in relation to closed-eye visual hallucinations during resting-state. Results indicated that the early visual system (i.e., retinotopically mapped regions in V1 and V3) is affected by LSD and behaves “as if” it were receiving spatially localized visual information.

LSD and ketanserin and their impact on the human autonomic nervous system

2021| Olbrich, S., Preller, K. H., Vollenweider, F. X.

This placebo-controlled randomized, crossover study (n=17) investigated the impact of LSD (100 μg) and the counteracting influence of the 5-HT2A receptor antagonist ketanserin (40mg) on the autonomic nervous system within healthy subjects. LSD predominantly increased the sympathetic activity, while ketanserin increased the parasympathetic influence, thus antagonizing the effects of LSD on the autonomic nervous system completely. The magnitude of subjective experiences during the interventions was positively correlated with the sympathetic activity and negatively correlated with the parasympathetic activity, independent of the intervention.

Glutamate and the Neural Basis of the Subjective Effects of Ketamine: A Pharmaco–Magnetic Resonance Imaging Study

2007| Dursun, S., Hallak, J. E., Lees, J., McKie, S., William Deakin, J. F., Williams, S. R.

This double-blind, placebo-controlled, randomized, crossover, counterbalanced study (n=33) investigated whether ketamine-induced (20.5mg/70kg) dissociative mental state is blocked via pretreatment with the glutamate release inhibitor lamotrigine (300mg/70kg). Ketamine produced dissociative effects which corresponded to decreased activity in the ventromedial frontal cortex, including the orbitofrontal cortex and subgenual cingulate, and increased activity in mid-posterior cingulate, thalamus, and temporal cortical regions. Most of these effects were mitigated by lamotrigine, thereby indicating that the dissociative effects of ketamine are mediated by glutamate release.

Ketamine Treatment and Global Brain Connectivity in Major Depression

2016| Abdallah, C. G., Anticevic, A., Averill, L. A., Averill, C., Charney, D. S., Collins, K. A., DeWilde, K. E., Geha, P., Iosifescu, D. V., Murrough, J. W., Schwartz, J., Tang, C. Y., Wong, E.

This open-label, counterbalanced, between-subjects study (n=43) compared brain activity before and after ketamine (35mg/70kg) administration across healthy control and patients with major depression. The treatment normalized restored abnormally low brain connectivity levels in the prefrontal cortex of patients with depression, which may be indicative of a potential mechanism whereby ketamine restores synaptic dysconnectivity related to chronic stress and increased extracellular glutamate in the prefrontal cortex. The authors highlight the method of global brain connectivity with signal regression as a useful biomarker for quantifying treatment response to rapid-acting antidepressants.

Psychedelic Effects of Ketamine in Healthy Volunteers: Relationship to Steady-state Plasma Concentrations

1998| Bowdle, A. T., Cowley, D. S., Kharash, E. D., Radant, A. D., Roy-Byrne, P. P., Strassman, R. J.

This single-blinded, placebo-controlled, within-subjects, crossover study (n=10) quantified the subjective "psychedelic" effects of subanesthetic ketamine (9, 18, 26, 35 mg/70kg), administered in a stepwise manner that gradually increased plasma concentration. Ketamine produced dose-related psychedelic effects on the Hallucinogen rating scale, with similar scores to DMT, and this effect exhibited a highly linear relationship to plasma concentration.

Psilocybin – Summary of knowledge and new perspectives

2013| Horacek, J., Páleníček, T., Tylš, F.

This review (2014) provides a history of psilocybin and a summary of its pharmacology within humans and animals, its psychedelic effects as measured via neuroimaging and psychometric assessments, whilst highlighting its potential for both therapy and abuse.

Neural Correlates of the Shamanic State of Consciousness

2021| Bel-Bahar, T., Blain-Moraes, S., Colmenero, A. V., Harris, R. E., Huels, E. R., Kim, H., Lee, U., Mashour, G. A., Nelson, A.

This brain imaging (EEG) study (n=37) found that the shamanic practitioners showed significant differences to control participants on an altered states of consciousness scale (OAV) and EEG measures. Their brainwaves resembled that of earlier data on those under the influence of psychedelics but still were identified as unique, sometimes stronger, patterns.

Baseline power of theta oscillations predicts mystical-type experiences induced by DMT

2021| Cavanna, F., de la Fuente, L. A., Pallavicini, C., Perl, Y. S., Romero, C., Tagliazucchi, E., Zamberlan, F.

This EEG study (n=35) showed that the baseline power of theta oscillations (associated with mind-wandering) negatively correlated with the intensity of mystical-type (MEQ30) experiences after smoking DMT.

Ayahuasca: pharmacology, neuroscience and therapeutic potential

2016| Álvarez, E., de la Fuente Revenga, M., Domínguez-Clavé, E., Elices, M., Feilding, A., Friedlander, P., Pascual, J. C., Riba, J., Soler, J.

This review (2016) examines the pharmacology and neuroscience of ayahuasca, and preliminary findings which indicate the psychological mechanisms associated with its therapeutic benefits are similar to those of mindfulness-based therapy. Ayahuasca appears to enhance self-acceptance and decentering, which converges on evidence from neuroimaging studies that show activation in areas associated with emotional processing and memory formation, thereby enabling individuals to review emotional events with increased vividness and a heightened sense of “reality”. This suggests potential to treat trauma-related conditions and other disorders like borderline personality disorder.

Ketamine-induced modulation of the thalamo-cortical network in healthy volunteers as a model for schizophrenia

2015| Hahn, A., Höflich, A., Kasper, S., Kranz, G. S., Küblböck, M., Lanzenberger, R., Saria, A., Vanicek, T., Windischberger, C., Winkler, P.

This double-blind, randomized, placebo-controlled, within-subjects crossover study (n=30) investigated the effects of S-Ketamine (23.1mg/70kg) on the modulation of thalamocortical circuitry during resting state in healthy volunteers, to investigate whether their brain connectivity exhibits a similar profile as patients with schizophrenia. They found that a subanesthetic dose of ketamine leads to significantly higher functional connectivity in the thalamus hub network, and the strengthening of functional cortico-thalamic connectivity for the somatosensory and temporal seed regions but not for prefrontal, occipital, and parietal regions, in accordance with the connectivity profile of schizophrenia.

The Psychedelic State Induced by Ayahuasca Modulates the Activity and Connectivity of the Default Mode Network

2015| Andrade, K. C., Crippa, J. A., de Araujo, D. B., Hallak, J. E., Palhano-Fontes, F., Ribeiro, S., Santos, A. C., Tófoli, L.F.

This open-label within-subjects study (n=10) investigated the effects of ayahuasca (154 mL/70kg; containing 123.2mg/70kg DMT and 32.34mg/70kg harmine) on brain activity during resting state using fMRI. Results indicated that ayahuasca decreases activation and functional connectivity throughout most parts of the Default Mode Network (DMN), similar to the activation profile of altered states related to psilocybin, meditation, and sleep.

Recreational use of psychedelics is associated with elevated personality trait openness: Exploration of associations with brain serotonin markers

2019| Carhart-Harris, R. L., Erritzoe, D., Fisher, P. M., Frokjaer, V. G., Knudsen, G. M., Smith, J. M.

This cross-sectional study (n=45) evaluates associations between recreational use of psychedelics and MDMA and (a) personality measures and (b) key markers of cerebral serotonergic signaling (serotonin transporter and serotonin-2A-receptor binding).

Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo

2021| Delagarza, K., Gregg, I., Kwan, A. C., Liao, C., Savalia, N., Shao, L-X,

This pre-print article shows that brain cells, specifically the layer five pyramidal neurons in mice, grew by 10% after the introduction of psilocybin. The effects were still present 30 days later, providing more evidence for brain plasticity as an underlying mechanism of psychedelic-assisted therapies' long-lasting effects.

Effects of ketamine on brain function during metacognition of episodic memory

2021| Delis, A., Ettinger, U., Hurlemann, R., Lehmann, M., Neumann, C., Schultz, J., Trautner, P., Wasserthal, S.

This double-blind placebo-controlled fMRI study (n=53) on ketamine (r-ketamine, continuous iv) and cognition found that ketamine increased metacognitive bias, negatively impacted metacognitive sensitivity, and increased activation of posterior brain areas.

Broadband Cortical Desynchronization Underlies the Human Psychedelic State

2013| Bolstridge, M., Brookes, M. J., Carhart-Harris, R. L., Erritzoe, D., Feilding, A., Friston, K. J., Moran, R. J., Muthukumaraswamy, S., Nutt, D. J., Papadopoulos, A., Sessa, B., Singh, K. D., Williams, T. M.

This study (n=15) suggests that the subjective effects of psychedelics (psilocybin, 2mg iv) may be due to the desynchronization of oscillatory rhythms in the cortex. This effect was caused by the increased excitability of deep-layer pyramidal neurons (by serotonin 2a receptor excitation).

The default-mode, ego-functions and free-energy: a neurobiological account of Freudian ideas

2010| Carhart-Harris, R. L., Friston, K. J.

This theory-building paper (2010) attempts to provide models of neural substrates for a variety of Freudian hypothetical constructs.

Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior

2007| Ang, R., Bradley-Moore, M., Chan, P., Ge, Y., Gingrich, J. A., González-Maeso, J., Ivic, L., Lira, A., Sealfon, S. C., Weisstaub, N. V., Zhou, M., Zhou, Q.

This study (2007) identifies the biological reasons, the specific regulation of Gi/o proteins and Src, why psychedelics that affect the 5-HT2A receptor have hallucinogenic effects while agonists (lusuride) do not.

Neural and subjective effects of inhaled N,N-dimethyltryptamine in natural settings

2021| Arias, M., Carhart-Harris, R. L., Cavanna, F., de la Fuente, L. A., Ilksoy, Y., Pallavicini, C., Perl, Y. S., Romero, C., Tagliazucchi, E., Timmermann, C., Zamberlan, F.

This naturalistic (open-label) study (n=35) with smoked DMT (~40mg) confirmed earlier findings (but now outside the lab) that DMT significantly decreased alpha, and increased delta and gamma oscillations. The latter also correlated with subjective mystical-type experiences (MEQ).

The psychedelic state induced by ayahuasca modulates the activity and connectivity of the default mode network

2015| Andrade, K. C., Crippa, J. A., de Araujo, D. B., Hallak, J. E., Palhano-Fontes, F., Ribeiro, S., Santos, A. C., Tófoli, L.F.

This open-label study (n=9) investigated the effects of ayahuasca (123,2mg DMT, 32,34mg Harmine) on the functional brain connectivity of experienced users, and found a decrease in the activity of core structures of the Default Mode Network (DMN).

Psilocybin-induced decrease in amygdala reactivity correlates with enhanced positive mood in healthy volunteers

2015| Bosch, O. G., Kraehenmann, R., Pokorny, T., Preller, K. H., Scheidegger, M., Seifritz, E., Vollenweider, F. X.

This double-blind, placebo-controlled, fMRI study (n=25) found that a moderate dose of psilocybin (11.2mg/70kg) lowered amygdala (which is hyperactive in those with major depression) reactivity to negative and neutral (visual) stimuli. The decrease in emotional processing was correlated with an increase in positive mood.

Therapeutic mechanisms of psilocybin: Changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression

2020| Carhart-Harris, R. L., Demetriou, L., Mertens, L. J., Nutt, D. J., Roseman, L., Wall, M. B.

This further analysis of an fMRI study (n=19) investigated changes in brain function before versus after psilocybin (with psychological support) in patients with depression (TRD). After treatment, patients showed changes in amygdala function connectivity.

Preliminary report on the effects of a low dose of LSD on resting-state amygdala functional connectivity

2020| Bershad, A. K., Bremmer, M. P., de Wit, H., Keedy, S., Lee, R., Preller, K. H., Wren-Jarvis, J.

In this double-blind, placebo-controlled study, a microdose of LSD (13 µg) was found to increase and decrease connectivity in various areas of the brain. One of these effects correlated positively with mood increases, but overall mood changes were variable.

Compared

This section compares the research with psychedelics to other therapies, medicines, or treatments.

Measured

This section highlights the various measures used and their use in research.

Researchers

Who are the top researches in this area, the ones who have done the groundbreaking research.

Gaps

What do we not know at this time? Where are the gaps in our knowledge and are we closing it?

Companies

The companies that are actively engaged in researching this topic or (planning to) provide therapy focussed on this topic.

Outside Academia

This section highlights everything done outside of academia, from popular press to books and non academic research.