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Neuroscience

What are the effects of psychedelics on neuroplasticity?

Psychedelics appear to consistently produce long-lasting behavioural changes in the individuals who use them. Research focus has recently shifted to understand the accompanying changes in brain function and structure, which are hypothesised to occur through neuroplasticity. In this interview, Cato de Vos, MSc, explains what neuroplasticity is, how it can be measured in humans and animals, its importance in brain development, and the mechanisms by which psychedelic compounds and other practices can generate it.

Author: Maxim Siegel
Interviewee: Cato de Vos

Over the past couple of decades, accumulating evidence has shown that psychedelics consistently produce strong subjective effects, often leaving a perennial imprint on the individuals ingesting them. 

The subjective effects of the acute psychedelic experience are remarkable in and of themselves. At higher doses, they may occasion mystical-type experiences, considered by the individuals who have them as some of the most meaningful experiences of their lives, on par with one’s wedding day or the birth of a child. Perhaps even more remarkable are the sustained effects of these experiences on positive changes in attitudes and behaviours, lasting up to 14 months following the experience in one study.

Other studies have found similar long-lasting effects of these acute psychedelic experiences on depressive symptoms in patients with treatment-resistant depression, on smoking cessation in nicotine-dependent individuals, and on alcohol consumption in alcohol-dependent individuals. In each case, the quality of the acute psychedelic experience predicted the long-term changes from 6 to 12 months later. 

It is clear from the available scientific literature that psychedelics have an important therapeutic potential that needs to be investigated, and that therapeutic outcome may be determined by the subjective psychedelic effects. As a neuroscientist however, it is challenging to consider long-term behavioural changes without any accompanying structural or functional brain alterations. These findings pose the following question: do psychedelics affect brain structure and/or function in a way that can lead to long-term changes? And if so, by which processes?

Cato M. H. de Vos holds an MSc in neurobiology at the University of Amsterdam. She currently works as a research-assistant at the mental health organisation 1nP in the Netherlands where she assists Dr. Heval Özgen and Gerard van Kesteren (PhD cand.) in several clinical trials investigating the safety, feasibility, and efficacy of MDMA-assisted therapy. Soon, she will also start a part-time study in Psychology to become a therapist. In September 2021, she published a systematic review in Frontiers in Psychiatry, with Natasha L. Mason, PhD., and Professor Kim P. C. Kuypers, PhD., from Maastricht University. 

The aim of the paper was to review the evidence pertaining to psychedelics’ ability to induce molecular and cellular adaptations related to neuroplasticity, and to see whether they paralleled clinical effects. In total, 16 preclinical and 4 clinical studies were reviewed, revealing that a single administration of a psychedelic produced rapid, multi-level changes in plasticity-related mechanisms, including changes in the expression of BDNF, a neurotrophin involved in the growth, maturation, and maintenance of neurons.

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Q&A with Cato de Vos, MSc.

Question 1. What is neuroplasticity? What is its role in brain development?

Neuroplasticity is the brain’s ability to change throughout life. These changes may occur in cell structure, known as structural plasticity, or in the efficacy of synaptic transmission, known as functional plasticity. An example of structural plasticity is dendritogenesis, where dendrites – the receiving end of neurons – expand, and an example of functional plasticity is synaptogenesis, where new synapses – neuronal junctions – are formed, enabling better communication between neurons. 

Structural and functional plasticity are interconnected processes at a molecular and subcellular level, which eventually give rise to changes at the behavioural level. These changes allow your brain to adapt and change, promoting the ability to learn new things, enhancing your existing cognitive capabilities, supporting recovery from strokes and traumatic brain injuries, strengthening brain areas where functionality has been lost or has declined, and boosting brain fitness. However, neuroplasticity is a double-edged sword. Changes in the structure and function of the brain can confer adaptive benefits but can also lead to maladaptive disadvantages. To illustrate, misdirected activation of neuroplasticity can cause forms of severe tinnitus (‘ringing in the ears’) and neuroplasticity in the brain’s reward system induced by repeated use of certain drugs, such as cocaine, leads to more compulsive drug use. So the risk / benefit ratio also depends on the area where neuroplasticity is occurring.

For a long time researchers believed that the brain stopped developing during adolescence, and that there was a fixed number of neurons in the adult brain that could not be replaced when the cells died. In the 1960s, neurobiologist Joseph Altman discovered the creation of new neurons in the brain. His discovery was largely ignored, until the rediscovery of adult neurogenesis by Elizabeth Gould in 1999. Ensuing research on neurogenesis has since shown that the brain can change throughout life. Specifically the hippocampus, that part of the brain involved in spatial memory, learning processes and even emotion, continues to form new neurons throughout life. Thus,  neuroplasticity is the process by which the brain can modify, change and adapt structure and function in response to the environment.

Question 2. How can neuroplasticity be measured?

There are different ways to measure neuroplasticity in animals and in humans, but it really depends on the level you’re looking at. Neuroplasticity occurs at different levels in the brain (molecular and cellular), involves communication between different brain regions (structural and functional), and eventually affects behaviour, so it depends on the particular area that is being studied. When looking at the molecular level, for example, certain protein levels can be measured. If certain proteins are more expressed than others, then you can infer that they play a bigger role in the process, which can be an indication of neuroplasticity, although it’s a fairly indirect measure.

At a cellular level, a microscope can be used to examine dendrites. If you see that neurons have progressively more elaborate dendrites, that they look like a tree with more branches than before, then you can assume dendritogenesis is at work. 

This type of examination can be performed in animals, but is not as easy in humans, whose brains are not as easily available for research. An alternative is measuring the levels of certain proteins – like BDNF –  in the blood and other parts of the body. With humans, unlike with animals, biological and psychological parameters can be combined, which enables you to investigate the relation between biological and behavioural changes. That’s one of the things that is lacking in animal research: you can’t ask a mouse how it’s feeling. 

Question 3. By which mechanisms do psychedelics induce neuroplasticity?

The changes in neuroplasticity induced by psychedelics are believed to result from the neurobiological pathways they activate. Classic psychedelics act on a serotonergic receptor called “2A” (5-HT2AR). When psychedelics activate this receptor, specific pathways – cascades of different proteins communicating and transferring a signal – are activated. These cascades, or pathways, are different to non-psychedelic-induced activations of the same receptor. 

Following the activation of these cascades, two neurotransmitter systems are activated: the inhibitory serotonergic system, and the excitatory glutamatergic system. The activation of these systems leads to the release of both serotonin and glutamate and subsequently, brain-derived neurotrophic factor (BDNF), a direct indicator of neuroplasticity. Indeed, high levels of BDNF in the brain are associated with increased neuroplasticity. Psychedelics also influence neuroplasticity indirectly, by affecting the transcription of plasticity-related genes and proteins, which modulates the expression of other genes and proteins involved in neuroplasticity. 

Not every study shows that psychedelic administration necessarily stimulates neuroplasticity. It’s therefore not possible to say that it always happens, but there are some good indications that it does. There is also a lot of uncertainty when it comes to the molecular mechanisms I mentioned because measuring molecular cascades is very challenging, so more research is needed to draw definite conclusions.

Question 4. Have the clinical findings in humans mirrored the preclinical findings in animals so far ?

It’s hard to compare the two. Since different techniques are used to investigate humans and animals, making any comparison is like comparing apples and oranges. They both have their pros and cons. 

Clinical research can investigate both the biological and psychological parameters, which is good because you can then investigate correlations between the two. I believe the psychological state is important if you want to be able to observe improvements in the state of a patient, but it’s more difficult to measure direct biological parameters such as cerebrospinal fluid BDNF, like you can in animals. There are many translational issues, which is why we need to keep combining clinical and pre-clinical research, and be mindful of these limitations.

Question 5. Can neuroplasticity alone be therapeutic? What are your thoughts on psychedelic-inspired, neuroplasticity-inducing compounds like TBG, that lack the subjective effects of classic psychedelics?

Personally I am somewhat sceptical about not having the hallucinogenic effects in the context of therapy, but I think it really depends on the reason for psychedelic therapy, because there is a difference between using it for cluster headaches, or PTSD and depression. I believe you need to look at the origin and underlying layers or deep processes within yourself, within your system, that could cause these pathologies which are different in each of these cases. Cluster headaches might be solved with non-hallucinogenic neuroplasticity-inducing compounds, but for the psychiatric disorders – PTSD and depression for example – which are often accompanied by deep-rooted psychological issues, the hallucinogenic effects may be very important. In those cases the peak subjective experience might be necessary, as has already been shown in some studies: the stronger the psychedelic experience, the better the therapeutic outcome. 

That said, I believe that everything is connected – mind and body – and we’re so conditioned to be in our heads and not be aware of what’s going on in our bodies. I feel that psychedelics can restore some of this connection, on a psychological level. Perhaps the hallucinogenic effects may also have a positive impact on cluster headaches. David Olson’s work with TGB is great in that  he is making psychedelics accessible to a bigger audience. A lot of people are excluded from clinical trials because they have a history or family history of certain conditions, and they don’t have access to therapy at all, so this could be a very good thing.

Question 6. Any additional thoughts on neuroplasticity and psychedelics ?

Bear in mind that neuroplasticity can be stimulated by other means, such as taking good care of yourself, engaging in physical activity, meditation, eating healthy food and getting enough sleep. All these can be beneficial and contribute to positive treatment outcomes. We also want to be cautious here, because we don’t know when neuroplasticity stops being a good thing. I believe everything is about balance, so it is good to remain critical. As my colleague Erwin Krediet once said to me: “A plant doesn’t survive when you give it fertiliser every day, it’s too much.”

References:

1. Griffiths, R. R., Richards, W. A., McCann, U., & Jesse, R. (2006). Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology, 187(3), 268–292.

2. Griffiths, R. R., Johnson, M. W., Richards, W. A., Richards, B. D., McCann, U., & Jesse, R. (2011). Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects. Psychopharmacology, 218(4), 649–665.

3. Carhart-Harris, R. L., Bolstridge, M., Day, C., Rucker, J., Watts, R., Erritzoe, D. E., Kaelen, M., Giribaldi, B., Bloomfield, M., Pilling, S., Rickard, J. A., Forbes, B., Feilding, A., Taylor, D., Curran, H. V., & Nutt, D. J. (2018). Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology, 235(2), 399–408.

4. Johnson, M. W., Garcia-Romeu, A., & Griffiths, R. R. (2017). Long-term follow-up of psilocybin-facilitated smoking cessation. The American journal of drug and alcohol abuse, 43(1), 55–60.

5. Bogenschutz, M. P., Forcehimes, A. A., Pommy, J. A., Wilcox, C. E., Barbosa, P. C., & Strassman, R. J. (2015). Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study. Journal of psychopharmacology (Oxford, England), 29(3), 289–299.

6. de Vos, C., Mason, N. L., & Kuypers, K. (2021). Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics. Frontiers in psychiatry, 12, 724606.

Illustration modified version of Milad Fakurian on Unsplash

Habenula Connectivity and Intravenous Ketamine in Treatment-Resistant Depression

Abstract

Background: Ketamine’s potent and rapid antidepressant properties have shown great promise to treat severe forms of major depressive disorder (MDD). A recently hypothesized antidepressant mechanism of action of ketamine is the inhibition of N-methyl-D-aspartate receptor-dependent bursting activity of the habenula (Hb), a small brain structure that modulates reward and affective states.

Methods: Resting-state functional magnetic resonance imaging was conducted in 35 patients with MDD at baseline and 24 hours following treatment with i.v. ketamine. A seed-to-voxel functional connectivity (FC) analysis was performed with the Hb as a seed-of-interest. Pre-post changes in FC and the associations between changes in FC of the Hb and depressive symptom severity were examined.

Results: A reduction in Montgomery-Åsberg Depression Rating Scale scores from baseline to 24 hours after ketamine infusion was associated with increased FC between the right Hb and a cluster in the right frontal pole (t = 4.65, P = .03, false discovery rate [FDR]-corrected). A reduction in Quick Inventory of Depressive Symptomatology-Self Report score following ketamine was associated with increased FC between the right Hb and clusters in the right occipital pole (t = 5.18, P < .0001, FDR-corrected), right temporal pole (t = 4.97, P < .0001, FDR-corrected), right parahippocampal gyrus (t = 5.80, P = .001, FDR-corrected), and left lateral occipital cortex (t = 4.73, P = .03, FDR-corrected). Given the small size of the Hb, it is possible that peri-habenular regions contributed to the results.

Conclusions: These preliminary results suggest that the Hb might be involved in ketamine’s antidepressant action in patients with MDD, although these findings are limited by the lack of a control group.

Rivas-Grajales, A. M., Salas, R., Robinson, M. E., Qi, K., Murrough, J. W., & Mathew, S. J. (2021). Habenula Connectivity and Intravenous Ketamine in Treatment-Resistant Depression. The international journal of neuropsychopharmacology, 24(5), 383–391. https://doi.org/10.1093/ijnp/pyaa089

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Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice

Abstract

Depression is a widespread and devastating mental illness and the search for rapid-acting antidepressants remains critical. There is now exciting evidence that the psychedelic compound psilocybin produces not only powerful alterations of consciousness, but also rapid and persistent antidepressant effects. How psilocybin exerts its therapeutic actions is not known, but it is widely presumed that these actions require altered consciousness, which is known to be dependent on serotonin 2A receptor (5-HT2AR) activation. This hypothesis has never been tested, however. We therefore asked whether psilocybin would exert antidepressant-like responses in mice and, if so, whether these responses required 5-HT2AR activation. Using chronically stressed male mice, we observed that a single injection of psilocybin reversed anhedonic responses assessed with the sucrose preference and female urine preference tests. The antianhedonic response to psilocybin was accompanied by a strengthening of excitatory synapses in the hippocampus-a characteristic of traditional and fast-acting antidepressants. Neither behavioral nor electrophysiological responses to psilocybin were prevented by pretreatment with the 5-HT2A/2C antagonist ketanserin, despite positive evidence of ketanserin’s efficacy. We conclude that psilocybin’s mechanism of antidepressant action can be studied in animal models and suggest that altered perception may not be required for its antidepressant effects. We further suggest that a 5-HT2AR-independent restoration of synaptic strength in cortico-mesolimbic reward circuits may contribute to its antidepressant action. The possibility of combining psychedelic compounds and a 5-HT2AR antagonist offers a potential means to increase their acceptance and clinical utility and should be studied in human depression.

Hesselgrave, N., Troppoli, T. A., Wulff, A. B., Cole, A. B., & Thompson, S. M. (2021). Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice. Proceedings of the National Academy of Sciences of the United States of America, 118(17), e2022489118. https://doi.org/10.1073/pnas.2022489118

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Spontaneous and deliberate creative cognition during and after psilocybin exposure

Abstract

Creativity is an essential cognitive ability linked to all areas of our everyday functioning. Thus, finding a way to enhance it is of broad interest. A large number of anecdotal reports suggest that the consumption of psychedelic drugs can enhance creative thinking; however, scientific evidence is lacking. Following a double-blind, placebo-controlled, parallel-group design, we demonstrated that psilocybin (0.17 mg/kg) induced a time- and construct-related differentiation of effects on creative thinking. Acutely, psilocybin increased ratings of (spontaneous) creative insights, while decreasing (deliberate) task-based creativity. Seven days after psilocybin, number of novel ideas increased. Furthermore, we utilized an ultrahigh field multimodal brain imaging approach, and found that acute and persisting effects were predicted by within- and between-network connectivity of the default mode network. Findings add some support to historical claims that psychedelics can influence aspects of the creative process, potentially indicating them as a tool to investigate creativity and subsequent underlying neural mechanisms. Trial NL6007; psilocybin as a tool for enhanced cognitive flexibility; https://www.trialregister.nl/trial/6007 .

Mason, N. L., Kuypers, K., Reckweg, J. T., Müller, F., Tse, D., Da Rios, B., Toennes, S. W., Stiers, P., Feilding, A., & Ramaekers, J. G. (2021). Spontaneous and deliberate creative cognition during and after psilocybin exposure. Translational psychiatry, 11(1), 209. https://doi.org/10.1038/s41398-021-01335-5

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

Abstract

The interest in lysergic acid diethylamide (LSD) has sparked again due to its supposed positive effects on psychopathological conditions. Yet, most research focuses on the actions of LSD on the central nervous system. The interaction with the autonomic nervous system (ANS) has been neglected so far. Therefore, the aim was to assess the effects of LSD and the serotonin 2A receptor antagonist ketanserin on the ANS as assessed by heart rate variability (HRV) measures and their correlation with subjective drug-induced effects in a randomized, placebo-controlled crossover trial. Thus, ANS activity was derived from electrocardiogram recordings after intake of placebo, LSD or ketanserin, and LSD by calculating R-peak-based measures of sympathetic and parasympathetic activity. Repeated measure ANOVA and partial correlation for HRV measures and subjective experience questionnaires were performed. LSD predominantly increased sympathetic activity, while ketanserin counteracted this effect on the ANS via an increase of parasympathetic tone. Sympathetic activity was positively and parasympathetic activity negatively associated with psychedelic effects of LSD. Furthermore, Placebo HRV measures predicted subjective experiences after LSD intake. The association between trait ANS activity and LSD-induced subjective experiences may serve as a candidate biomarker set for the effectiveness of LSD in the treatment of psychopathological conditions.

Olbrich, S., Preller, K. H., & Vollenweider, F. X. (2021). LSD and ketanserin and their impact on the human autonomic nervous system. Psychophysiology, 58(6), e13822. https://doi.org/10.1111/psyp.13822

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Predicting Reactions to Psychedelic Drugs: A Systematic Review of States and Traits Related to Acute Drug Effects

Abstract

Psychedelic drugs are increasingly being incorporated into therapeutic contexts for the purposes of promoting mental health. However, they can also induce adverse reactions in some individuals, and it is difficult to predict before treatment who is likely to experience positive or adverse acute effects. Although consideration of setting and dosage as well as excluding individuals with psychotic predispositions has thus far led to a high degree of safety, it is imperative that researchers develop a more nuanced understanding of how to predict individual reactions. To this end, the current systematic review coalesced the results of 14 studies that included baseline states or traits predictive of the acute effects of psychedelics. Individuals high in the traits of absorption, openness, and acceptance as well as a state of surrender were more likely to have positive and mystical-type experiences, whereas those low in openness and surrender or in preoccupied, apprehensive, or confused psychological states were more likely to experience acute adverse reactions. Participant sex was not a robust predictor of drug effects, but 5-HT2AR binding potential, executive network node diversity, and rACC volume may be potential baseline biomarkers related to acute reactions. Finally, increased age and experience with psychedelics were individual differences related to generally less intense effects, indicating that users may become slightly less sensitive to the effects of the drugs after repeated usage. Although future well-powered, placebo-controlled trials directly comparing the relative importance of these predictors is needed, this review synthesizes the field’s current understanding of how to predict acute reactions to psychedelic drugs.

Aday, J. S., Davis, A. K., Mitzkovitz, C. M., Bloesch, E. K., & Davoli, C. C. (2021). Predicting Reactions to Psychedelic Drugs: A Systematic Review of States and Traits Related to Acute Drug Effects. ACS pharmacology & translational science, 4(2), 424–435. https://doi.org/10.1021/acsptsci.1c00014

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Lysergic acid diethylamide differentially modulates the reticular thalamus, mediodorsal thalamus, and infralimbic prefrontal cortex: An in vivo electrophysiology study in male mice

Abstract

Background: The reticular thalamus gates thalamocortical information flow via finely tuned inhibition of thalamocortical cells in the mediodorsal thalamus. Brain imaging studies in humans show that the psychedelic lysergic acid diethylamide (LSD) modulates activity and connectivity within the cortico-striato-thalamo-cortical (CSTC) circuit, altering consciousness. However, the electrophysiological effects of LSD on the neurons in these brain areas remain elusive.

Methods: We employed in vivo extracellular single-unit recordings in anesthetized adult male mice to investigate the dose-response effects of cumulative LSD doses (5-160 µg/kg, intraperitoneal) upon reticular thalamus GABAergic neurons, thalamocortical relay neurons of the mediodorsal thalamus, and pyramidal neurons of the infralimbic prefrontal cortex.

Results: LSD decreased spontaneous firing and burst-firing activity in 50% of the recorded reticular thalamus neurons in a dose-response fashion starting at 10 µg/kg. Another population of neurons (50%) increased firing and burst-firing activity starting at 40 µg/kg. This modulation was accompanied by an increase in firing and burst-firing activity of thalamocortical neurons in the mediodorsal thalamus. On the contrary, LSD excited infralimbic prefrontal cortex pyramidal neurons only at the highest dose tested (160 µg/kg). The dopamine D2 receptor (D2) antagonist haloperidol administered after LSD increased burst-firing activity in the reticular thalamus neurons inhibited by LSD, decreased firing and burst-firing activity in the mediodorsal thalamus, and showed a trend towards further increasing the firing activity of neurons of the infralimbic prefrontal cortex.

Conclusion: LSD modulates firing and burst-firing activity of reticular thalamus neurons and disinhibits mediodorsal thalamus relay neurons at least partially in a D2-mediated fashion. These effects of LSD on thalamocortical gating could explain its consciousness-altering effects in humans.

Inserra, A., De Gregorio, D., Rezai, T., Lopez-Canul, M. G., Comai, S., & Gobbi, G. (2021). Lysergic acid diethylamide differentially modulates the reticular thalamus, mediodorsal thalamus, and infralimbic prefrontal cortex: An in vivo electrophysiology study in male mice. Journal of psychopharmacology (Oxford, England), 35(4), 469–482. https://doi.org/10.1177/0269881121991569

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Functional connectivity between the amygdala and subgenual cingulate gyrus predicts the antidepressant effects of ketamine in patients with treatment-resistant depression

Aim: Approximately one-third of patients with major depressive disorder develop treatment-resistant depression. One-third of patients with treatment-resistant depression demonstrate resistance to ketamine, which is a novel antidepressant effective for this disorder. The objective of this study was to examine the utility of resting-state functional magnetic resonance imaging for the prediction of treatment response to ketamine in treatment-resistant depression.

Methods: An exploratory seed-based resting-state functional magnetic resonance imaging analysis was performed to examine baseline resting-state functional connectivity differences between ketamine responders and nonresponders before treatment with multiple intravenous ketamine infusions.

Results: Fifteen patients with treatment-resistant depression received multiple intravenous subanesthetic (0.5 mg/kg/40 minutes) ketamine infusions, and nine were identified as responders. The exploratory resting-state functional magnetic resonance imaging analysis identified a cluster of significant baseline resting-state functional connectivity differences associating ketamine response between the amygdala and subgenual anterior cingulate gyrus in the right hemisphere. Using anatomical region of interest analysis of the resting-state functional connectivity, ketamine response was predicted with 88.9% sensitivity and 100% specificity. The resting-state functional connectivity of significant group differences between responders and nonresponders retained throughout the treatment were considered a trait-like feature of heterogeneity in treatment-resistant depression.

Conclusion: This study suggests the possible clinical utility of resting-state functional magnetic resonance imaging for predicting the antidepressant effects of ketamine in treatment-resistant depression patients and implicated resting-state functional connectivity alterations to determine the trait-like pathophysiology underlying treatment response heterogeneity in treatment-resistant depression.

Nakamura, T., Tomita, M., Horikawa, N., Ishibashi, M., Uematsu, K., Hiraki, T., Abe, T., & Uchimura, N. (2021). Functional connectivity between the amygdala and subgenual cingulate gyrus predicts the antidepressant effects of ketamine in patients with treatment-resistant depression. Neuropsychopharmacology reports, 41(2), 168–178. https://doi.org/10.1002/npr2.12165

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

Abstract

Background: N,N-dimethyltryptamine is a short-acting psychedelic tryptamine found naturally in many plants and animals. Few studies to date have addressed the neural and psychological effects of N,N-dimethyltryptamine alone, either administered intravenously or inhaled in freebase form, and none have been conducted in natural settings.

Aims: Our primary aim was to study the acute effects of inhaled N,N-dimethyltryptamine in natural settings, focusing on questions tuned to the advantages of conducting field research, including the effects of contextual factors (i.e. “set” and “setting”), the possibility of studying a comparatively large number of subjects, and the relaxed mental state of participants consuming N,N-dimethyltryptamine in familiar and comfortable settings.

Methods: We combined state-of-the-art wireless electroencephalography with psychometric questionnaires to study the neural and subjective effects of naturalistic N,N-dimethyltryptamine use in 35 healthy and experienced participants.

Results: We observed that N,N-dimethyltryptamine significantly decreased the power of alpha (8-12 Hz) oscillations throughout all scalp locations, while simultaneously increasing power of delta (1-4 Hz) and gamma (30-40 Hz) oscillations. Gamma power increases correlated with subjective reports indicative of some features of mystical-type experiences. N,N-dimethyltryptamine also increased global synchrony and metastability in the gamma band while decreasing those measures in the alpha band.

Conclusions: Our results are consistent with previous studies of psychedelic action in the human brain, while at the same time the results suggest potential electroencephalography markers of mystical-type experiences in natural settings, thus highlighting the importance of investigating these compounds in the contexts where they are naturally consumed.

Pallavicini, C., Cavanna, F., Zamberlan, F., de la Fuente, L. A., Ilksoy, Y., Perl, Y. S., Arias, M., Romero, C., Carhart-Harris, R., Timmermann, C., & Tagliazucchi, E. (2021). Neural and subjective effects of inhaled N,N-dimethyltryptamine in natural settings. Journal of psychopharmacology (Oxford, England), 35(4), 406–420. https://doi.org/10.1177/0269881120981384

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Lysergic acid diethylamide (LSD) promotes social behavior through mTORC1 in the excitatory neurotransmission

Abstract

Clinical studies have reported that the psychedelic lysergic acid diethylamide (LSD) enhances empathy and social behavior (SB) in humans, but its mechanism of action remains elusive. Using a multidisciplinary approach including in vivo electrophysiology, optogenetics, behavioral paradigms, and molecular biology, the effects of LSD on SB and glutamatergic neurotransmission in the medial prefrontal cortex (mPFC) were studied in male mice. Acute LSD (30 μg/kg) injection failed to increase SB. However, repeated LSD (30 μg/kg, once a day, for 7 days) administration promotes SB, without eliciting antidepressant/anxiolytic-like effects. Optogenetic inhibition of mPFC excitatory neurons dramatically inhibits social interaction and nullifies the prosocial effect of LSD. LSD potentiates the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and 5-HT2A, but not N-methyl-D-aspartate (NMDA) and 5-HT1A, synaptic responses in the mPFC and increases the phosphorylation of the serine-threonine protein kinases Akt and mTOR. In conditional knockout mice lacking Raptor (one of the structural components of the mTORC1 complex) in excitatory glutamatergic neurons (Raptor f/f :Camk2alpha-Cre), the prosocial effects of LSD and the potentiation of 5-HT2A/AMPA synaptic responses were nullified, demonstrating that LSD requires the integrity of mTORC1 in excitatory neurons to promote SB. Conversely, in knockout mice lacking Raptor in GABAergic neurons of the mPFC (Raptor f/f :Gad2-Cre), LSD promotes SB. These results indicate that LSD selectively enhances SB by potentiating mPFC excitatory transmission through 5-HT2A/AMPA receptors and mTOR signaling. The activation of 5-HT2A/AMPA/mTORC1 in the mPFC by psychedelic drugs should be explored for the treatment of mental diseases with SB impairments such as autism spectrum disorder and social anxiety disorder.

De Gregorio, D., Popic, J., Enns, J. P., Inserra, A., Skalecka, A., Markopoulos, A., Posa, L., Lopez-Canul, M., Qianzi, H., Lafferty, C. K., Britt, J. P., Comai, S., Aguilar-Valles, A., Sonenberg, N., & Gobbi, G. (2021). Lysergic acid diethylamide (LSD) promotes social behavior through mTORC1 in the excitatory neurotransmission. Proceedings of the National Academy of Sciences of the United States of America, 118(5), e2020705118. https://doi.org/10.1073/pnas.2020705118

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