OPEN Foundation

Psychopharmacology

The Evolved Psychology of Psychedelic Set and Setting: Inferences Regarding the Roles of Shamanism and Entheogenic Ecopsychology

March 14, 2022 / Anthropology, History, Indigenous use, Mushrooms / Psilocybin, Other disciplines, Papers, Psychopharmacology, Spirituality / Leave a Comment / By /

Abstract

This review illustrates the relevance of shamanism and its evolution under effects of psilocybin as a framework for identifying evolved aspects of psychedelic set and setting. Effects of 5HT2 psychedelics on serotonin, stress adaptation, visual systems and personality illustrate adaptive mechanisms through which psychedelics could have enhanced hominin evolution as an environmental factor influencing selection for features of our evolved psychology. Evolutionary psychology perspectives on ritual, shamanism and psychedelics provides bases for inferences regarding psychedelics’ likely roles in hominin evolution as exogenous neurotransmitter sources through their effects in selection for innate dispositions for psychedelic set and setting. Psychedelics stimulate ancient brain structures and innate modular thought modules, especially self-awareness, other awareness, “mind reading,” spatial and visual intelligences. The integration of these innate modules are also core features of shamanism. Cross-cultural research illustrates shamanism is an empirical phenomenon of foraging societies, with its ancient basis in collective hominid displays, ritual alterations of consciousness, and endogenous healing responses. Shamanic practices employed psychedelics and manipulated extrapharmacological effects through stimulation of serotonin and dopamine systems and augmenting processes of the reptilian and paleomammalian brains. Differences between chimpanzee maximal displays and shamanic rituals reveal a zone of proximal development in hominin evolution. The evolution of the mimetic capacity for enactment, dance, music, and imitation provided central capacities underlying shamanic performances. Other chimp-human differences in ritualized behaviors are directly related to psychedelic effects and their integration of innate modular thought processes. Psychedelics and other ritual alterations of consciousness stimulate these and other innate responses such as soul flight and death-and-rebirth experiences. These findings provided bases for making inferences regarding foundations of our evolved set, setting and psychology. Shamanic setting is eminently communal with singing, drumming, dancing and dramatic displays. Innate modular thought structures are prominent features of the set of shamanism, exemplified in animism, animal identities, perceptions of spirits, and psychological incorporation of spirit others. A shamanic-informed psychedelic therapy includes: a preparatory set with practices such as sexual abstinence, fasting and dream incubation; a set derived from innate modular cognitive capacities and their integration expressed in a relational animistic worldview; a focus on internal imagery manifesting a presentational intelligence; and spirit relations involving incorporation of animals as personal powers. Psychedelic research and treatment can adopt this shamanic biogenetic paradigm to optimize set, setting and ritual frameworks to enhance psychedelic effects.

Winkelman M. J. (2021). The Evolved Psychology of Psychedelic Set and Setting: Inferences Regarding the Roles of Shamanism and Entheogenic Ecopsychology. Frontiers in pharmacology, 12, 619890. https://doi.org/10.3389/fphar.2021.619890

Link to full text

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

February 6, 2022 / Depression, Ketamine, Neuroscience, Papers, Psychiatry, Psychopharmacology / Leave a Comment / By / , , , , , , ,

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

Link to full text

First study of safety and tolerability of 3,4-methylenedioxymethamphetamine-assisted psychotherapy in patients with alcohol use disorder

February 6, 2022 / Addiction, MDMA, Papers, Psychopharmacology, Psychotherapy, Safety / Leave a Comment / By / , , , , , , , , , , , , ,

Abstract

Background: 3,4-methylenedioxymethamphetamine (MDMA) therapy has qualities that make it potentially well suited for patients with addictions, but this has never been explored in a research study. We present data from the Bristol Imperial MDMA in Alcoholism (BIMA) study. This is the first MDMA addiction study, an open-label safety and tolerability proof-of-concept study investigating the potential role for MDMA therapy in treating patients with alcohol use disorder (AUD).

Aims: This study aimed to assess if MDMA-assisted psychotherapy can be delivered safely and can be tolerated by patients with AUD post detoxification. Outcomes regarding drinking behaviour, quality of life and psychosocial functioning were evaluated.

Methods: Fourteen patients with AUD completed a community alcohol detoxification and received an eight-week course of recovery-based therapy. Participants received two sessions with MDMA (187.5 mg each session). Psychological support was provided before, during and after each session. Safety and tolerability were assessed alongside psychological and physiological outcome measures. Alcohol use behaviour, mental well-being and functioning data were collected for nine months after alcohol detoxification.

Results: MDMA treatment was well tolerated by all participants. No unexpected adverse events were observed. Psychosocial functioning improved across the cohort. Regarding alcohol use, at nine months post detox, the average units of alcohol consumption by participants was 18.7 units per week compared to 130.6 units per week before the detox. This compares favourably to a previous observational study (the ‘Outcomes’ study) by the same team with a similar population of people with AUD.

Conclusions: This study provides preliminary support for the safety and tolerability of a novel intervention for AUD post detox. Further trials to examine better the therapeutic potential of this approach are now indicated.

Sessa, B., Higbed, L., O’Brien, S., Durant, C., Sakal, C., Titheradge, D., Williams, T. M., Rose-Morris, A., Brew-Girard, E., Burrows, S., Wiseman, C., Wilson, S., Rickard, J., & Nutt, D. J. (2021). First study of safety and tolerability of 3,4-methylenedioxymethamphetamine-assisted psychotherapy in patients with alcohol use disorder. Journal of psychopharmacology (Oxford, England), 35(4), 375–383. https://doi.org/10.1177/0269881121991792

Link to full text

Single, Fixed-Dose Intranasal Ketamine for Alleviation of Acute Suicidal Ideation. An Emergency Department, Trans-Diagnostic Approach: A Randomized, Double-Blind, Placebo-Controlled, Proof-of-Concept Trial

February 6, 2022 / Depression, Ketamine, Medicine, Papers, Psychiatry, Psychopharmacology / Leave a Comment / By / ,

Abstract

Background: Suicidal patients often present to the emergency department, where specific anti-suicidal treatment is lacking. Ketamine, a Glutamate modulator and a rapidly acting antidepressant with anti-suicidal properties, might offer relief.

Aims: Evaluation of single, fixed-dosed intranasal ketamine for acute suicidal ideation in the emergency department.

Methods: Between August 2016 and April 2018, 30 eligible suicidal subjects, scheduled for psychiatric hospitalization, independently of their psychiatric diagnosis, were randomized to intranasal ketamine 40 mg or saline placebo. Safety and efficacy evaluations were scheduled for 30, 60, 120 and 240 min post administration and on days 1, 2, 3, 4, 5, 7, 21 and 28. Primary outcome was suicidal ideation.

Results: Fifteen subjects were randomized for each study group. All were analyzed for primary and secondary outcomes. Four hours post administration, the mean difference in suicidal symptoms between the groups, measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) item of suicidal thoughts (MADRS-SI), was 1.267 (95% confident interval 0.1-2.43, p < 0.05) favoring treatment. Remission from suicidal ideation was evident in 80% for the ketamine group compared with 33% for the controls (p < 0.05). The mean difference in depressive symptoms, measured by MADRS, at the same time was 9.75 (95% confident interval 0.72-18.79, p < 0.05) favoring ketamine. Treatment was safe and well-tolerated. Conclusions: Single, fixed-dose, intranasal ketamine alleviated suicidal ideation and improved depressive symptoms four hours post administration. We present here an innovative paradigm for emergency department management of suicidal individuals. Future larger-scale studies are warranted. ClinicalTrials.gov Identifier: NCT02183272.

Domany, Y., & McCullumsmith, C. B. (2021). Single, Fixed-Dose Intranasal Ketamine for Alleviation of Acute Suicidal Ideation. An Emergency Department, Trans-Diagnostic Approach: A Randomized, Double-Blind, Placebo-Controlled, Proof-of-Concept Trial. Archives of suicide research : official journal of the International Academy for Suicide Research, 1–16. Advance online publication. https://doi.org/10.1080/13811118.2021.1878078

Link to full text

What is the clinical evidence on psilocybin for the treatment of psychiatric disorders? A systematic review

June 17, 2022 / Addiction, Depression, Mushrooms / Psilocybin, Papers, Psychiatry, Psychopharmacology, Psychotherapy / Leave a Comment / By / ,

Abstract

Background: Psilocybin is a predominant agonist of 5HT1A and 5HT2A/C receptors and was first isolated in 1958, shortly before it became a controlled substance. Research on the potential therapeutic effects of this compound has recently re-emerged alongside what is being addressed as a psychedelic renaissance.

Methods: In this paper we performed a systematic review of the clinical trials conducted so far regarding the therapeutic effects of psilocybin on psychiatric disorders. The eligibility criteria included clinical trials that assessed psilocybin’s potential therapeutic effects on patients with psychiatric disorders. Nine hundred seven articles were found and screened in regard to the title, from which 94 were screened through abstract and 9 met the eligibility criteria and were included.

Results: The papers published focused on 3 disorders: depression, obsessive-compulsive disorder (OCD) and substance use disorder (namely tobacco and alcohol). Psilocybin has shown a relatively safe profile and very promising results, with reductions found on most of the psychiatric rating scales’ scores. Research on depression showed the most solid evidence, supported by 3 randomized controlled trials. Studies on OCD and substance use disorder showed more limitations due to their open-label design.

Conclusions: Altogether, the results from the studies reviewed in this paper suggest a substantial therapeutic potential. This calls for further research to confirm the results observed so far and further explain the underlying mechanisms.

Castro Santos, H., & Gama Marques, J. (2021). What is the clinical evidence on psilocybin for the treatment of psychiatric disorders? A systematic review. Porto biomedical journal, 6(1), e128. https://doi.org/10.1097/j.pbj.0000000000000128

Link to full text

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

February 6, 2022 / DMT, Neuroscience, Papers, Psychopharmacology, Spirituality / Leave a Comment / By / , , , , , , , , , ,

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

Link to full text

Pharmacokinetics and Pharmacodynamics of Salvinorin A and Salvia divinorum: Clinical and Forensic Aspects

February 6, 2022 / Papers, Psychopharmacology, Salvia / Salvinorin A / Leave a Comment / By / , , , ,

Abstract

Salvia divinorum Epling and Játiva is a perennial mint from the Lamiaceae family, endemic to Mexico, predominantly from the state of Oaxaca. Due to its psychoactive properties, S. divinorum had been used for centuries by Mazatecans for divinatory, religious, and medicinal purposes. In recent years, its use for recreational purposes, especially among adolescents and young adults, has progressively increased. The main bioactive compound underlying the hallucinogenic effects, salvinorin A, is a non-nitrogenous diterpenoid with high affinity and selectivity for the k-opioid receptor. The aim of this work is to comprehensively review and discuss the toxicokinetics and toxicodynamics of S. divinorum and salvinorin A, highlighting their psychological, physiological, and toxic effects. Potential therapeutic applications and forensic aspects are also covered in this review. The leaves of S. divinorum can be chewed, drunk as an infusion, smoked, or vaporised. Absorption of salvinorin A occurs through the oral mucosa or the respiratory tract, being rapidly broken down in the gastrointestinal system to its major inactive metabolite, salvinorin B, when swallowed. Salvinorin A is rapidly distributed, with accumulation in the brain, and quickly eliminated. Its pharmacokinetic parameters parallel well with the short-lived psychoactive and physiological effects. No reports on toxicity or serious adverse outcomes were found. A variety of therapeutic applications have been proposed for S. divinorum which includes the treatment of chronic pain, gastrointestinal and mood disorders, neurological diseases, and treatment of drug dependence. Notwithstanding, there is still limited knowledge regarding the pharmacology and toxicology features of S. divinorum and salvinorin A, and this is needed due to its widespread use. Additionally, the clinical acceptance of salvinorin A has been hampered, especially due to the psychotropic side effects and misuse, turning the scientific community to the development of analogues with better pharmacological profiles.

Brito-da-Costa, A. M., Dias-da-Silva, D., Gomes, N., Dinis-Oliveira, R. J., & Madureira-Carvalho, Á. (2021). Pharmacokinetics and Pharmacodynamics of Salvinorin A and Salvia divinorum: Clinical and Forensic Aspects. Pharmaceuticals (Basel, Switzerland), 14(2), 116. https://doi.org/10.3390/ph14020116

Link to full text

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

February 6, 2022 / LSD, Neuroscience, Papers, Psychology, Psychopharmacology / Leave a Comment / By / , , , , , , , , , , , , , ,

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

Link to full text

Within-treatment changes in a novel addiction treatment program using traditional Amazonian medicine

March 14, 2022 / Addiction, Ayahuasca, Papers, Psychology, Psychopharmacology, Psychotherapy / Leave a Comment / By / , , , ,

Abstract

Aims: The therapeutic use of psychedelics is regaining scientific momentum, but similarly psychoactive ethnobotanical substances have a long history of medical (and other) uses in indigenous contexts. Here we aimed to evaluate patient outcomes in a residential addiction treatment center that employs a novel combination of Western and traditional Amazonian methods.

Methods: The study was observational, with repeated measures applied throughout treatment. All tests were administered in the center, which is located in Tarapoto, Peru. Data were collected between 2014 and 2015, and the study sample consisted of 36 male inpatients who were motivated to seek treatment and who entered into treatment voluntarily. Around 58% of the sample was from South America, 28% from Europe, and the remaining 14% from North America. We primarily employed repeated measures on a psychological test battery administered throughout treatment, measuring perceived stress, craving frequency, mental illness symptoms, spiritual well-being, and physical and emotional health. Addiction severity was measured on intake, and neuropsychological performance was assessed in a subsample from intake to at least 2 months into treatment.

Results: Statistically significant and clinically positive changes were found across all repeated measures. These changes appeared early in the treatment and were maintained over time. Significant improvements were also found for neuropsychological functioning.

Conclusion: These results provide evidence for treatment safety in a highly novel addiction treatment setting, while also suggesting positive therapeutic effects.

O’Shaughnessy, D. M., Berlowitz, I., Rodd, R., Sarnyai, Z., & Quirk, F. (2021). Within-treatment changes in a novel addiction treatment program using traditional Amazonian medicine. Therapeutic advances in psychopharmacology, 11, 2045125320986634. https://doi.org/10.1177/2045125320986634

Link to full text

Ketamine and Serotonergic Psychedelics: Common Mechanisms Underlying the Effects of Rapid-Acting Antidepressants

January 7, 2022 / Depression, Ketamine, Neuroscience, Other substances, Papers, Psychiatry, Psychopharmacology, Psychotherapy / Leave a Comment / By / , , , , , ,

Abstract

Background: The glutamatergic modulator ketamine has created a blueprint for studying novel pharmaceuticals in the field. Recent studies suggest that “classic” serotonergic psychedelics (SPs) may also have antidepressant efficacy. Both ketamine and SPs appear to produce rapid, sustained antidepressant effects after a transient psychoactive period.

Methods: This review summarizes areas of overlap between SP and ketamine research and considers the possibility of a common, downstream mechanism of action. The therapeutic relevance of the psychoactive state, overlapping cellular and molecular effects, and overlapping electrophysiological and neuroimaging observations are all reviewed.

Results: Taken together, the evidence suggests a potentially shared mechanism wherein both ketamine and SPs may engender rapid neuroplastic effects in a glutamatergic activity-dependent manner. It is postulated that, though distinct, both ketamine and SPs appear to produce acute alterations in cortical network activity that may initially produce psychoactive effects and later produce milder, sustained changes in network efficiency associated with therapeutic response. However, despite some commonalities between the psychoactive component of these pharmacologically distinct therapies-such as engagement of the downstream glutamatergic pathway-the connection between psychoactive impact and antidepressant efficacy remains unclear and requires more rigorous research.

Conclusions: Rapid-acting antidepressants currently under investigation may share some downstream pharmacological effects, suggesting that their antidepressant effects may come about via related mechanisms. Given the prototypic nature of ketamine research and recent progress in this area, this platform could be used to investigate entirely new classes of antidepressants with rapid and robust actions.

Kadriu, B., Greenwald, M., Henter, I. D., Gilbert, J. R., Kraus, C., Park, L. T., & Zarate, C. A. (2021). Ketamine and Serotonergic Psychedelics: Common Mechanisms Underlying the Effects of Rapid-Acting Antidepressants. The international journal of neuropsychopharmacology, 24(1), 8–21. https://doi.org/10.1093/ijnp/pyaa087

Link to full text

7 May - Psychedelics, Nature & Mental Health with Sam Gandy

REGISTER NOW!
X