Models of psychedelic drug action: modulation of cortical-subcortical circuits.

Classic psychedelic drugs such as psilocybin and lysergic acid diethylamide (LSD) have recaptured the imagination of both science and popular culture, and may have efficacy in treating a wide range of psychiatric disorders. Human and animal studies of psychedelic drug action in the brain have demonstrated the involvement of the serotonin 2A (5-HT2A) receptor and the cerebral cortex in acute psychedelic drug action, but different models have evolved to try to explain the impact of 5-HT2A activation on neural systems. Two prominent models of psychedelic drug action (the cortico-striatal thalamo-cortical, or CSTC, model and relaxed beliefs under psychedelics, or REBUS, model) have emphasized the role of different subcortical structures as crucial in mediating psychedelic drug effects. We describe these models and discuss gaps in knowledge, inconsistencies in the literature and extensions of both models. We then introduce a third circuit-level model involving the claustrum, a thin strip of grey matter between the insula and the external capsule that densely expresses 5-HT2A receptors (the cortico-claustro-cortical, or CCC, model). In this model, we propose that the claustrum entrains canonical cortical network states, and that psychedelic drugs disrupt 5-HT2A-mediated network coupling between the claustrum and the cortex, leading to attenuation of canonical cortical networks during psychedelic drug effects. Together, these three models may explain many phenomena of the psychedelic experience, and using this framework, future research may help to delineate the functional specificity of each circuit to the action of both serotonergic and non-serotonergic hallucinogens.

Psilocybin induces spatially constrained alterations in thalamic functional organizaton and connectivity.

BACKGROUND: Classic psychedelics, such as psilocybin and LSD, and other serotonin 2A receptor (5-HT2AR) agonists evoke acute alterations in perception and cognition. Altered thalamocortical connectivity has been hypothesized to underlie these effects, which is supported by some functional MRI (fMRI) studies. These studies have treated the thalamus as a unitary structure, despite known differential 5-HT2AR expression and functional specificity of different intrathalamic nuclei. Independent Component Analysis (ICA) has been previously used to identify reliable group-level functional subdivisions of the thalamus from resting-state fMRI (rsfMRI) data. We build on these efforts with a novel data-maximizing ICA-based approach to examine psilocybin-induced changes in intrathalamic functional organization and thalamocortical connectivity in individual participants. METHODS: Baseline rsfMRI data (n=38) from healthy individuals with a long-term meditation practice was utilized to generate a statistical template of thalamic functional subdivisions. This template was then applied in a novel ICA-based analysis of the acute effects of psilocybin on intra- and extra-thalamic functional organization and connectivity in follow-up scans from a subset of the same individuals (n=18). We examined correlations with subjective reports of drug effect and compared with a previously reported analytic approach (treating the thalamus as a single functional unit). RESULTS: Several intrathalamic components showed significant psilocybin-induced alterations in spatial organization, with effects of psilocybin largely localized to the mediodorsal and pulvinar nuclei. The magnitude of changes in individual participants correlated with reported subjective effects. These components demonstrated predominant decreases in thalamocortical connectivity, largely with visual and default mode networks. Analysis in which the thalamus is treated as a singular unitary structure showed an overall numerical increase in thalamocortical connectivity, consistent with previous literature using this approach, but this increase did not reach statistical significance. CONCLUSIONS: We utilized a novel analytic approach to discover psilocybin-induced changes in intra- and extra-thalamic functional organization and connectivity of intrathalamic nuclei and cortical networks known to express the 5-HT2AR. These changes were not observed using whole-thalamus analyses, suggesting that psilocybin may cause widespread but modest increases in thalamocortical connectivity that are offset by strong focal decreases in functionally relevant intrathalamic nuclei.

Psychedelics and Consciousness: Distinctions, Demarcations, and Opportunities.

Psychedelic substances produce unusual and compelling changes in conscious experience that have prompted some to propose that psychedelics may provide unique insights explaining the nature of consciousness. At present, psychedelics, like other current scientific tools and methods, seem unlikely to provide information relevant to the so-called "hard problem of consciousness," which involves explaining how first-person experience can emerge. However, psychedelics bear on multiple "easy problems of consciousness," which involve relations between subjectivity, brain function, and behavior. In this review, we discuss common meanings of the term "consciousness" when used with regard to psychedelics and consider some models of the effects of psychedelics on the brain that have also been associated with explanatory claims about consciousness. We conclude by calling for epistemic humility regarding the potential for psychedelic research to aid in explaining the hard problem of consciousness while pointing to ways in which psychedelics may advance the study of many specific aspects of consciousness.

Classic Psychedelic Coadministration with Lithium, but Not Lamotrigine, is Associated with Seizures: An Analysis of Online Psychedelic Experience Reports.

INTRODUCTION: Psychedelics show promise in treating unipolar depression, though patients with bipolar disorder have been excluded from recent psychedelic trials. There is limited information on the use of classic psychedelics (e. g., LSD or psilocybin) in individuals using mood stabilizers to treat bipolar disorder. This is important to know, as individuals with bipolar depression may attempt to treat themselves with psychedelics while on a mood stabilizer, particularly given enthusiastic media reports of the efficacy of psilocybin for depression. METHODS: This study analyzed reports of classic psychedelics administered with mood stabilizers from 3 websites (Erowid.org, Shroomery.org, and Reddit.com). RESULTS: Strikingly, 47% of 62 lithium plus psychedelic reports involved seizures, and an additional 18% resulted in bad trips while none of 34 lamotrigine reports did. Further, 39% of lithium reports involved medical attention. Most of the lamotrigine reports (65%) but few (8%) of the lithium reports were judged to not affect the psychedelic experience. DISCUSSION: Although further research is needed, we provisionally conclude that psychedelic use may pose a significant seizure risk for patients on lithium.

Psilocybin acutely alters the functional connectivity of the claustrum with brain networks that support perception, memory, and attention.

Psychedelic drugs, including the serotonin 2a (5-HT2A) receptor partial agonist psilocybin, are receiving renewed attention for their possible efficacy in treating a variety of neuropsychiatric disorders. Psilocybin induces widespread dysregulation of cortical activity, but circuit-level mechanisms underlying this effect are unclear. The claustrum is a subcortical nucleus that highly expresses 5-HT2A receptors and provides glutamatergic inputs to arguably all areas of the cerebral cortex. We therefore tested the hypothesis that psilocybin modulates claustrum function in humans. Fifteen healthy participants (10M, 5F) completed this within-subjects study in which whole-brain resting-state blood-oxygenation level-dependent (BOLD) signal was measured 100 â€‹min after blinded oral administration of placebo and 10 mg/70 â€‹kg psilocybin. Left and right claustrum signal was isolated using small region confound correction. Psilocybin significantly decreased both the amplitude of low frequency fluctuations as well as the variance of BOLD signal in the left and right claustrum. Psilocybin also significantly decreased functional connectivity of the right claustrum with auditory and default mode networks (DMN), increased right claustrum connectivity with the fronto-parietal task control network (FPTC), and decreased left claustrum connectivity with the FPTC. DMN integrity was associated with right-claustrum connectivity with the DMN, while FPTC integrity and modularity were associated with right claustrum and left claustrum connectivity with the FPTC, respectively. Subjective effects of psilocybin predicted changes in the amplitude of low frequency fluctuations and the variance of BOLD signal in the left and right claustrum. Observed effects were specific to claustrum, compared to flanking regions of interest (the left and right insula and putamen). This study used a pharmacological intervention to provide the first empirical evidence in any species for a significant role of 5-HT2A receptor signaling in claustrum functioning, and supports a possible role of the claustrum in the subjective and therapeutic effects of psilocybin.

Resting state functional connectivity and cognitive task-related activation of the human claustrum.

Structural and functional analyses of the human claustrum, a poorly understood telencephalic gray matter structure, are hampered by its sheet-like anatomical arrangement. Here, we first describe a functional magnetic resonance imaging (fMRI) method to reveal claustrum signal with no linear relationship with adjacent regions in human subjects. We applied this approach to resting state functional connectivity (RSFC) analysis of the claustrum at high resolution (1.5 mm isotropic voxels) using a 7T dataset (n = 20) and a separate 3T dataset for replication (n = 35). We then assessed claustrum activation during performance of a cognitive task, the multi-source interference task, at 3T (n = 33). Extensive functional connectivity was observed between claustrum and cortical regions associated with cognitive control, including anterior cingulate, prefrontal and parietal cortices. Cognitive task performance was associated with widespread activation and deactivation that overlapped with the cortical areas showing functional connectivity to the claustrum. Furthermore, during high cognitive conflict conditions of the task, the claustrum was significantly activated at the onset of the task, but not during the remainder of the difficult condition. Both of these findings suggest that the human claustrum can be functionally isolated with fMRI, and that it may play a role in cognitive control, and specifically task switching, independent of sensorimotor processing.

Serotonin 2A Receptor Signaling Underlies LSD-induced Alteration of the Neural Response to Dynamic Changes in Music.

Classic psychedelic drugs (serotonin 2A, or 5HT2A, receptor agonists) have notable effects on music listening. In the current report, blood oxygen level-dependent (BOLD) signal was collected during music listening in 25 healthy adults after administration of placebo, lysergic acid diethylamide (LSD), and LSD pretreated with the 5HT2A antagonist ketanserin, to investigate the role of 5HT2A receptor signaling in the neural response to the time-varying tonal structure of music. Tonality-tracking analysis of BOLD data revealed that 5HT2A receptor signaling alters the neural response to music in brain regions supporting basic and higher-level musical and auditory processing, and areas involved in memory, emotion, and self-referential processing. This suggests a critical role of 5HT2A receptor signaling in supporting the neural tracking of dynamic tonal structure in music, as well as in supporting the associated increases in emotionality, connectedness, and meaningfulness in response to music that are commonly observed after the administration of LSD and other psychedelics. Together, these findings inform the neuropsychopharmacology of music perception and cognition, meaningful music listening experiences, and altered perception of music during psychedelic experiences.

Psychedelics and music: neuroscience and therapeutic implications.

From the beginning of therapeutic research with psychedelics, music listening has been consistently used as a method to guide or support therapeutic experiences during the acute effects of psychedelic drugs. Recent findings point to the potential of music to support meaning-making, emotionality, and mental imagery after the administration of psychedelics, and suggest that music plays an important role in facilitating positive clinical outcomes of psychedelic therapy. This review explores the history of, contemporary research on, and future directions regarding the use of music in psychedelic research and therapy, and argues for more detailed and rigorous investigation of the contribution of music to the treatment of psychiatric disorders within the novel framework of psychedelic therapy.

Molecular imaging of serotonin degeneration in mild cognitive impairment.

Neuropathological and neuroimaging studies have consistently demonstrated degeneration of monoamine systems, especially the serotonin system, in normal aging and Alzheimer's disease. The evidence for degeneration of the serotonin system in mild cognitive impairment is limited. Thus, the goal of the present study was to measure the serotonin transporter in vivo in mild cognitive impairment and healthy controls. The serotonin transporter is a selective marker of serotonin terminals and of the integrity of serotonin projections to cortical, subcortical and limbic regions and is found in high concentrations in the serotonergic cell bodies of origin of these projections (raphe nuclei). Twenty-eight participants with mild cognitive impairment (age 66.6±6.9, 16 males) and 28 healthy, cognitively normal, demographically matched controls (age 66.2±7.1, 15 males) underwent magnetic resonance imaging for measurement of grey matter volumes and high-resolution positron emission tomography with well-established radiotracers for the serotonin transporter and regional cerebral blood flow. Beta-amyloid imaging was performed to evaluate, in combination with the neuropsychological testing, the likelihood of subsequent cognitive decline in the participants with mild cognitive impairment. The following hypotheses were tested: 1) the serotonin transporter would be lower in mild cognitive impairment compared to controls in cortical and limbic regions, 2) in mild cognitive impairment relative to controls, the serotonin transporter would be lower to a greater extent and observed in a more widespread pattern than lower grey matter volumes or lower regional cerebral blood flow and 3) lower cortical and limbic serotonin transporters would be correlated with greater deficits in auditory-verbal and visual-spatial memory in mild cognitive impairment, not in controls. Reduced serotonin transporter availability was observed in mild cognitive impairment compared to controls in cortical and limbic areas typically affected by Alzheimer's disease pathology, as well as in sensory and motor areas, striatum and thalamus that are relatively spared in Alzheimer's disease. The reduction of the serotonin transporter in mild cognitive impairment was greater than grey matter atrophy or reductions in regional cerebral blood flow compared to controls. Lower cortical serotonin transporters were associated with worse performance on tests of auditory-verbal and visual-spatial memory in mild cognitive impairment, not in controls. The serotonin system may represent an important target for prevention and treatment of MCI, particularly the post-synaptic receptors (5-HT4 and 5-HT6), which may not be as severely affected as presynaptic aspects of the serotonin system, as indicated by the observation of lower serotonin transporters in MCI relative to healthy controls.

Association between serotonin denervation and resting-state functional connectivity in mild cognitive impairment.

Resting-state functional connectivity alterations have been demonstrated in Alzheimer's disease (AD) and mild cognitive impairment (MCI) before the observation of AD neuropathology, but mechanisms driving these changes are not well understood. Serotonin neurodegeneration has been observed in MCI and AD and is associated with cognitive deficits and neuropsychiatric symptoms, but the role of the serotonin system in relation to brain network dysfunction has not been a major focus of investigation. The current study investigated the relationship between serotonin transporter availability (SERT; measured using positron emission tomography) and brain network functional connectivity (measured using resting-state functional MRI) in 20 participants with MCI and 21 healthy controls. Two SERT regions of interest were selected for the analysis: the Dorsal Raphe Nuclei (DRN) and the precuneus which represent the cell bodies of origin and a cortical target of projections of the serotonin system, respectively. Both regions show decreased SERT in MCI compared to controls and are the site of early AD pathology. Average resting-state functional connectivity did not differ between MCI and controls. Decreased SERT in DRN was associated with lower hippocampal resting-state connectivity in MCI participants compared to controls. Decreased SERT in the right precuneus was also associated with lower resting-state connectivity of the retrosplenial cortex to the dorsal lateral prefrontal cortex and higher resting-state connectivity of the retrosplenial cortex to the posterior cingulate and in patients with MCI but not in controls. These results suggest that a serotonergic mechanism may underlie changes in brain functional connectivity in MCI. Hum Brain Mapp 38:3391-3401, 2017. © 2017 Wiley Periodicals, Inc.

Opioid Overdose History, Risk Behaviors, and Knowledge in Patients Taking Prescribed Opioids for Chronic Pain.

OBJECTIVE: More than 100 million adults in the United States experience chronic pain, and prescription opioids are the third most widely prescribed class of medications. Current opioid overdose prevention efforts almost exclusively target illicit opioid users, and little is known about the experience of overdose among patients being treated for chronic pain (CP) with a prescription opioid. METHODS: Patients experiencing CP for three or more months and receiving a prescription opioid for pain management (N = 502) completed a self-report survey that asked questions about opioid overdose history, past 30-day risk factors, and knowledge of opioid overdose, overdose risk, and naloxone. RESULTS: Approximately one in five CP participants reported experiencing a lifetime overdose. CP participants reported engaging in several behaviors associated with overdose risk and were unlikely to have been trained to administer naloxone. Fewer than 50% of participants answered any knowledge item correctly. The likelihood of having experienced an overdose increased as the scores on the SOAPP-R and DSM-5 opioid use disorder checklist increased, and a SOAPP-R score of 7 or higher or meeting DSM-5 mild opioid use disorder criteria were significantly associated with reporting a lifetime overdose (85% and 84% of participants who experienced an overdose, respectively). CONCLUSIONS: Opioid overdose occurs at a high rate among CP participants, and this group is relatively uninformed about risk factors for overdose. Established SOAPP-R and DSM thresholds provide an opportunity to identify participants at elevated risk for having experienced an opioid overdose. These data support development of additional concentrated efforts to prevent overdose among chronic pain patients.

Neuroticism is associated with challenging experiences with psilocybin mushrooms.

OBJECTIVES: Classic hallucinogens (e.g. psilocybin and LSD) have substantial effects on perception, cognition, and emotion that can often be psychologically challenging, however we know very little regarding the source of significant individual variability that has been observed in the frequency and intensity of challenging experiences (i.e. "bad trips") with psychedelics. Previous clinical and observational literature suggests that there may be an association between neuroticism and challenging psychedelic experiences. METHODS: Data from two online surveys of challenging experiences with psilocybin were analyzed. Multivariate analysis was used to estimate the associations between total score and scores from seven sub-factors (fear, grief, physical distress, insanity, isolation, death, and paranoia) of the Challenging Experience Questionnaire (CEQ), and scale scores from the Ten Item Personality Inventory (TIPI) in Study 1 (N=1993) and the Big Five Inventory (BFI) in Study 2 (N = 981). RESULTS: CEQ scores were negatively associated with emotional stability scores (the inverse of neuroticism) in Study 1 and positively associated with neuroticism scores in Study 2. CONCLUSIONS: Neuroticism may contribute to the strength of challenging experiences in uncontrolled settings.

The ROC Toolbox: A toolbox for analyzing receiver-operating characteristics derived from confidence ratings.

Signal-detection theory, and the analysis of receiver-operating characteristics (ROCs), has played a critical role in the development of theories of episodic memory and perception. The purpose of the current paper is to present the ROC Toolbox. This toolbox is a set of functions written in the Matlab programming language that can be used to fit various common signal detection models to ROC data obtained from confidence rating experiments. The goals for developing the ROC Toolbox were to create a tool (1) that is easy to use and easy for researchers to implement with their own data, (2) that can flexibly define models based on varying study parameters, such as the number of response options (e.g., confidence ratings) and experimental conditions, and (3) that provides optimal routines (e.g., Maximum Likelihood estimation) to obtain parameter estimates and numerous goodness-of-fit measures.The ROC toolbox allows for various different confidence scales and currently includes the models commonly used in recognition memory and perception: (1) the unequal variance signal detection (UVSD) model, (2) the dual process signal detection (DPSD) model, and (3) the mixture signal detection (MSD) model. For each model fit to a given data set the ROC toolbox plots summary information about the best fitting model parameters and various goodness-of-fit measures. Here, we present an overview of the ROC Toolbox, illustrate how it can be used to input and analyse real data, and finish with a brief discussion on features that can be added to the toolbox.

Development of the Japanese version of the Challenging Experience Questionnaire.

INTRODUCTION: The therapeutic potential of psychedelics for various mental disorders has gained significant interest. Previous studies have highlighted that psychedelics induce psychoactive effects, including challenging aspects of experiences. These experiences are assessed using the Challenging Experience Questionnaire (CEQ), yet its Japanese version has been unavailable. This study aimed to create a Japanese version of the CEQ. METHODS: We followed the "Principles of Good Practice for the Translation and Cultural Adaptation Process for Patient-Reported Outcomes (PRO) Measures: Report of the ISPOR Task Force for Translation and Cultural Adaptation." Initially, two Japanese psychiatrists independently conducted the forward translations. These were then reconciled into a single version, which was back-translated into English. The original authors reviewed this back-translation for accuracy, leading to revisions through continuous dialogue until the original authors approved the final version. RESULTS: The final, approved back-translated version of the CEQ is presented in the figure. CONCLUSIONS: This study developed a Japanese version of the CEQ, enabling the assessment of challenging experiences during psychedelic-assisted therapy for Japanese speakers. Further studies are needed to assess the reliability and validity of this newly translated version.

Unique effects of sedatives, dissociatives, psychedelics, stimulants, and cannabinoids on episodic memory: A review and reanalysis of acute drug effects on recollection, familiarity, and metamemory.

Despite distinct classes of psychoactive drugs producing putatively unique states of consciousness, there is surprising overlap in terms of their effects on episodic memory and cognition more generally. Episodic memory is supported by multiple subprocesses that have been mostly overlooked in psychopharmacology and could differentiate drug classes. Here, we reanalyzed episodic memory confidence ratings from 10 previously published data sets (28 drug conditions total) using signal detection models to estimate two conscious states involved in episodic memory and one consciously controlled metacognitive process of memory: autonoetic retrieval of specific details (recollection), noetic recognition absent of retrieved details (familiarity), and retrospective introspection of memory decisions (metamemory). Sedatives, dissociatives, psychedelics, stimulants, and cannabinoids had unique patterns of effects on these mnemonic processes dependent on whether they impacted encoding, consolidation, or retrieval (the formation, stabilization, and access to memory traces, respectively). Sedatives at encoding reliably impaired both recollection and familiarity but at consolidation enhanced recollection. Dissociatives and cannabinoids at encoding impaired recollection but less reliably impaired familiarity, and cannabinoids at retrieval increased false recollections. These drug-induced encoding impairments occasionally came with metamemory enhancements, perhaps because of less interstimulus interference. Psychedelics at encoding impaired recollection but tended to enhance familiarity and did not impact metamemory. Stimulants at encoding enhanced metamemory, at consolidation impaired metamemory, and at retrieval enhanced familiarity and metamemory. These findings allude to mechanisms underlying the idiosyncratic phenomena of drugs, such as blackouts from sedatives and presque vu from psychedelics. Finally, these findings converge on a model in which memory quantity and stability influence metamemory. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The therapeutic alliance between study participants and intervention facilitators is associated with acute effects and clinical outcomes in a psilocybin-assisted therapy trial for major depressive disorder.

We examined if the therapeutic alliance between study participants and intervention facilitators in a psilocybin-assisted therapy (PAT) trial changed over time and whether there were relationships between alliance, acute psilocybin experiences, and depression outcomes. In a randomized, waiting list-controlled clinical trial for major depressive disorder in adults (N = 24), participants were randomized to an immediate (N = 13) or delayed (N = 11) condition with two oral doses of psilocybin (20mg/70kg and 30mg/70kg). Ratings of therapeutic alliance significantly increased from the final preparation session to one-week post-intervention (p = .03, d = .43). A stronger total alliance at the final preparation session predicted depression scores at 4 weeks (r = -.65, p = .002), 6 months (r = -.47, p = .036), and 12 months (r = -.54, p = .014) post-intervention. A stronger total alliance in the final preparation session was correlated with higher peak ratings of mystical experiences (r = .49, p = .027) and psychological insight (r = .52, p = .040), and peak ratings of mystical experience and psychological insight were correlated with depression scores at 4 weeks (r = -.45, p = .030 for mystical; r = -.75, p < .001 for insight). Stronger total alliance one week after the final psilocybin session predicted depression scores at 4 weeks (r = -.85, p < .001), 3 months (r = -.52, p = .010), 6 months (r = -.77, p < .001), and 12 months (r = -.61, p = .001) post-intervention. These findings highlight the importance of the therapeutic relationship in PAT. Future research should explore therapist and participant characteristics which maximize the therapeutic alliance and evaluate its relationship to treatment outcomes. Trial registration: Registration: Clinicaltrials.gov NCT03181529. https://classic.clinicaltrials.gov/ct2/show/NCT03181529.

The costs and benefits of psychedelics on cognition and mood.

Anecdotal evidence has indicated that psychedelic substances may acutely enhance creative task performance, although empirical support for this claim is mixed at best. Clinical research has shown that psychedelics might have enduring effects on mood and well-being. However, there is no neurocognitive framework that ties acute changes in cognition to long-term effects in mood. In this review, we operationalize creativity within an emerging cognitive control framework and assess the current empirical evidence of the effects of psychedelics on creativity. Next, we leverage insights about the mechanisms and computations by which other psychoactive drugs act to enhance versus impair cognition, in particular to those that act on catecholamines, the neurophysiological consequences of which are relatively well understood. Finally, we use the same framework to link the suggested psychedelic-induced improvements in creativity with enduring psychedelic-induced improvements in mood.

Subtypes of the psychedelic experience have reproducible and predictable effects on depression and anxiety symptoms.

BACKGROUND: Subjective experiences seem to play an important role in the enduring effects of psychedelic experiences. Although the importance of the subjective experience on the impact of psychedelics is frequently discussed, a more detailed understanding of the subtypes of psychedelic experiences and their associated impacts on mental health has not been well documented. METHODS: In the current study, machine learning cluster analysis was used to derive three subtypes of psychedelic experience in a large (n = 985) cross sectional sample. RESULTS: These subtypes are not only associated with reductions in anxiety and depression symptoms and other markers of psychological wellbeing, but the structure of these subtypes and their subsequent impact on mental health are highly reproducible across multiple psychedelic substances. LIMITATIONS: Data were obtained via retrospective self-report, which does not allow for definitive conclusions about the direction of causation between baseline characteristics of respondents, qualities of subjective experience, and outcomes. CONCLUSIONS: The present analysis suggests that psychedelic experiences, in particular those that are associated with enduring improvements in mental health, may be characterized by reproducible and predictable subtypes of the subjective psychedelic effects. These subtypes appear to be significantly different with respect to the baseline demographic characteristics, baseline measures of mental health, and drug type and dose. These findings also suggest that efforts to increase psychedelic associated personal and mystical insight experiences may be key to maximizing beneficial impact of clinical approaches using this treatment in their patients.