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... Entactogens are used for both basic and clinical research, and experimental therapy, but also in recreational and psychospiritual settings where this practice is illicit or strictly regulated due to health concerns. Millions of people worldwide consume entactogens as recreational drugs at rave parties because they induce the feeling of euphoria, sharpened sensory perception and a greater capacity for social interactions (1). ...
... The O-demethylenation represents the main pathway which was predicted for almost all investigated molecules (96 %) with exception of 1-(2,2-difluorobenzo[d] [1,3]dioxol-5-yl) propan-2-amine (DiFMDA, 23) in which the 2,2-disubstitution enhanced the metabolic stability of this drug (50). For this metabolic reaction the main cytochrome P450 enzymes, i.e., CYP1A2 and 2D6 were predicted with the highest probability, however, CYP2C9, 2C19 and 3A4 were also predicted, but to significantly less extent (Table S-6-1). ...
... The relationship between lipophilicity MlogP of entactogens is Fig. 6. The highest Th_pyr_ pIGC 50 scores were obtained for N- (1-(benzo[d] [1,3]dioxol-5-yl)propan-2-yl)hydroxyl-amine (MDOH, 12) and N- (1-(benzo[d] [1,3] , 14), which might suggest that the presence of N-O bond in the entactogen structure reduces toxicity against T. pyriformis as was the case with increase of lipophilicity. ...
The impact of the selected entactogens and their o -quinone metabolites on the environment was explored in QSAR studies by the use of predicted molecular descriptors, ADMET properties and environmental toxicity parameters, i.e. , acute toxicity in Tetrahymena pyriformis (TOX_ATTP) expressed as Th_pyr_pIGC50 /mmol L ⁻¹ , acute toxicity in Pimephales promelas , the fathead minnow (TOX_FHM) expressed as Minnow LC50 /mg L ⁻¹ , the acute toxicity in Daphnia magna (TOX_DM) expressed as Daphnia LC50 /mg L ⁻¹ and bioconcentration factor (BCF).
The formation of corresponding o -quinones via benzo-dioxo-lone ring, O -demethylenation was predicted as the main metabolic pathway for all entactogens except for 1-(2,2-difluorobenzo[ d ][1,3]dioxol-5-yl)propan-2-amine (DiFMDA). The least favourable ADMET profile was revealed for N -(1-(benzo[ d ][1,3]dioxol-5-yl)propan-2-yl)- O- methylhydroxylamine (MDMEO).
QSAR studies revealed significant linear correlations between MlogP of entactogens and MlogP of o -quinone metabolites ( R = 0.99), and Th_pyr_pIGC50 /mmol L ⁻¹ ( R = 0.94), also their MlogP s with Minnow_LC50 /mg L ⁻¹ ( R = 0.80 and R = 0.78), BCF ( R = 0.86 and R = 0.82) and percentage of o -quinones’ yields ( R = 0.73 and R = 0.80). Entactogens were predicted as non-biodegradable molecules, whereas the majority of their o -quinones were biodegradable.
... Classic psychedelics and MDMA have been found to produce acute and persistent positive personality changes and improved well-being in healthy individuals (Elsey, 2017;Jungaberle et al., 2018). These substances have been linked to heightened mindfulness (Soler et al., 2016, a sense of connection to nature (Forstmann and Sagioglou, 2017), creativity (Kuypers et al., 2016;Uthaug et al., 2018;Mason et al., 2019), and openness (Liechti et al., 2017). ...
... However, the acute and long-term or persistent effects (more relevant for treatment effects) differ substantially , so the specific psychological mechanisms that account for their therapeutic efficacy are still not comprehensively understood. Various acute and persistent effects of psychedelics and entactogens were outlined by Jungaberle et al. (2018) and include, amongst others, positive effects on wellbeing, mood, empathy, cognitive flexibility, self-transcendence, and openness. However, individual experiences might be extremely variable and generalizations based on single sessions and small sample sizes are problematic (Grof, 2000;Bogenschutz et al., 2018) due to different personality structures of the client (Sandison and Whitelaw, 1957;Cohen, 1960;Gucker, 1963) amongst other individual differences. ...
... Thereby, prior fixed beliefs may be more easily challenged and restructured by novel information. This might be reflected by lasting changes in attitudes (i.e., increased openness and extraversion and decreased neuroticism; Erritzoe et al., 2018) and beliefs in individuals who used psychedelics (Nour et al., 2017;Jungaberle et al., 2018). ...
The present narrative review is the first in a series of reviews about the appropriate conduct in substance-assisted psychotherapy (SAPT). It outlines a current perspective onpreconditions and theoretical knowledge that have been identified as valuable in the literaturefor appropriate therapeutic conduct in SAPT. In this context, considerations regarding ethics and the spiritual emphasis of the therapeutic approaches are discussed. Further, current methods, models, and concepts of psychological mechanism of action and therapeutic effects of SAPT are summarized, and similarities between models, approaches, and potential mediators for therapeutic effects are outlined. It is argued that a critical assessment of the literature might indicate that the therapeutic effect of SAPT may be mediated by intra- and interpersonal variables within the therapeutic context rather than specific therapeutic models per se. The review provides a basis for the development and adaptation of future investigations, therapeutic models, training programs for therapists, and those interested in the therapeutic potential of SAPT. Limitations and future directions for research are discussed.
... MDMA has been shown across multiple studies to affect the action of brain systems related to social bonding and positive reinforcement related to social encounters (22). At a subjective level, people ingesting MDMA report feeling peace, safety, and love (27) and a subjective sense of desire to be with others (44), which comports with observations that MDMA increases motivation to affiliate with others during active dosing. At a neurochemical level, MDMA has been shown to induce the release of oxytocin and prolactin, two hormones centrally implicated in the ability to form social connections (45,46). ...
... MDMA-AT participants often report feeling very safe with therapists during dosing sessions (78) and the tendency for MDMA to elicit expressions of warm and positive emotions toward therapists is also likely to elicit reciprocal responding from therapists (120,121). Furthermore, the tendency for MDMA to strengthen emotional responses to positive social stimuli (44,122) is likely to make therapists' responses of compassion and warmth more salient at a visceral level. If the core fear of people with SAD is that the exposure of a seemingly flawed and inferior self will result in rejection and shaming from others (94), then this enhanced therapeutic bond should potentiate corrective interpersonal learning experiences by both encouraging the person to be authentic and thereby reveal this core defective self, while also resulting in a prediction error when the person experiences acceptance and caring as a response, rather than the expected ridicule or rejection. ...
Social anxiety disorder (SAD) is a prevalent and often debilitating psychiatric disorder that can assume a chronic course even when treated. Despite the identification of evidence-based pharmacological and behavioral treatments for SAD, much room for improved outcomes exists and 3,4-methylenedioxymethamphetamine (MDMA) has been proposed as a promising adjunctive treatment to psychological interventions for disorders characterized by social dysfunction. A small randomized, placebo-controlled trial of MDMA-assisted therapy (MDMA-AT) for social anxiety in autistic adults offered encouraging results, but more research is sorely needed to explore the potential for MDMA-AT in treating SAD. This review aims to stimulate future study by summarizing research on disruptions in neurological, perceptual, receptive, and expressive systems regulating social behavior in SAD and proposing how MDMA-AT may alter these systems across four domains. First, we review research highlighting the roles of social anhedonia and reduced social reward sensitivity in maintaining SAD, with specific attention to the reduction in positive affect in social situations, infrequent social approach behaviors, and related social skills deficits. We posit that MDMA-AT may enhance motivation to connect with others and alter perceptions of social reward for an extended period following administration, thereby potentiating extinction processes, and increasing the reinforcement value of social interactions. Second, we review evidence for the central role of heightened social evaluative threat perception in the development and maintenance of SAD and consider how MDMA-AT may enhance experiences of affiliation and safety when interacting with others. Third, we consider the influence of shame and the rigid application of shame regulation strategies as important intrapersonal processes maintaining SAD and propose the generation of self-transcendent emotions during MDMA sessions as a mechanism of shame reduction that may result in corrective emotional experiences and boost memory reconsolidation. Finally, we review research on the role of dysfunctional interpersonal behaviors in SAD that interfere with social functioning and, in particular, the development and maintenance of close and secure relationships. We discuss the hypothesized role of MDMA-AT in improving social skills to elicit positive interpersonal responses from others, creating a greater sense of belonging, acceptance, and social efficacy.
... These drugs differ from other amphetamine derivatives, in that they much more selective for 5-HT transporters, compared with dopamine and glutamate transport 71 . This means they retain some of the characteristic amphetamine stimulant effects, but they also induce feelings of empathy and warmth towards oneself and others; the word that was coined in the 1980s to describe them is 'entactogen' 75 . MDMA analogue toxicity can be resolved into acute and chronic toxicity -the acute toxicity is well understood and described. ...
... In addition, it has to be considered whether the deficits recorded in an individual are because of the drug -were they instead previously psychologically impaired, which somehow predisposes them to take the drug? 75,79 However, a mixture of controlled and compensated neuroimaging, spatial/ motor and other testing protocols has been developed for humans and it appears that chronic use of MDMA does downregulate 5-HT pathway activity 81 , and the drug also impacts motor activity. This translates as a deficit in thalamo-corticostriatal connectivity and behavioural control and the region tries to compensate with increased activity, but to little gain. ...
... Second, the majority of studies on the socioemotional effects of MDMA provide converging evidence that MDMA specifically increases social reward processing (e.g., increased emotional disclosure, increased recognition of positive facial cues; Baggott et al., 2016;Bedi, Hyman, & de Wit, 2010;Bedi, Phan, Angstadt, & de Wit, 2009;Carlyle et al., 2019;Gabay et al., 2018;Hysek, Domes, & Liechti, 2012;Hysek et al., 2014). As a result, MDMA has been discussed as increasing feelings of positive emotional empathy, as well as associated feelings of trust, both within the self and with others, all of which have been posited to improve the therapeutic alliance and treatment outcomes (Bershad, Miller, Baggott, & de Wit, 2016;Jungaberle et al., 2018). Importantly, the experience of emotional empathy implicates awareness and recognition of a variety of emotions both in the self and others, the opposite of which is, arguably, alexithymia, or difficulties in identifying and labeling emotional feelings (Taylor, Bagby, & Parker, 1997). ...
... This in turn might have facilitated approach toward and adaptive reprocessing and reconsolidation of traumatic memories, when empathically supported throughout the dosing and integrations sessions by study therapists Johansen & Krebs, 2009). Second, MDMA might have reduced participants' difficulties in effectively recognizing rewarding internal and external emotional cues in the therapeutic space (e.g., understanding feelings of joy or even euphoria during dosing, and/or recognizing empathic validation by study therapists while revisiting traumatic memories; Bershad et al., 2016;Jungaberle et al., 2018). In removing these alexithymic barriers to adequate emotional engagement with trauma-related memories, MDMA might have also facilitated corrective interpersonal interactions and concurrent PTSD symptom reduction during dosing and integration sessions . ...
MDMA-assisted psychotherapy was shown in previous clinical trials to be efficacious and safe for alleviating treatment-resistant posttraumatic stress disorder (PTSD). However, due to low ethnoracial diversity, the question remains as to whether ethnoracial minority participants would benefit similarly. Thus, in Study 1, ethnoracial differences in PTSD symptoms, secondary outcomes (emotion regulation, alexithymia, self-compassion), and suicidality were examined for a recent multisite, open-label trial of MDMA-assisted psychotherapy. In Study 2, a mixed-methods case study was conducted on an ethnoracial minority participant from the same open-label trial, to provide a culturally informed lens on recovery from PTSD in a participant of color. Lastly, recommendations for diversifying ongoing MDMA-assisted psychotherapy trials were provided.
[Dissertation defended; portions of abstract not shown pending MAPS approval for public release]
... Psychedelics acting as 5-hydroxytryptamine 2A receptor (5-HT 2A R) agonists have gained immense interest as potential treatments for anxiety, substance use disorder, and treatment-resistant depression (Carhart-Harris and Goodwin, 2017;Nichols et al., 2017). Psychedelic drugs are suggested to promote cognitive flexibility through a 5-HT 2A R-mediated increase in brain entropy that possibly underlies the lasting therapeutic effects of these drugs (Petri et al., 2014;Carhart-Harris et al., 2016;Kuypers et al., 2016;Carhart-Harris and Nutt, 2017;Nichols et al., 2017;Jungaberle et al., 2018). Rat studies show that the nonselective 5-HT 2A R agonist lysergic acid diethylamide (LSD) can promote reversal learning (King et al., 1974), while selective blockade of 5-HT 2A Rs impairs reversal learning (Boulougouris et al., 2008;Furr et al., 2012). ...
... Our results also raise attention to challenges with studying cognitive flexibility. If psychedelics induce an entropic state of brain networks and produce lasting changes in psychological measures of cognitive flexibility (MacLean et al., 2011;Carhart-Harris et al., 2016;Jungaberle et al., 2018), then why do they not improve performance in standard tests of cognitive flexibility in the laboratory (Pokorny et al., 2020;Amodeo et al., 2020)? Psychedelics can impair executive functions related to attentional performance (Umbricht et al., 2003;Carter et al., 2005), which could affect performance in other standardized cognitive laboratory tests in humans and rodents, possibly explaining the contradictory results. ...
Psychedelic 5-hydroxytryptamine 2A receptor (5-HT2AR) agonists are showing promise in the treatment of psychiatric disorders, such as treatment-resistant depression and anxiety. Human studies suggest that enhanced cognitive flexibility may contribute to their clinical efficacy. Both improvement and impairment of cognitive flexibility has been reported with 5-HT2AR ligands, making the link between 5-HT2AR pharmacology and cognitive flexibility equivocal. We tested the selective 5-HT2AR agonist 25CN-NBOH in healthy male C57BL/6JOlaHsd mice in a touchscreen-based mouse reversal learning test. No effects were observed on acquisition of the new stimulus-reward contingency, learning errors, or perseverative responses during reversal. Our results suggest that 25CN-NBOH does not affect reversal learning in the schedule used in this study.
... Though many experimental, non-clinical studies have examined the effects of MDMA in humans (for reviews see Feduccia & Mithoefer, 2018;Jungaberle et al., 2018), some of which are reviewed below, processes of change associated with MDMA have been notably understudied. Quantitative data on the subject are sparse, with only one available randomized, controlled trial showing that MDMA-AT resulted in larger changes in the personality trait of openness to experience compared to a placebo condition among people with PTSD (Wagner et al., 2017). ...
... Accordingly, clients ingesting MDMA are likely to engage in warm and positive expressions toward therapists that will in turn trigger greater expressions of affiliative emotions from therapists, as research shows that affiliative behavior cues affiliative behavior in others (Markey et al., 2003;Sadler et al., 2009), at least in part through the operation of the mirror neuron system (Jeon & Lee, 2018). The tendency for MDMA to strengthen responses (measured at both a subjective and neurophysiological level and often called emotional empathy) to positive interpersonal situations and emotional expressions of others (Bedi et al., 2009;Hysek et al., 2014;Jungaberle et al., 2018;Kuypers et al., 2017; may make therapist expressions of positive emotion such as compassion and liking more salient at both a visceral and cognitive level. This may also be enhanced by the tendency for MDMA to make people perceive others as more empathic of them (Bershad et al., 2016). ...
Researchers have suggested that psychotherapy may be enhanced by the addition of 3,4-methylenedioxymethamphetamine (MDMA), particularly in the treatment of disorders wherein interpersonal dysfunction is central, such as social anxiety disorder. We review literature pertaining to three potential processes of change that may be instigated during sessions involving MDMA administration in the treatment of social anxiety disorder.
This is a narrative review that integrates research on the etiology and maintenance of social anxiety disorder and mechanisms of action of MDMA to examine how MDMA may enhance psychotherapy outcomes.
We first outline how MDMA may enhance memory reconsolidation in social anxiety disorder. We then discuss how MDMA may induce experiences of self-transcendence and self-transcendent emotions such as compassion, love, and awe; and how these experiences may be therapeutic in the context of social anxiety disorder. We subsequently discuss the possibility that MDMA may enhance the strength and effectiveness of the therapeutic relationship which is a robust predictor of outcomes across many disorders as well as a potential key ingredient in treating disorders where shame and social disconnection are central factors.
We discuss how processes of change may extend beyond the MDMA dosing sessions themselves.
... The search was conducted between October 23rd and 31st, 2019. In addition, we hand searched recent systematic reviews (Aday et al., 2020;Bouso, dos Santos, Alcázar-Córcoles, & Hallak, 2018;dos Santos et al., 2018;Jungaberle et al., 2018;Muttoni et al., 2019;Reiche et al., 2018;Reiff et al., 2020;Schenberg, 2018). ...
Scientific interest in the therapeutic effects of classical psychedelics has increased in the past two decades. The psychological effects of these substances outside the period of acute intoxication have not been fully characterized. This study aimed to: (1) quantify the effects of psilocybin, ayahuasca, and lysergic acid diethylamide (LSD) on psychological outcomes in the post-acute period; (2) test moderators of these effects; and (3) evaluate adverse effects and risk of bias.
We conducted a systematic review and meta-analysis of experimental studies (single-group pre-post or randomized controlled trials) that involved administration of psilocybin, ayahuasca, or LSD to clinical or non-clinical samples and assessed psychological outcomes ⩾24 h post-administration. Effects were summarized by study design, timepoint, and outcome domain.
A total of 34 studies (24 unique samples, n = 549, mean longest follow-up = 55.34 weeks) were included. Classical psychedelics showed significant within-group pre-post and between-group placebo-controlled effects on a range of outcomes including targeted symptoms within psychiatric samples, negative and positive affect-related measures, social outcomes, and existential/spiritual outcomes, with large between-group effect in these domains (Hedges' gs = 0.84 to 1.08). Moderator tests suggest some effects may be larger in clinical samples. Evidence of effects on big five personality traits and mindfulness was weak. There was no evidence of post-acute adverse effects.
High risk of bias in several domains, heterogeneity across studies, and indications of publication bias for some models highlight the need for careful, large-scale, placebo-controlled randomized trials.
... Although psychedelics instill a range of both positive and negative effects, we will focus on effects that users typically find desirable. Our focus should not be viewed as an attempt to discount valid reasons for not consuming psychedelics; for example, concerns about panic or other acute effects, as well as the lack of longitudinal research necessary to identify long-term risks (Elsey, 2017;Jungaberle et al., 2018). Any substance that radically changes the perception of reality may induce anxiety due to the apparent loss of personal control. ...
We review data on the mental effects of psychedelics and their corresponding neurobiology to advance a model of consciousness based on the global neuronal workspace theory and an evolutionary perspective. Although some restrict the term psychedelics to certain serotonergic drugs, we opt for a broader definition. The term comprises five categories of substances: classical psychedelics, empathogens, cannabinergics, dissociatives, and deliriants. The neurobiological correlates of the perceptual and cognitive effects are discussed for each category. Finally, we consider the relevance of psychedelics for research on consciousness as well as for mental health.
... Some of the strongest evidence that drug use can lead to changes in personality comes from the effect of psychedelics on personality change, usually through controlled clinical trials (Jackson, Beck & Mike, in press). Common results are both acute and long-term effects on depression, well-being, self-esteem, life satisfaction, and openness to experience (Jungaberle et al., 2018;Nour, Evans, & Carhart-Harris, 2017). Previous studies have not directly examined the relationship of psychedelics on impulsivity or sensation-seeking, although sensation-seeking's association with openness suggests the possibility of a relationship. ...
Personality traits predict both the initiation and continued usage of alcohol and drugs. Less established is if substance use is associated with subsequent changes in personality, especially during the sensitive period of adolescence. We used three novel approaches to disentangle selection and socialization effects to address whether substance use is associated with personality development (impulsivity, sensation-seeking, depression, self-esteem). First, we used a multi-wave longitudinal sample of adolescents (N = 8,303) from the National Longitudinal Study of Youth - Child and Young Adult dataset to study the first use of a controlled substance. Second, we used propensity score weighting to equate users and abstainers on a range of background variables. Third, we investigated changes before, during, and after initiation of substances. Overall, there was unique variability and effects in personality across time for average levels, trajectories, and magnitudes of change both between users and abstainers as well as within users of specific substances. Results suggest that initiation of substance use leads to changes in personality; the specifics of which are largely contingent upon the substance being used. Impulsivity and sensation-seeking were the traits that changed the most while cocaine and cigarettes were the substances that had the largest impact.
... We included all classes of psychedelics used in a psychotherapeutic context, including the classical psychedelics (e.g., lysergic acid diethylamide [LSD], psilocybin) and nonclassical psychedelics (e.g., 3,4methylenedioxymethamphetamine [MDMA], ketamine). We omitted cannabis from our review, consistent with other reviews, (a) because of its debated classification as a psychedelic (Richards, 2018) and comparably weaker psychedelic-like effects, which are not reliably induced compared with other psychedelics, and (b) because cannabis is often used as a standalone, ongoing treatment without psychotherapy (Allan et al., 2018;Jungaberle et al., 2018;Krebs & Johansen, 2013). ...
Research on psychedelics has seen a recent revival, with many clinical trials focused on their therapeutic potential to treat a range of mental health conditions. The purpose of this systematic review was to evaluate clinical trials of psychedelic-assisted psychotherapy for mental health conditions from the present wave of psychedelic research (1990s to present). A total of 43 studies met criteria and were included. The conditions reviewed were substance use disorders; anxiety and/or depression, often associated with terminal illness; posttraumatic stress disorder; and obsessive– compulsive disorder. Quantitative results indicate that psychedelics can significantly reduce clinical outcomes associated with these mental health conditions. Common themes identified from qualitative reports included increased acceptance and processing of emotions, connectedness to others, forgiveness, self-compassion, insights into the self, peak or mystical experiences, ego dissolution, positive changes in worldview, motivation and commitment to change, changes in the relationship to the substance of abuse for those with substance use disorder, and acceptance of death for those with terminal illness. No serious, long-term adverse events were reported directly attributable to drug ingestion. We discuss the strengths and limitations of the research base, along with suggestions for clinical practice, potential therapeutic mechanisms, and directions for future research. Despite promising results, further work is needed to determine which psychedelic is best suited for diverse mental health conditions, the most appropriate type of psychotherapy to employ, and the psychological and neurobiological mechanisms underlying clinical benefits.
Keywords: psychedelics, psychotherapy, review, mental health, ego
... Relatedly, data indicate the deployment of this intervention may yield benefits beyond diagnosed mental illness. For example, given observed improvements in psychological wellbeing (Jungaberle et al., 2018;Walsh, 1982) including resilience-related changes (Close et al., 2020;Davis et al., 2019), it is conceivable that psychedelic therapy could be used as a prophylactic or preventative intervention, for example, promoting adaptability in adversity (Close et al., 2020;Davis et al., 2020;Murphy Beiner and Soar, 2020). We are aware that similar inferences have Figure 6. ...
This paper introduces a new construct, the ‘pivotal mental state’, which is defined as a hyper-plastic state aiding rapid and deep learning that can mediate psychological transformation. We believe this new construct bears relevance to a broad range of psychological and psychiatric phenomena. We argue that pivotal mental states serve an important evolutionary function, that is, to aid psychological transformation when actual or perceived environmental pressures demand this. We cite evidence that chronic stress and neurotic traits are primers for a pivotal mental state, whereas acute stress can be a trigger. Inspired by research with serotonin 2A receptor agonist psychedelics, we highlight how activity at this particular receptor can robustly and reliably induce pivotal mental states, but we argue that the capacity for pivotal mental states is an inherent property of the human brain itself. Moreover, we hypothesize that serotonergic psychedelics hijack a system that has evolved to mediate rapid and deep learning when its need is sensed. We cite a breadth of evidences linking stress via a variety of inducers, with an upregulated serotonin 2A receptor system (e.g. upregulated availability of and/or binding to the receptor) and acute stress with 5-HT release, which we argue can activate this primed system to induce a pivotal mental state. The pivotal mental state model is multi-level, linking a specific molecular gateway (increased serotonin 2A receptor signaling) with the inception of a hyper-plastic brain and mind state, enhanced rate of associative learning and the potential mediation of a psychological transformation.
... The effects of MDMA are believed to be mediated by a number of mechanisms, including monoamine release, serotonin and norepinephrine transporter reuptake inhibition, monoamine oxidase inhibition, partial agonism of serotonin receptors (5-HT 2A , 5-HT 1A , and 5-HT 2C receptors), and increase in blood concentrations of oxytocin (94)(95)(96)(97)(98). To date, studies with healthy volunteers have confirmed that MDMA produces an easily controlled and reversible state of altered consciousness characterized by euphoria, empathy, well-being, insightfulness, extraversion, positive mood, gregariousness, feelings of authenticity, increased access to emotionally intense material, increased interpersonal trust, and compassion for oneself and others (96,(99)(100)(101)(102)(103). In the clinical population, anxiety has been reported in a majority of study participants, and painful emotions such as grief, fear, and rage are not uncommon in participants with a diagnosis of PTSD (104-106). ...
The authors provide an evidenced-based summary of the literature on the clinical application of psychedelic drugs in psychiatric disorders.
Searches of PubMed and PsycINFO via Ovid were conducted for articles in English, in peer-reviewed journals, reporting on "psilocybin," "lysergic acid diethylamide," "LSD," "ayahuasca," "3,4-methylenedioxymethamphetamine," and "MDMA," in human subjects, published between 2007 and July 1, 2019. A total of 1,603 articles were identified and screened. Articles that did not contain the terms "clinical trial," "therapy," or "imaging" in the title or abstract were filtered out. The 161 remaining articles were reviewed by two or more authors. The authors identified 14 articles reporting on well-designed clinical trials investigating the efficacy of lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine (MDMA), psilocybin, and ayahuasca for the treatment of mood and anxiety disorders, trauma and stress-related disorders, and substance-related and addictive disorders as well as in end-of-life care.
The most significant database exists for MDMA and psilocybin, which have been designated by the U.S. Food and Drug Administration (FDA) as "breakthrough therapies" for posttraumatic stress disorder (PTSD) and treatment-resistant depression, respectively. The research on LSD and ayahuasca is observational, but available evidence suggests that these agents may have therapeutic effects in specific psychiatric disorders.
Randomized clinical trials support the efficacy of MDMA in the treatment of PTSD and psilocybin in the treatment of depression and cancer-related anxiety. The research to support the use of LSD and ayahuasca in the treatment of psychiatric disorders is preliminary, although promising. Overall, the database is insufficient for FDA approval of any psychedelic compound for routine clinical use in psychiatric disorders at this time, but continued research on the efficacy of psychedelics for the treatment of psychiatric disorders is warranted.
... One such avenue for pursuing the potential benefits to mental health that is currently receiving considerable attention and can be considered as existing within the intellectual envelope of transpersonal ecopsychology is the growing research renaissance of psychedelic-assisted psychotherapy in the treatment of depression, anxiety and addictions, as well as prophylactically for enhanced mood, wellbeing, prosocial behaviour, empathy, creativity, cognitive flexibility, openness and spirituality (Jungaberle et al., 2018). The psychedelically-induced mystical experience appears to be key in these transformations to mental health, with those studies which have explored the use of psilocybin for the treatment of addiction, anxiety and depression in relation to the mystical experience finding it to be a significant indicator of the improved clinical efficacy of the treatment (Johnson, Hendricks, Barrett & Griffiths, 2019). ...
This paper has been accepted for publication in Transpersonal Psychology Review
This paper explores both transpersonal psychology and ecopsychology individually and in conjunction, followed by an inspection of their relationship with mystical experiences and the impact of these within a transpersonal ecopsychological context. Specifically, nature as a trigger for such experiences is examined, alongside an analysis of the effect of these nature mystical experiences on an individuals' ego-boundaries and their psychological well-being. A special case is made for the re-emerging study of psychedelics-as positive agents of mental health, wellbeing, spiritual and creative growth, and social change-as inherently belonging to a transpersonal ecopsychology. The final thoughts will be based upon a more critical evaluation of these key concepts and their implications in modern psychology. The term transpersonal ecopsychology can be identified as two individual concepts connected by underlying theory and application. Transpersonal psychology is defined as the study of mankind's highest potential through the exploration of altered states of consciousness in which their spiritual, unitive and transcendent nature is recognised and sought to be understood (Lajoie & Shapiro, 1992). It outlines the notion of self-transcendence in altered states of consciousness and their accompanying mystical experiences within a modern psychological framework (Davis, 1998). In comparison, ecopsychology examines the persistent questions rooted in our psyche, our perception
... Another important area of psychedelic treatments that needs conceptual, risk mitigation, and legal consideration concerns the salutogenic effects of psychedelics . "Patients frequently report on clinical effects beyond their own psychiatric diagnosis, which may be indicative of the cross-diagnostic action of psychedelic drugs, by setting in motion therapeutic processes that address core elements of a shared psychopathology across mental disorders" . ...
... Therefore, psychedelics may also affect cognitive flexibility, which could explain their effects on creativity, executive functioning (i.e., set-shifting), openness, and depression. Indeed, Jungaberle et al. (2018) noted that cognitive flexibility is generally heightened in psychedelic states. Carhart-Harris et al. (2014) proposed an exhaustive model of the effects of psychedelic drugs that begins at the 5-HT2A receptor level and builds into the desynchronization of higher-level networks in the brain (see Carhart-Harris 2018, 2019, for further discussion of the entropic brain hypothesis). ...
Older adulthood can be characterized by various cognitive and affective changes. In general, older adults show declines in creativity and executive functioning. They also score lower in openness to experience, empathy, and many suffer from a paucity of meaningful experiences. Further, depression, pessimism, and suicide can be major concerns for this population. Although currently there are few interventions that can effectively address these changes, recent findings from psychedelic science suggest myriad parallels between the effects of these drugs and the cognitive/affective shifts seen in older adulthood. Studies have shown that psychedelics are associated with enhanced creativity and executive functioning. They can also lead to increases in openness and empathy, and induce personally meaningful experiences. Lastly, psychedelics’ efficacy for treating mood disorders and their role in palliative care are rapidly growing areas of scientific research. In this article, we analyze findings from contemporary psychedelic studies and integrate them with research on cognitive/affective changes in older adulthood to assess whether these drugs have potential to be incorporated into older adult research. We also assess the intuitive follow-up questions of potential mechanisms of action and safety concerns. Findings indicate that psychedelics have effects on a number of cognitive/affective processes that are altered in older adulthood, and are relatively safe when used with professional preparation and supervision. Increased neuroplasticity, neurogenesis, connectedness, and mystical experiences have been argued to underlie cognitive/affective changes. However, further research is needed to overcome current experimental limitations such as generalizability, unstandardized dosages, inadequate controls, and self-selection/experimenter biases.
... Naturalistic research into peyote (71) and ayahuasca (72) "users" revealed a better mental health profile in this population than in matched controls. A recent review of clinical trials and epidemiological studies (N = 77 eligible studies with 9,876 participants) documented that the use of psychedelics in various settings and populations was associated with aggregate improvements in a variety of indices of mental health (73). Other psychological changes linked to psychedelic use include prosocial attitudes and behavior (74), increased nature-relatedness (75,76), and increases in the personality traits "self-transcendence" and "openness to experience" (77,78). ...
Addressing global mental health is a major 21st-century challenge. Current treatments have recognized limitations; in this context, new ones that are prophylactic and effective across diagnostic boundaries would represent a major advance. The view that there exists a core of transdiagnostic overlap between psychiatric disorders has re-emerged in recent years, and evidence that psychedelic therapy holds promise for a range of psychiatric disorders supports the position that it may be transdiagnostically effective. Here, we propose that psychedelic therapy's core, transdiagnostically relevant action lies in its ability to increase neuronal and mental plasticity, thus enhancing the potential for change, which we consider to be a key to its therapeutic benefits. Moreover, we suggest that enhanced plasticity via psychedelics, combined with a psychotherapeutic approach, can aid healthy adaptability and resilience, which are protective factors for long-term well-being. We present candidate neurological and psychological markers of this plasticity and link them with a predictive processing model of the action of psychedelics. We propose that a model of psychedelic-induced plasticity combined with an adequate therapeutic context has prophylactic and transdiagnostic potential, implying that it could have a broad, positive impact on public health.
Psychedelic microdosing is the trending practice of using tiny repeated doses of psychedelic substances to facilitate a range of supposed benefits. With only a few published studies to date, the subject is still under-researched, and more knowledge is warranted. Social media and internet discussion forums have played a vital role in the growing visibility of the microdosing phenomenon, and the present study utilized YouTube contents to improve comprehension of the microdosing practice as well as the social interactions and discussions around microdosing.
Microdosing self-disclosure in YouTube videos and their following comments were qualitatively analyzed by inductive thematic analysis. Various software was utilized to enable gathering and sorting relevant data.
Microdosing of psychedelic substances, primarily LSD and psilocybin, was used for therapeutic and enhancement purposes, and predominantly beneficial effects were reported. Many different applications and outcomes were discussed, and therapeutic effects for depression appeared especially noteworthy. Intentions for use were recognized as an influencing factor for the progression and outcomes of microdosing. The function of social interactions was mainly to discuss views on the microdosing phenomenon, strategies for optimal results, minimize risks, and share emotional support.
Potentially, microdosing could provide some of the same benefits (for certain conditions) as full-dose interventions with less risk of adverse reactions related to the sometimes intense experiences of higher doses. Microdosing may well also mean additional benefits, as well as risks, through the repeated exposure over extended periods.
Despite a politically vilified past, classical psychedelics, including lysergic acid diethylamide (LSD), psilocybin, and dimethyltryptamine (DMT), are experiencing a revival in scientific and clinical research. When used under the appropriate guidance and setting, these substances show promise for substantially improving well-being and reducing mental ill-health alongside an excellent safety profile. Elite athletes are known to experience mental health disorder symptomatology and psychological distress at similar, if not higher, rates to the general population. Therefore, this promising line of research may be relevant to mental health treatment within elite sport. Psychedelic treatment may reduce the incidence and experience of mental ill-health in athletes, particularly when related to a range of issues commonly seen in elite sport, including therapeutic resistance, challenges to identity and meaning through career transitions and injury, and managing interpersonal stress and conflict. As a number of psychedelic treatments are currently advancing through the drug development pathway in the US and EU, it is timely to develop an understanding of the clinical application of psychedelics within elite sport, and the legislative and sport-specific regulations that will need to be addressed if psychedelics become registered medicines. In this article, we outline the sport-specific relevance of psychedelic treatments, the role of sports psychologists and psychiatrists in delivering and managing prospective psychedelic treatment, the key ethical and regulatory issues this treatment raises, as well as propose initial research questions the field could address. We argue that psychedelic-assisted psychotherapy should be investigated as a novel treatment option for addressing mental ill-health in elite athletes.
Lay summary: Psychedelic-assisted treatments are attracting increased attention and impressive efficacy in early research. We outline the potential for psychedelic therapies to treat the mental health problems seen in athletes. We describe the rationale for their use specifically within elite athletes, the sport-specific considerations and challenges that need to be addressed, the role of sports clinicians, and define the research required to demonstrate their feasibility, safety and efficacy within athletes.
• IMPLICATIONS FOR PRACTICE
• With poor mental health a growing concern in elite sport, the clinically-supported application of psychedelics may be well positioned to treat these issues and the sport-specific factors that can contribute to them.
• Various regulatory and sport-specific ethical factors will make research in this context challenging; however, these are tractable, and preliminary research in the application of psychedelic treatments for mental ill-health associated with elite sport is warranted.
• There is no evidence yet to support the safety and efficacy of psychedelic treatment in elite sport, and psychedelic compounds are not currently registered for medical use. Accordingly, the ideas explored within this commentary should not be taken as support for independent self-medication or recreational use of psychedelics.
Drugs are tested at the preclinical stage in animal populations that are usually inbred and display little variation from animal to animal. Data from animal studies in one country are usually comparable with that of another, provided the animal species and strain are the same. This chapter discusses some of the major factors related to patient genetic identity and how they live their lives, on drug metabolism and how these factors affect the goal of maintaining drug levels within the patient's therapeutic window. The factors discussed in the chapter are the effects of age, diet, disease, gender, ethanol, and smoking. Genetic diversity manifests in differences in single DNA nucleotides and/or whole genes that code for particular proteins. The chapter discusses genetic polymorphisms in Cytochrome P450 systems and nonconjugative systems, conjugative polymorphisms such as acetylation, methylation, uridine diphosphate glucuronosyl transferase 1A1, and sulphonation, and transporter polymorphisms.
The COVID-19 pandemic and its consequences represent a major challenge to the mental health and well-being of the general population. Some groups may be more vulnerable than others, depending on factors such as preexisting conditions, personality, and past life experiences. Building on previous work on the potential long-term benefits of psychedelics, we hypothesized that lifetime use of these drugs could be linked to better mental health indicators in the context of the ongoing pandemic.
Two anonymous online surveys were conducted between April 2020 and June 2020, including questions about lifetime experience with psychedelics and other psychoactive drugs, and psychometric scales designed to measure personality traits, anxiety, negative and positive affect, well-being and resilience. Principal component analysis was applied to divide the sample into groups of subjects based on their drug use reports.
5618 participants (29.15 ± 0.12 years, 71.97% female) completed both surveys and met the inclusion criteria, with 32.43% of the final sample reporting at least one use of a psychedelic drug. Lifetime psychedelic use was linked to increased openness and decreased conscientiousness, and with higher scores of positive affect. The reported number of past psychedelic experiences predicted higher scores of the secondary personality trait beta factor, which has been interpreted as a measure of plasticity. No significant associations between lifetime use of psychedelics and indicators of impaired mental health were observed.
We did not find evidence of an association between lifetime use of psychedelics and poor mental health indicators. Conversely, experience with psychedelic drugs was linked to increased positive affect and to personality traits that favor resilience and stability in the light of the ongoing crisis. Future studies should be conducted to investigate these results from a causal perspective.
Existing research demonstrates a positive connection between psychedelics and increased nature relatedness. Enhanced affective ties toward nature are widely framed as being built into the pharmakon itself, and the relevance of experiences remains little understood. This paper turns to neoshamanic ayahuasca ceremonies in Europe, exploring the way specialists and attendants refer to nature in speech and performance. I argue that ritual framings performed during these ceremonies provide fertile ground for affective ties to emerge through substance‐induced experiences. I trace such framings by exploring how medicine and healers are being coded; how specific materialities are rendered meaningful; and how individual experiences are discussed at such retreats. I argue that even while participants prioritize individual healing, personal development, or the satisfaction of psychonautical curiosity, environmentalism appears to be anchored by the proceedings themselves. Thus, this paper opens up for analysis ceremonial substance use as a contact zone where coherence is produced intersubjectively.
Background and aims
The COVID-19 pandemic and its consequences represent a major challenge to the mental health and well-being of the general population. Building on previous work on the potential long-term benefits of psychedelics, we hypothesized that lifetime use of these drugs could be linked to better mental health indicators in the context of the ongoing pandemic.
Two anonymous online surveys were conducted between April and June 2020, including questions about lifetime experience with psychedelics and other psychoactive drugs, and psychometric scales designed to measure personality traits, anxiety, negative, and positive affect, well-being, and resilience. Principal component analysis was applied to divide the sample into groups of subjects based on their drug use reports.
Five thousand six hundred eighteen participants (29.15 0.12 years, 71.97% female) completed both surveys and met the inclusion criteria, with 32.43% of the sample reporting at least one use of a psychedelic drug. Preliminary analyses showed that certain psychedelics were linked to improved mental health indicators, while other psychoactive drugs exhibited the opposite behavior. Lifetime psychedelic use was linked to increased openness and decreased conscientiousness, and to higher scores of positive affect. The reported number of past psychedelic experiences predicted higher scores of the secondary personality trait beta factor, which has been interpreted as a measure of plasticity. No significant associations between lifetime use of psychedelics and indicators of impaired mental health were observed.
We did not find evidence of an association between lifetime use of psychedelics and poor mental health indicators. Conversely, experience with psychedelic drugs was linked to increased positive affect and to personality traits that favor resilience and stability in the light of the ongoing crisis.
In the last 15 years, psychedelic substances, such as LSD and psilocybin, have regained legitimacy in clinical research. In the general population as well as across various psychiatric populations, mental well-being has been found to significantly improve after a psychedelic experience. Mental well-being has large socioeconomic relevance, but it is a complex, multifaceted construct. In this naturalistic observational study, a comprehensive approach was taken to assessing well-being before and after a taking a psychedelic compound to induce a “psychedelic experience.” Fourteen measures of well-being related constructs were included in order to examine the breadth and specificity of change in well-being. This change was then analysed to examine clusters of measures changing together. Survey data was collected from volunteers that intended to take a psychedelic. Four key time points were analysed: 1 week before and 2 weeks, 4 weeks, and 2 years after the experience (N = 654, N = 315, N = 212, and N = 64, respectively). Change on the included measures was found to cluster into three factors which we labelled: 1) “Being well”, 2) “Staying well,” and 3) “Spirituality.” Repeated Measures Multivariate Analysis of Variance revealed all but the spirituality factor to be improved in the weeks following the psychedelic experience. Additional Mixed model analyses revealed selective increases in Being Well and Staying Well (but not Spirituality) that remained statistically significant up to 2 years post-experience, albeit with high attrition rates. Post-hoc examination suggested that attrition was not due to differential acute experiences or mental-health changes in those who dropped out vs. those who did not. These findings suggest that psychedelics can have a broad, robust and sustained positive impact on mental well-being in those that have a prior intention to use a psychedelic compound. Public policy implications are discussed.
This presentation addresses the increasingly evident resonance between certain aspects of mindfulness-based interventions (MBIs) and psychedelic research and practice. An overview of recent academic literature suggests that both MBIs and psychedelics may have shared phenomenological effects, mechanism of action and therapeutic potentials, and the increasing use of mindfulness and self-compassion scales as outcome measures in psychedelic research substantiates this relationship. The thus emerging picture reveals the potential of psychoactive compounds as novel pharmacological pathways for establishing mindfulness-related capacities on the one hand as well as novel areas of the application of MBIs in the context of psychedelic practice on the other. It also highlights the need to address the broader theoretical and paradigmatic questions related to what may be the underlying spectrum on which both of these interventions may be conceptualized despite their dramatic differences.
Given the successful mainstreaming of mindfulness in the recent decades based on research into its effectiveness together with its increasing spread and acceptance in various sectors of society, this presentation also reflects on what the psychedelic renaissance may learn from the recent growth and proliferation of MBIs. When also the greater historical and cultural contexts are considered, the recent research also has potential to shed new light on the disputed relationship of the Buddhist traditions to both mindfulness and psychedelics – while simultaneously allowing space for more traditional Buddhist soteriological critiques of these increasingly common practices.
The increasing number of legally ambiguous and precarious Novel Psychoactive Substances (NPS) constitutes a challenge for policy makers and public health. Scientific and more in-depth knowledge about the motivations for using NPS is scarce and often consist of predetermined, non-systematic, or poorly described reasons deduced from top-down approaches. Therefore, the aim of the present study was to explore and characterize the users' self-reported reasons for NPS use inductively and more comprehensively.
The self-reported reasons of a self-selected sample of 613 international NPS users were collected via an online survey promoted at the international drug discussion forum bluelight.org and later analyzed qualitatively using inductive thematic analysis.
The analysis showed that the participants used NPS because these compounds reportedly: 1) enabled safer and more convenient drug use, 2) satisfied a curiosity and interest about the effects, 3) facilitated a novel and exciting adventure, 4) promoted self-exploration and personal growth, 5) functioned as coping agents, 6) enhanced abilities and performance, 7) fostered social bonding and belonging, and 8) acted as a means for recreation and pleasure. The consumption of NPS was also driven by 9) problematic and unintentional use.
The present study contributed to a more comprehensive understanding of the users' own and self-reported reasons for using NPS, which needs to be acknowledged not only in order to minimize drug related harm and drug user alienation but also to improve prevention efforts and reduce the potentially counter-intuitive effects of strictly prohibitive policies.
Psychedelika (klassische bzw. serotonerge Halluzinogene) sind psychoaktive Substanzen, welche Wahrnehmung, Affekte sowie eine Reihe kognitiver Prozesse intensiv verändern können. Die Mehrheit ihrer Vertreter gilt als physiologisch sicher und nicht addiktiv. Ihre Geschichte reicht bis in prähistorische Zeit zurück. Mit der Entdeckung der Wirkstoffe Meskalin, Lysergsäurediethylamid (LSD), Dimethyltryptamin (DMT) und Psilocybin begann sowohl ihre wissenschaftliche Erforschung als auch die Verbreitung ihres nicht medizinischen Gebrauchs. Psychedelika stellen eine pharmakologisch, psychometrisch und tierexperimentell abgrenzbare Substanzklasse dar, die zunehmend im Interesse der medizinischen Grundlagen- und Therapieforschung steht. Dieses Kapitel strebt hinsichtlich der relevanten Wissensgebiete einen ausgewogenen Kurzüberblick über die Substanzklasse und ihre wichtigsten Vertreter an, wobei dem historisch komplexen Wirkgefüge zwischen Medizin- und Sozialgeschichte der Substanzklasse ein Schwerpunkt gewidmet ist.
RationaleLysergic acid diethylamide (LSD) and other serotonergic hallucinogens can induce profound alterations of consciousness and mystical-type experiences, with reportedly long-lasting effects on subjective well-being and personality. Methods
We investigated the lasting effects of a single dose of LSD (200 μg) that was administered in a laboratory setting in 16 healthy participants. The following outcome measures were assessed before and 1 and 12 months after LSD administration: Persisting Effects Questionnaire (PEQ), Mysticism Scale (MS), Death Transcendence Scale (DTS), NEO-Five Factor Inventory (NEO-FFI), and State-Trait Anxiety Inventory (STAI). ResultsOn the PEQ, positive attitudes about life and/or self, positive mood changes, altruistic/positive social effects, positive behavioral changes, and well-being/life satisfaction significantly increased at 1 and 12 months and were subjectively attributed by the subjects to the LSD experience. Five-Dimensions of Altered States of Consciousness (5D-ASC) total scores, reflecting acutely induced alterations in consciousness, and Mystical Experience Questionnaire (MEQ30) total scores correlated with changes in well-being/life satisfaction 12 months after LSD administration. No changes in negative attitudes, negative mood, antisocial/negative social effects, or negative behavior were attributed to the LSD experience. After 12 months, 10 of 14 participants rated their LSD experience as among the top 10 most meaningful experiences in their lives. Five participants rated the LSD experience among the five most spiritually meaningful experiences in their lives. On the MS and DTS, ratings of mystical experiences significantly increased 1 and 12 months after LSD administration compared with the pre-LSD screening. No relevant changes in personality measures were found. Conclusions
In healthy research subjects, the administration of a single dose of LSD (200 μg) in a safe setting was subjectively considered a personally meaningful experience that had long-lasting subjective positive effects. Trial registrationRegistration identification number: NCT01878942.
Chronic use of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") has repeatedly been associated with deficits in working memory, declarative memory, and executive functions. However, previous findings regarding working memory and executive function are inconclusive yet, as in most studies concomitant stimulant use, which is known to affect these functions, was not adequately controlled for. Therefore, we compared the cognitive performance of 26 stimulant-free and largely pure (primary) MDMA users, 25 stimulant-using polydrug MDMA users, and 56 MDMA/stimulant-naïve controls by applying a comprehensive neuropsychological test battery. Neuropsychological tests were grouped into four cognitive domains. Recent drug use was objectively quantified by 6-month hair analyses on 17 substances and metabolites. Considerably lower mean hair concentrations of stimulants (amphetamine, methamphetamine, methylphenidate, cocaine), opioids (morphine, methadone, codeine), and hallucinogens (ketamine, 2C-B) were detected in primary compared to polydrug users, while both user groups did not differ in their MDMA hair concentration. Cohen's d effect sizes for both comparisons, i.e., primary MDMA users vs. controls and polydrug MDMA users vs. controls, were highest for declarative memory (dprimary=.90, dpolydrug=1.21), followed by working memory (dprimary=.52, dpolydrug=.96), executive functions (dprimary=.46, dpolydrug=.86), and attention (dprimary=.23, dpolydrug=.70). Thus, primary MDMA users showed strong and relatively discrete declarative memory impairments, whereas MDMA polydrug users displayed broad and unspecific cognitive impairments. Consequently, even largely pure chronic MDMA use is associated with decreased performance in declarative memory, while additional deficits in working memory and executive functions displayed by polydrug MDMA users are likely driven by stimulant co-use.
Psychedelic drugs are creating ripples in psychiatry as evidence accumulates of their therapeutic potential. An important question remains unresolved however: how are psychedelics effective? We propose that a sense of connectedness is key, provide some preliminary evidence to support this, and suggest a roadmap for testing it further.
This paper argues that therapy with the drug MDMA (also known as Ecstasy) can have positive results in pain reduction for post-traumatic stress disorder and can also encourage moral development and the growth of compassion as well as religious and spiritual insight. Today, small-scale drug trials of MDMA are being performed in a highly controlled clinical environment without any spiritual or moral interpretative framework to help the subjects understand their experiences. Such a framework could help patients integrate and find meaning in the intense, traumatic experiences they have undergone. Pastoral counselors, psychologists, and religious professionals might find it useful to explore this form of therapy further.
The potential of psychedelic drugs in the treatment of mental health problems is increasingly being recognized. However, relatively little thrust has been given to the suggestion that individuals without any mental health problems may benefit from using psychedelic drugs, and that they may have a right to do so. This review considers contemporary research into the use of psychedelic drugs in healthy individuals, including neurobiological and subjective effects. In line with findings suggesting positive effects in the treatment of mental health problems, such research highlights the potential of psychedelic drugs for the enhancement of wellbeing even in healthy individuals. The relatively low risk associated with usage does not appear to align with stringent drug laws that impose heavy penalties for their use. Some policy implications, and suggestions for future research, are considered.
A growing body of research suggests that traumatic events lead to persisting personality change characterized by increased neuroticism. Relevantly, enduring improvements in Post-Traumatic Stress Disorder (PTSD) symptoms have been found in response to 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy. There is evidence that lasting changes in the personality feature of “openness” occur in response to hallucinogens, and that this may potentially act as a therapeutic mechanism of change. The present study investigated whether heightened Openness and decreased Neuroticism served as a mechanism of change within a randomized trial of MDMA-assisted psychotherapy for chronic, treatment-resistant PTSD. The Clinician-Administered PTSD Scale (CAPS) Global Scores and NEO PI-R Personality Inventory (NEO) Openness and Neuroticism Scales served as outcome measures. Results indicated that changes in Openness but not Neuroticism played a moderating role in the relationship between reduced PTSD symptoms and MDMA treatment. Following MDMA-assisted psychotherapy, increased Openness and decreased Neuroticism when comparing baseline personality traits with long-term follow-up traits also were found. These preliminary findings suggest that the effect of MDMA-assisted psychotherapy extends beyond specific PTSD symptomatology and fundamentally alters personality structure, resulting in long-term persisting personality change. Results are discussed in terms of possible mechanisms of psychotherapeutic change.
Ayahuasca is a plant tea containing the psychedelic 5-HT2A agonist N,N-dimethyltryptamine (DMT) and harmala monoamine-oxidase inhibitors. Acute administration leads to neurophysiological modifications in brain regions of the default mode network (DMN), purportedly through a glutamatergic mechanism. Post-acutely, ayahuasca potentiates mindfulness capacities in volunteers, and induces rapid and sustained antidepressant effects in treatment-resistant patients. However, the mechanisms underlying these fast and maintained effects are poorly understood. Here we investigated in an open-label uncontrolled study in sixteen healthy volunteers ayahuasca-induced post-acute neurometabolic and connectivity modifications, and their association with mindfulness measures.
Using 1H-magnetic resonance spectroscopy (MRS) and functional connectivity, we compared baseline and post-acute neurometabolites and seed-to-voxel connectivity in the posterior (PCC) and anterior (ACC) cingulate cortex after a single ayahuasca dose.
MRS showed post-acute reductions in Glx (glutamate+glutamine), creatine and NAA-NAAG (N-acetylaspartate+N-acetylaspartylglutamate) in the PCC. Connectivity was increased between the PCC and the ACC, and between the ACC and limbic structures in the right medial temporal lobe (MTL). Glx reductions correlated with increases in the "Non-Judging" subscale of the Five Facets Mindfulness Questionnaire. Increased ACC-MTL connectivity correlated with increased scores on the Self-Compassion questionnaire. Post-acute neural changes predicted sustained elevations in "Non-Judging" two months later.
These results support the involvement of glutamate neurotransmission in the effects of psychedelics in humans. They further suggest that neurometabolic changes in the PCC, a key region within the DMN, and increased connectivity between the ACC and MTL structures involved in emotion and memory, potentially underlie the post-acute psychological effects of ayahuasca.
The psychological mechanisms of action involved in psilocybin-assisted psychotherapy are not yet well understood. Despite a resurgence of quantitative research regarding psilocybin, the current study is the first qualitative study of participant experiences in psilocybin-assisted psychotherapy. Semistructured interviews were carried out with 13 adult participants aged 22 to 69 years (M = 50 years) with clinically elevated anxiety associated with a cancer diagnosis. Participants received a moderate dose of psilocybin and adjunctive psychotherapy with an emphasis on the process of meaning-making. Verbatim transcribed interviews were analyzed by a five-member research team using interpretative phenomenological analysis. General themes found in all or nearly all transcripts included relational embeddedness, emotional range, the role of music as conveyor of experience, meaningful visual phenomena, wisdom lessons, revised life priorities, and a desire to repeat the psilocybin experience. Typical themes found in the majority of transcripts included the following: exalted feelings of joy, bliss, and love; embodiment; ineffability; alterations to identity; a movement from feelings of separateness to interconnectedness; experiences of transient psychological distress; the appearance of loved ones as guiding spirits; and sharing the experience with loved ones posttreatment. Variant themes found in a minority of participant transcripts include lasting changes to sense of identity, synesthesia experiences, catharsis of powerful emotion, improved relationships after treatment, surrender or “letting go,” forgiveness, and a continued struggle to integrate experience. The findings support the conclusion that psilocybin-assisted psychotherapy may provide an effective treatment for psychological distress in cancer patients. Implications for theory and treatment are discussed.
Lysergic acid diethylamide (LSD) induces profound changes in various mental domains, including perception, self-awareness and emotions. We used functional magnetic resonance imaging (fMRI) to investigate the acute effects of LSD on the neural substrate of emotional processing in humans. Using a double-blind, randomised, cross-over study design, placebo or 100 µg LSD were orally administered to 20 healthy subjects before the fMRI scan, taking into account the subjective and pharmacological peak effects of LSD. The plasma levels of LSD were determined immediately before and after the scan. The study (including the a priori-defined study end point) was registered at ClinicalTrials.gov before study start (NCT02308969). The administration of LSD reduced reactivity of the left amygdala and the right medial prefrontal cortex relative to placebo during the presentation of fearful faces (P<0.05, family-wise error). Notably, there was a significant negative correlation between LSD-induced amygdala response to fearful stimuli and the LSD-induced subjective drug effects (P<0.05). These data suggest that acute administration of LSD modulates the engagement of brain regions that mediate emotional processing.
Previous placebo-controlled experimental studies have shown that a single dose of MDMA can increase emotional empathy in the multifaceted empathy test (MET) without affecting cognitive empathy. Although sufficiently powered to detect main effects of MDMA, these studies were generally underpowered to also validly assess contributions of additional parameters, such as sex, drug use history, trait empathy and MDMA or oxytocin plasma concentrations. The present study examined the robustness of the MDMA effect on empathy and investigated the moderating role of these additional
parameters. Participants (n = 118) from six placebo-controlled within-subject studies and two laboratories were included in the present pooled analysis. Empathy (MET), MDMA and oxytocin plasma concentrations were assessed after oral administration of MDMA (single dose, 75 or 125 mg). Trait empathy was assessed using the interpersonal reactivity index. We confirmed that MDMA increased emotional empathy at both doses without affecting cognitive empathy. This MDMA-related increase in empathy was most pronounced during presentation of positive emotions as compared with negative emotions. MDMA-induced empathy enhancement was positively related to MDMA blood concentrations measured before the test, but independent of sex, drug use history and trait empathy. Oxytocin concentrations increased after MDMA administration but were not associated with behavioral effects. The MDMA effects on emotional empathy were stable across laboratories and doses. Sex did not play a moderating role in this effect, and oxytocin levels, trait empathy and drug use history were also unrelated. Acute drug exposure was of significant relevance in the MDMA-induced emotional empathy elevation.
Clinically significant anxiety and depression are common in patients with cancer, and are associated with poor psychiatric and medical outcomes. Historical and recent research suggests a role for psilocybin to treat cancer-related anxiety and depression.
In this double-blind, placebo-controlled, crossover trial, 29 patients with cancer-related anxiety and depression were randomly assigned and received treatment with single-dose psilocybin (0.3 mg/kg) or niacin, both in conjunction with psychotherapy. The primary outcomes were anxiety and depression assessed between groups prior to the crossover at 7 weeks.
Prior to the crossover, psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression and led to decreases in cancer-related demoralization and hopelessness, improved spiritual wellbeing, and increased quality of life. At the 6.5-month follow-up, psilocybin was associated with enduring anxiolytic and anti-depressant effects (approximately 60-80% of participants continued with clinically significant reductions in depression or anxiety), sustained benefits in existential distress and quality of life, as well as improved attitudes towards death. The psilocybin-induced mystical experience mediated the therapeutic effect of psilocybin on anxiety and depression.
In conjunction with psychotherapy, single moderate-dose psilocybin produced rapid, robust and enduring anxiolytic and anti-depressant effects in patients with cancer-related psychological distress.
ClinicalTrials.gov Identifier: NCT00957359.
Developing methods for improving creativity is of broad interest. Classic psychedelics may enhance creativity; however, the underlying mechanisms of action are unknown. This study was designed to assess whether a relationship exists between naturalistic classic psychedelic use and heightened creative problem-solving ability and if so, whether this is mediated by lifetime mystical experience. Participants (N = 68) completed a survey battery assessing lifetime mystical experience and circumstances surrounding the most memorable experience. They were then administered a functional fixedness task in which faster completion times indicate greater creative problem-solving ability. Participants reporting classic psychedelic use concurrent with mystical experience (n = 11) exhibited significantly faster times on the functional fixedness task (Cohen’s d = –.87; large effect) and significantly greater lifetime mystical experience (Cohen’s d = .93; large effect) than participants not reporting classic psychedelic use concurrent with mystical experience. However, lifetime mystical experience was unrelated to completion times on the functional fixedness task (standardized β = –.06), and was therefore not a significant mediator. Classic psychedelic use may increase creativity independent of its effects on mystical experience. Maximizing the likelihood of mystical experience may need not be a goal of psychedelic interventions designed to boost creativity.
RationaleLysergic acid diethylamide (LSD) is used recreationally and in clinical research. Acute mystical-type experiences that are acutely induced by hallucinogens are thought to contribute to their potential therapeutic effects. However, no data have been reported on LSD-induced mystical experiences and their relationship to alterations of consciousness. Additionally, LSD dose- and concentration-response functions with regard to alterations of consciousness are lacking. Methods
We conducted two placebo-controlled, double-blind, cross-over studies using oral administration of 100 and 200 μg LSD in 24 and 16 subjects, respectively. Acute effects of LSD were assessed using the 5 Dimensions of Altered States of Consciousness (5D-ASC) scale after both doses and the Mystical Experience Questionnaire (MEQ) after 200 μg. ResultsOn the MEQ, 200 μg LSD induced mystical experiences that were comparable to those in patients who underwent LSD-assisted psychotherapy but were fewer than those reported for psilocybin in healthy subjects or patients. On the 5D-ASC scale, LSD produced higher ratings of blissful state, insightfulness, and changed meaning of percepts after 200 μg compared with 100 μg. Plasma levels of LSD were not positively correlated with its effects, with the exception of ego dissolution at 100 μg. Conclusions
Mystical-type experiences were infrequent after LSD, possibly because of the set and setting used in the present study. LSD may produce greater or different alterations of consciousness at 200 μg (i.e., a dose that is currently used in psychotherapy in Switzerland) compared with 100 μg (i.e., a dose used in imaging studies). Ego dissolution may reflect plasma levels of LSD, whereas more robustly induced effects of LSD may not result in such associations.
Acute and enduring adverse effects of psilocybin have been reported anecdotally, but have not been well characterized. For this study, 1993 individuals (mean age 30 yrs; 78% male) completed an online survey about their single most psychologically difficult or challenging experience (worst “bad trip”) after consuming psilocybin mushrooms. Thirty-nine percent rated it among the top five most challenging experiences of his/her lifetime. Eleven percent put self or others at risk of physical harm; factors increasing the likelihood of risk included estimated dose, duration and difficulty of the experience, and absence of physical comfort and social support. Of the respondents, 2.6% behaved in a physically aggressive or violent manner and 2.7% received medical help. Of those whose experience occurred >1 year before, 7.6% sought treatment for enduring psychological symptoms. Three cases appeared associated with onset of enduring psychotic symptoms and three cases with attempted suicide. Multiple regression analysis showed degree of difficulty was positively associated, and duration was negatively associated, with enduring increases in well-being. Difficulty of experience was positively associated with dose. Despite difficulties, 84% endorsed benefiting from the experience. The incidence of risky behavior or enduring psychological distress is extremely low when psilocybin is given in laboratory studies to screened, prepared, and supported participants.
3,4-Methylenedioxymethamphetamine (MDMA) is a popular recreational drug that enhances sociability and feelings of closeness with others. These “prosocial” effects appear to motivate the recreational use of MDMA and may also form the basis of its potential as an adjunct to psychotherapy. However, the extent to which MDMA differs from prototypic stimulant drugs, such as dextroamphetamine, methamphetamine, and methylphenidate, in either its behavioral effects or mechanisms of action, is not fully known. The purpose of this review is to evaluate human laboratory findings of the social effects of MDMA compared to other stimulants, ranging from simple subjective ratings of sociability to more complex elements of social processing and behavior. We also review the neurochemical mechanisms by which these drugs may impact sociability. Together, the findings reviewed here lay the groundwork for better understanding the socially enhancing effects of MDMA that distinguish it from other stimulant drugs, especially as these effects relate to the reinforcing and potentially therapeutic effects of the drug.
Ayahuasca is a South American psychotropic plant tea traditionally used in Amazonian shamanism. The tea contains the psychedelic 5-HT2A receptor agonist N,N-dimethyltryptamine (DMT), plus β-carboline alkaloids with monoamine oxidase-inhibiting properties. Increasing evidence from anecdotal reports and open-label studies indicates that ayahuasca may have therapeutic effects in treatment of substance use disorders and depression. A recent study on the psychological effects of ayahuasca found that the tea reduces judgmental processing and inner reactivity, classic goals of mindfulness psychotherapy. Another psychological facet that could potentially be targeted by ayahuasca is creative divergent thinking. This mode of thinking can enhance and strengthen psychological flexibility by allowing individuals to generate new and effective cognitive, emotional, and behavioral strategies. The present study aimed to assess the potential effects of ayahuasca on creative thinking.
We visited two spiritual ayahuasca workshops and invited participants to conduct creativity tests before and during the acute effects of ayahuasca. In total, 26 participants consented. Creativity tests included the "pattern/line meanings test" (PLMT) and the "picture concept test" (PCT), both assessing divergent thinking and the latter also assessing convergent thinking.
While no significant effects were found for the PLMT, ayahuasca intake significantly modified divergent and convergent thinking as measured by the PCT. While convergent thinking decreased after intake, divergent thinking increased.
The present data indicate that ayahuasca enhances creative divergent thinking. They suggest that ayahuasca increases psychological flexibility, which may facilitate psychotherapeutic interventions and support clinical trial initiatives.
Lysergic acid diethylamide (LSD) is used recreationally and has been evaluated as an adjunct to psychotherapy to treat anxiety in patients with life-threatening illness. LSD is well-known to induce perceptual alterations, but unknown is whether LSD alters emotional processing in ways that can support psychotherapy. We investigated the acute effects of LSD on emotional processing using the Face Emotion Recognition Task (FERT) and Multifaceted Empathy Test (MET). The effects of LSD on social behavior were tested using the Social Value Orientation (SVO) test. Two similar placebo-controlled, double-blind, random-order, cross-over studies were conducted using 100 μg LSD in 24 subjects and 200 μg LSD in 16 subjects. All of the subjects were healthy and mostly hallucinogen-naive 25- to 65-year-old volunteers (20 men, 20 women). LSD produced feelings of happiness, trust, closeness to others, enhanced explicit and implicit emotional empathy on the MET, and impaired the recognition of sad and fearful faces on the FERT. LSD enhanced the participants' desire to be with other people and increased their prosocial behavior on the SVO test. These effects of LSD on emotion processing and sociality may be useful for LSD-assisted psychotherapy.Neuropsychopharmacology accepted article preview online, 01 June 2016. doi:10.1038/npp.2016.82.
Social ties are crucial for physical and mental health. However, psychiatric patients frequently encounter social rejection. Moreover, an increased reactivity to social exclusion influences the development, progression, and treatment of various psychiatric disorders. Nevertheless, the neuromodulatory substrates of rejection experiences are largely unknown. The preferential serotonin (5-HT) 2A/1A receptor agonist, psilocybin (Psi), reduces the processing of negative stimuli, but whether 5-HT2A/1A receptor stimulation modulates the processing of negative social interactions remains unclear. Therefore, this double-blind, randomized, counterbalanced, cross-over study assessed the neural response to social exclusion after the acute administration of Psi (0.215 mg/kg) or placebo (Pla) in 21 healthy volunteers by using functional magnetic resonance imaging (fMRI) and resting-state magnetic resonance spectroscopy (MRS). Participants reported a reduced feeling of social exclusion after Psi vs. Pla administration, and the neural response to social exclusion was decreased in the dorsal anterior cingulate cortex (dACC) and the middle frontal gyrus, key regions for social pain processing. The reduced neural response in the dACC was significantly correlated with Psi-induced changes in self-processing and decreased aspartate (Asp) content. In conclusion, 5-HT2A/1A receptor stimulation with psilocybin seems to reduce social pain processing in association with changes in self-experience. These findings may be relevant to the normalization of negative social interaction processing in psychiatric disorders characterized by increased rejection sensitivity. The current results also emphasize the importance of 5-HT2A/1A receptor subtypes and the Asp system in the control of social functioning, and as prospective targets in the treatment of sociocognitive impairments in psychiatric illnesses.
Lysergic acid diethylamide (LSD) is a non-selective serotonin-receptor agonist that was first synthesized in 1938 and identified as (potently) psychoactive in 1943. Psychedelics have been used by indigenous cultures for millennia ; however, because of LSD's unique potency and the timing of its discovery (coinciding with a period of major discovery in psychopharmacology), it is generally regarded as the quintessential contemporary psychedelic . LSD has profound modulatory effects on consciousness and was used extensively in psychological research and psychiatric practice in the 1950s and 1960s . In spite of this, however, there have been no modern human imaging studies of its acute effects on the brain. Here we studied the effects of LSD on intrinsic functional connectivity within the human brain using fMRI. High-level association cortices (partially overlapping with the default-mode, salience, and frontoparietal attention networks) and the thalamus showed increased global connectivity under the drug. The cortical areas showing increased global connectivity overlapped significantly with a map of serotonin 2A (5-HT2A) receptor densities (the key site of action of psychedelic drugs ). LSD also increased global integration by inflating the level of communication between normally distinct brain networks. The increase in global connectivity observed under LSD correlated with subjective reports of "ego dissolution." The present results provide the first evidence that LSD selectively expands global connectivity in the brain, compromising the brain's modular and "rich-club" organization and, simultaneously, the perceptual boundaries between the self and the environment.
3,4-Methylenedioxymethamphetamine (MDMA) is associated with changes in neurocognitive performance. Recent studies in laboratory animals have provided additional support for the neurodegeneration hypothesis. However, results from animal research need to be applied to humans with caution. Moreover, several of the studies that examine MDMA users suffer from methodological shortcomings. Therefore, a prospective cohort study was designed in order to overcome these previous methodological shortcomings and to assess the relationship between the continuing use of MDMA and cognitive performance in incipient MDMA users. It was hypothesized that, depending on the amount of MDMA taken, the continued use of MDMA over a two-year period would lead to further decreases in cognitive performance, especially in visual paired association learning tasks. 96 subjects were assessed at the second follow-up assessment: 31 of these were non-users, 55 moderate-users and 10 heavy-users. Separate repeated measures analyses of variance were conducted for each cognitive domain, including attention and information processing speed, episodic memory and executive functioning. Furthermore, possible confounders including age, general intelligence, cannabis use, alcohol use, use of other concomitant substances, recent medical treatment, participation in sports, level of nutrition, sleep patterns and subjective well-being were assessed.The Repeated measures analysis of variance (rANOVA) revealed that a marginally significant change in immediate and delayed recall test performances of visual paired associates learning had taken place within the follow-up period of two years. No significant differences with the other neuropsychological tests were noted. It seems that MDMA use can impair visual paired associates learning in new users. However, in the recent study, further deterioration in continuing MDMA-users was not observed.
Ayahuasca is a psychotropic plant tea used for ritual purposes by the indigenous populations of the Amazon. In the last two decades, its use has expanded worldwide. The tea contains the psychedelic 5-HT2A receptor agonist N,N-dimethyltryptamine (DMT), plus β-carboline alkaloids with monoamine-oxidase-inhibiting properties. Acute administration induces an introspective dream-like experience characterized by visions and autobiographic and emotional memories. Studies of long-term users have suggested its therapeutic potential, reporting that its use has helped individuals abandon the consumption of addictive drugs. Furthermore, recent open-label studies in patients with treatment-resistant depression found that a single ayahuasca dose induced a rapid antidepressant effect that was maintained weeks after administration. Here, we conducted an exploratory study of the psychological mechanisms that could underlie the beneficial effects of ayahuasca.
We assessed a group of 25 individuals before and 24 h after an ayahuasca session using two instruments designed to measure mindfulness capacities: The Five Facets Mindfulness Questionnaire (FFMQ) and the Experiences Questionnaire (EQ).
Ayahuasca intake led to significant increases in two facets of the FFMQ indicating a reduction in judgmental processing of experiences and in inner reactivity. It also led to a significant increase in decentering ability as measured by the EQ. These changes are classic goals of conventional mindfulness training, and the scores obtained are in the range of those observed after extensive mindfulness practice.
The present findings support the claim that ayahuasca has therapeutic potential and suggest that this potential is due to an increase in mindfulness capacities.
There is renewed interest in the therapeutic potential of psychedelic drugs such as lysergic acid diethylamide (LSD). LSD was used extensively in the 1950s and 1960s as an adjunct in psychotherapy, reportedly enhancing emotionality. Music is an effective tool to evoke and study emotion and is considered an important element in psychedelic-assisted psychotherapy; however, the hypothesis that psychedelics enhance the emotional response to music has yet to be investigated in a modern placebo-controlled study.
The present study sought to test the hypothesis that music-evoked emotions are enhanced under LSD.
Ten healthy volunteers listened to five different tracks of instrumental music during each of two study days, a placebo day followed by an LSD day, separated by 5-7 days. Subjective ratings were completed after each music track and included a visual analogue scale (VAS) and the nine-item Geneva Emotional Music Scale (GEMS-9).
Results demonstrated that the emotional response to music is enhanced by LSD, especially the emotions "wonder", "transcendence", "power" and "tenderness".
These findings reinforce the long-held assumption that psychedelics enhance music-evoked emotion, and provide tentative and indirect support for the notion that this effect can be harnessed in the context of psychedelic-assisted psychotherapy. Further research is required to test this link directly.
±3,4-methylenedioxymethamphetamine (MDMA) is widely believed to increase sociability. The drug alters speech production and fluency, and may influence speech content. Here, we investigated the effect of MDMA on speech content, which may reveal how this drug affects social interactions.
Thirty-five healthy volunteers with prior MDMA experience completed this two-session, within-subjects, double-blind study during which they received 1.5 mg/kg oral MDMA and placebo. Participants completed a five-minute standardized talking task during which they discussed a close personal relationship (e.g. a friend or family member) with a research assistant. The conversations were analyzed for selected content categories (e.g. words pertaining to affect, social interaction, and cognition), using both a standard dictionary method (Pennebaker's Linguistic Inquiry and Word Count: LIWC) and a machine learning method using random forest classifiers.
Both analytic methods revealed that MDMA altered speech content relative to placebo. Using LIWC scores, the drug increased use of social and sexual words, consistent with reports that MDMA increases willingness to disclose. Using the machine learning algorithm, we found that MDMA increased use of social words and words relating to both positive and negative emotions.
These findings are consistent with reports that MDMA acutely alters speech content, specifically increasing emotional and social content during a brief semistructured dyadic interaction. Studying effects of psychoactive drugs on speech content may offer new insights into drug effects on mental states, and on emotional and psychosocial interaction.
Recent data show that MDMA (3,4 methylenedioxymethamphetamine) related deaths (MRDs) are on the rise in several countries. This rise in MRDs has caught the attention of public health officials and treatment practitioners. Although MDMA is not a new drug, misinformation regarding the root causes of MRDs is still widespread. For example, MRDs continue to be reported as “overdoses” in the media and by government. This erroneously gives the impression that these deaths are caused by ingesting too high a dose, when in fact MRDs are usually due to factors such as hyperthermia, dehydration, drug interactions, or hyponaetremia. When the real culprits behind MRDs are obscured, we are left with an inaccurate picture about the extent and nature of the risk of consuming the drug. This also inhibits the implementation of effective drug education and risk reduction messages. The purpose of this paper, therefore, is to explore MRDs further by: 1) providing a brief history of MDMA, 2) summarizing international prevalence rates of MRDs, 3) discussing factors that contribute to MRDs, and 4) identifying promising interventions to reduce MRDs. The information presented in this paper is particularly important given the international resurgence of recreational MDMA use (as molly) and the renewed interest in the drug’s therapeutic benefits.
Psychedelics comprise drugs come from various pharmacological classes including 5-HT2A agonists, indirect 5-HT agonists, e.g. MDMA, NMDA antagonists and κ-opioid receptor agonists. There is resurgence in developing psychedelics to treat psychiatric disorders with high unmet clinical need. Many, but not all, psychedelics are schedule 1 controlled drugs (CDs), i.e. no approved medical use. For existing psychedelics in development, regulatory approval will require a move from schedule 1 to a CD schedule for drugs with medical use, i.e. schedules 2-5. Although abuse of the psychedelics is well documented, a systematic preclinical and clinical evaluation of the risks they pose in a medical-use setting does not exist. We describe the non-clinical tests required for a regulatory evaluation of abuse/dependence risks, i.e. drug-discrimination, intravenous self-administration and physical dependence liability. A synopsis of the existing data for the various types of psychedelics is provided and we describe our findings with psychedelic drugs in these models. FDA recently issued its guidance on abuse/dependence evaluation of drug-candidates . We critically review the guidance, discuss the impact this document will have on non-clinical abuse/dependence testing, and offer advice on how non-clinical abuse/dependence experiments can be designed to meet not only the expectations of FDA, but also other regulatory agencies. Finally, we offer views on how these non-clinical tests can be refined to provide more meaningful information to aid the assessment of the risks posed by CNS drug-candidates for abuse and physical dependence.
Psychedelic drugs, such as lysergic acid diethylamide (LSD), mescaline, and psilocybin, exert profound effects on brain and behavior. After decades of difficulties in studying these compounds, psychedelics are again being tested as potential treatments for intractable biomedical disorders. Preclinical research of psychedelics complements human neuroimaging studies and pilot clinical trials, suggesting these compounds as promising treatments for addiction, depression, anxiety, and other conditions. However, many questions regarding the mechanisms of action, safety, and efficacy of psychedelics remain. Here, we summarize recent preclinical and clinical data in this field, discuss their pharmacological mechanisms of action, and outline critical areas for future studies of psychedelic drugs, with the goal of maximizing the potential benefits of translational psychedelic biomedicine to patients.
Hintergrund Der Einsatz von serotonergen Halluzinogenen (Psychedelika) wie Lysergsäure-Diethylamid (LSD) und Psilocybin und Entaktogenen wie 3,4-Methylendioxymethamphetamin (MDMA) im Rahmen von Psychotherapie ist in den letzten Jahren wieder zunehmend ins Licht des wissenschaftlichen Interesses gerückt. Die vorliegende Arbeit fasst die aktuelle Evidenz zur substanzunterstützten Psychotherapie mit serotonergen Psychoaktiva zusammen.
Methode Eine selektive Literaturrecherche erfolgte in PubMed und der Cochrane Library, wobei nach Studien gesucht wurde, in denen der Einsatz von serotonergen Psychoaktiva in der Psychotherapie seit 2000 untersucht wurde.
Ergebnisse Es fanden sich Studien für die folgenden Behandlungsindikationen: Alkoholabhängigkeit (LSD und Psilocybin), Nikotinabhängigkeit (Psilocybin), Behandlung von Angst und Depression bei lebensbedrohlicher körperlicher Erkrankung (LSD und Psilocybin), Zwangsstörungen (Psilocybin), therapieresistente Major Depression (Psilocybin) und posttraumatische Belastungsstörung (MDMA).
Diskussion Abhängigkeitserkrankungen, posttraumatische Belastungsstörung sowie Angst und Depression bei lebensbedrohlicher körperlicher Erkrankung stellen derzeit die am besten evaluierten Indikationen für die substanzunterstützte Psychotherapie mit serotonergen Psychoaktiva dar. Bisher zeigten sich Hinweise für eine Wirksamkeit bei relativ guter Verträglichkeit. Weitere Studien sind erforderlich, um einzuschätzen, ob diese Substanzen in Zukunft in der Behandlung bestimmter therapieresistenter psychischer Erkrankungen eine Option darstellen können.
Impaired empathic abilities lead to severe negative social consequences and influence the development and treatment of several psychiatric disorders. Furthermore, empathy has been shown to play a crucial role in moral and prosocial behaviour. Although the serotonin (5-HT) system has been implicated in modulating empathy and moral behaviour, the relative contribution of the various 5-HT receptor subtypes is still unknown.
We investigated the acute effect of psilocybin (0.215mg/kg p.o.) in healthy human subjects on different facets of empathy and hypothetical moral decision-making using the Multifaceted Empathy Test (MET) (n=32) and the Moral Dilemma Task (MDT) (n=24).
Psilocybin significantly increased emotional, but not cognitive empathy compared to placebo, and the increase in implicit emotional empathy was significantly associated with psilocybin-induced changed meaning of percepts. In contrast, moral decision-making remained unaffected by psilocybin.
These findings provide first evidence that psilocybin has distinct effects on social cognition by enhancing emotional empathy but not moral behaviour. Furthermore, together with previous findings psilocybin appears to promote emotional empathy presumably via activation of 5-HT2A/1A receptors suggesting that targeting 5-HT2A/1A receptors has implications for potential treatment of dysfunctional social cognition.
In a large-scale (N = 1487) general population online study, we investigated the relationship between past experience with classic psychedelic substances (e.g. LSD, psilocybin, mescaline), nature relatedness, and ecological behavior (e.g. saving water, recycling). Using structural equation modeling we found that experience with classic psychedelics uniquely predicted self-reported engagement in pro-environmental behaviors, and that this relationship was statistically explained by people’s degree of self-identification with nature. Our model controlled for experiences with other classes of psychoactive substances (cannabis, dissociatives, empathogens, popular legal drugs) as well as common personality traits that usually predict drug consumption and/or nature relatedness (openness to experience, conscientiousness, conservatism). Although correlational in nature, results suggest that lifetime experience with psychedelics in particular may indeed contribute to people’s pro-environmental behavior by changing their self-construal in terms of an incorporation of the natural world, regardless of core personality traits or general propensity to consume mind-altering substances. Thereby, the present research adds to the contemporary literature on the beneficial effects of psychedelic substance use on mental wellbeing, hinting at a novel area for future research investigating their potentially positive effects on a societal level. Limitations of the present research and future directions are discussed.
Objective: To identify patients’ perceptions of the value of psilocybin as a treatment for depression. Method: Twenty patients enrolled in an open-label trial of psilocybin for treatment-resistant depression participated in a semistructured interview at 6-month follow-up. Thematic analysis was used to identify patients’ experiences of the treatment and how it compared with previous treatments. Results: Two main change processes were identified in relation to the treatment. The first concerned change from disconnection (from self, others, and world) to connection, and the second concerned change from avoidance (of emotion) to acceptance. A third theme concerned comparison between psilocybin and conventional treatments. Patients reported that medications and some short-term talking therapies tended to reinforce their sense of disconnection and avoidance, whereas treatment with psilocybin encouraged connection and acceptance. Conclusions: These results suggest that psilocybin treatment for depression may work via paradigmatically novel means, antithetical to antidepressant medications, and some short-term talking therapies.
The psychedelic experience (including psychedelic-induced ego dissolution) can effect lasting change in a person's attitudes and beliefs. Here, we aimed to investigate the association between naturalistic psychedelic use and personality, political perspectives, and nature relatedness using an anonymous internet survey. Participants (N = 893) provided information about their naturalistic psychedelic, cocaine, and alcohol use, and answered questions relating to personality traits of openness and conscientiousness (Ten-Item Personality Inventory), nature relatedness (Nature-Relatedness Scale), and political attitudes (one-item liberalism-conservatism measure and five-item libertarian-authoritarian measure). Participants also rated the degree of ego dissolution experienced during their "most intense" recalled psychedelic experience (Ego-Dissolution Inventory). Multivariate linear regression analysis indicated that lifetime psychedelic use (but not lifetime cocaine use or weekly alcohol consumption) positively predicted liberal political views, openness and nature relatedness, and negatively predicted authoritarian political views, after accounting for potential confounding variables. Ego dissolution experienced during a participant's "most intense" psychedelic experience positively predicted liberal political views, openness and nature relatedness, and negatively predicted authoritarian political views. Further work is needed to investigate the nature of the relationship between the peak psychedelic experience and openness to new experiences, egalitarian political views, and concern for the environment.
Data suggest psychedelics such as psilocybin and lysergic acid diethylamide (LSD) may hold therapeutic potential in the treatment of addictions, including tobacco dependence. This retrospective cross-sectional anonymous online survey characterized 358 individuals (52 females) who reported having quit or reduced smoking after ingesting a psychedelic in a non-laboratory setting ⩾1 year ago. On average, participants smoked 14 cigarettes/day for 8 years, and had five previous quit attempts before their psychedelic experience. Of the 358 participants, 38% reported continuous smoking cessation after psychedelic use (quitters). Among quitters, 74% reported >2 years' abstinence. Of the 358 participants, 28% reported a persisting reduction in smoking (reducers), from a mode of 300 cigarettes/month before, to a mode of 1 cigarette/month after the experience. Among reducers, 62% reported >2 years of reduced smoking. Finally, 34% of the 358 participants (relapsers) reported a temporary smoking reduction before returning to baseline smoking levels, with a mode time range to relapse of 3-6 months. Relapsers rated their psychedelic experience significantly lower in personal meaning and spiritual significance than both other groups. Participants across all groups reported less severe affective withdrawal symptoms (e.g. depression, craving) after psychedelic use compared with previous quit attempts, suggesting a potential mechanism of action for psychedelic-associated smoking cessation/reduction. Changes in life priorities/values were endorsed as the most important psychological factor associated with smoking cessation/reduction. Results suggest psychedelics may hold promise in treating tobacco addiction as potentially mediated by spiritual experience, changed priorities/values, and improved emotional regulation.
Ayahuasca is the Quechua name for a tea obtained from the vine Banisteriopsis caapi, and used for ritual purposes by the indigenous populations of the Amazon. The use of a variation of the tea that combines B. caapi with the leaves of the shrub Psychotria viridis has experienced unprecedented expansion worldwide for its psychotropic properties. This preparation contains the psychedelic 5-HT2A receptor agonist N,N-dimethyltryptamine (DMT) from P. viridis, plus β-carboline alkaloids with monoamine-oxidase-inhibiting properties from B. caapi. Acute administration induces a transient modified state of consciousness characterized by introspection, visions, enhanced emotions and recollection of personal memories. A growing body of evidence suggests that ayahuasca may be useful to treat substance use disorders, anxiety and depression. Here we review the pharmacology and neuroscience of ayahuasca, and the potential psychological mechanisms underlying its therapeutic potential. We discuss recent findings indicating that ayahuasca intake increases certain mindfulness facets related to acceptance and to the ability to take a detached view of one’s own thoughts and emotions. Based on the available evidence, we conclude that ayahuasca shows promise as a therapeutic tool by enhancing self-acceptance and allowing safe exposure to emotional events. We postulate that ayahuasca could be of use in the treatment of impulse-related, personality and substance use disorders and also in the handling of trauma. More research is needed to assess the full potential of ayahuasca in the treatment of these disorders.
The drug 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”, “molly”) is a widely used illicit drug and experimental adjunct to psychotherapy. MDMA has unusual, poorly understood socioemotional effects, including feelings of interpersonal closeness and sociability. To better understand these effects, we conducted a small (n=12) within-subjects double-blind placebo controlled study of the effects of 1.5 mg/kg oral MDMA on social emotions and autobiographical disclosure in a controlled setting. MDMA displayed both sedative- and stimulant-like effects, including increased self-report anxiety. At the same time, MDMA positively altered evaluation of the self (i.e. increasing feelings of authenticity) while decreasing concerns about negative evaluation by others (i.e. decreasing social anxiety). Consistent with these feelings, MDMA increased how comfortable participants felt describing emotional memories. Overall, MDMA produced a prosocial syndrome that seemed to facilitate emotional disclosure and that appears consistent with the suggestion that it represents a novel pharmacological class.
Lysergic acid diethylamide (LSD) is a potent serotonergic hallucinogen or psychedelic that modulates consciousness in a marked and novel way. This study sought to examine the acute and mid-term psychological effects of LSD in a controlled study.
A total of 20 healthy volunteers participated in this within-subjects study. Participants received LSD (75 µg, intravenously) on one occasion and placebo (saline, intravenously) on another, in a balanced order, with at least 2 weeks separating sessions. Acute subjective effects were measured using the Altered States of Consciousness questionnaire and the Psychotomimetic States Inventory (PSI). A measure of optimism (the Revised Life Orientation Test), the Revised NEO Personality Inventory, and the Peter's Delusions Inventory were issued at baseline and 2 weeks after each session.
LSD produced robust psychological effects; including heightened mood but also high scores on the PSI, an index of psychosis-like symptoms. Increased optimism and trait openness were observed 2 weeks after LSD (and not placebo) and there were no changes in delusional thinking.
The present findings reinforce the view that psychedelics elicit psychosis-like symptoms acutely yet improve psychological wellbeing in the mid to long term. It is proposed that acute alterations in mood are secondary to a more fundamental modulation in the quality of cognition, and that increased cognitive flexibility subsequent to serotonin 2A receptor (5-HT2AR) stimulation promotes emotional lability during intoxication and leaves a residue of 'loosened cognition' in the mid to long term that is conducive to improved psychological wellbeing.
Recent scientific research into the therapeutic potential and mechanisms of psychedelic drugs raises intriguing and hitherto largely unexplored philosophical questions. A brief overview of the relevant science is given before addressing these questions. It is argued that psychedelic transformation is a distinctive psycho- pharmacological intervention because its mechanism of action ineliminably involves conscious mental representations, and thus is more transparent to the subject than the mechanisms of other drug therapies. This argument connects with issues in the philosophy of (cognitive) scientific explanation. It is also argued that transformative psychedelic experiences may well confer three distinct kinds of epistemic benefits: knowledge by acquaintance of the subject's psychological potential, knowledge by acquaintance of the meta-physical nature of the (sense of) self, and revitalized capacities for the acquisition of modal knowledge. Non-naturalistic metaphysical and epistemological claims abound in psychedelic circles; thus, it is important to realize that psychedelics may yield naturalistically acceptable epistemic benefits.
Users of ±3,4-methylenedioxymethamphetamine (MDMA; 'ecstasy') report prosocial effects such as sociability and empathy. Supporting these apparently unique social effects, data from controlled laboratory studies indicate that MDMA alters social feelings, information processing, and behavior in humans, and social behavior in rodents. Here, we review this growing body of evidence. In rodents, MDMA increases passive prosocial behavior (adjacent lying) and social reward while decreasing aggression, effects that may involve serotonin 1A receptor mediated oxytocin release interacting with vasopressin receptor 1A. In humans, MDMA increases plasma oxytocin and produces feelings of social affiliation. It decreases identification of negative facial expressions (cognitive empathy) and blunts responses to social rejection, while enhancing responses to others' positive emotions (emotional empathy) and increasing social approach. Thus, consistent with drug folklore, laboratory administration of MDMA robustly alters social processing in humans and increases social approach in humans and animals. Effects are consistent with increased sociability, with mixed evidence about enhanced empathy. These neurobiologically-complex prosocial effects likely motivate recreational ecstasy use.
Health-related psychedelic research should focus on helping us flourish, not just remedying ill-health or addiction. We don’t know enough about how psychedelics could enhance human flourishing. Factors promoting health-through-flourishing include finding meaning in life, spiritual practices, comfortable levels of social bonds, emotionally/physically satisfying sex in a long-term monogamous relationship and control over one’s daily life. Psychedelic research could find more. Neuroscience anchors psychedelic research into disease and disorder, e.g. addiction, PSTD, migraine, anxiety, pain etc. Neurophenomenological psychedelics research could illuminate relationships between health, ASC/NOSCs and cognitive liberty to promote human flourishing. If we accept the self as an epiphenomenon of subsystems within the brain, we ‘know’ ‘unconsciously’, but are not aware of, many things which affect our lives profoundly. These include control over identifying, remembering and forgetting our states of mind and how to move between them. A prerequisite for integrated investigations into ASC/NOSCs is the establishment of a taxonomic knowledge base which lists, categorises and characterises ASC/NOSCs to enable us to choose specific states of mind and move securely among them. Or, in other words, to enable us to exercise our cognitive liberty safely. I believe that human health and flourishing would be enhanced were we able to direct our states of being by consciously choosing them. Given the promise of mindfulness techniques to enhance our health, happiness and spiritual growth, constructing both personal and generic classifications of salient ASC/NOSCs makes sense. Laws need to change. The neuroscience of pleasure, love, spirituality, decision-making, pattern recognition and location of meaning should inform health-enhancing psychedelic research while promoting flourishing through cognitive liberty. As part of cognitive liberty, our end-of-life choices should include how we die. In other words, our idea of the good death should include access to psychedelics. Dying high is increasingly likely to become a popular choice as baby boomers age and place their economic clout behind the reform of end-of-life laws as well as drug laws. Achieving such crucial legal changes depends partly on the ability to produce research to anchor evidence based law and policy. Research into psychedelics, ASC/NOSCs and the neurobiology of the dying process is essential.