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Alicia Danforth on ethical challenges in psychedelic medicine

Alicia Danforth, PhD, is a licensed clinical psychologist and researcher and has participated in three major studies on psychedelic-assisted therapy, the latest of which is still unpublished. She began her work in clinical research with psychedelic medicines as a coordinator and co-facilitator on the pilot study of psilocybin treatment for existential anxiety related to advanced cancer. More recently, she was an investigator for the first study of MDMA-assisted therapy for the treatment of social anxiety in autistic adults.
Your first study with psychedelics was about end-of-life anxiety, the second one was about social anxiety, and this latest one also has to do with anxiety to some extent. Is there a thread regarding anxiety in your research work?
I didn’t set out to go that way. The first study had to do with anxiety facing the end of life, yes. But to be candid, social anxiety wasn’t the initial focus of the autism research. I had made the false assumption that autistic individuals lack empathy, which isn’t more than an outdated cliché that I mistakenly took at face value. My initial thinking was that MDMA is an empathogen, so it might help this population experience empathy.
Once I started interviewing autistic adults for my dissertation, I found out that they were quite empathic in many domains of empathy, and they told me what they were struggling with is social anxiety. The desire to connect was there, but the ability to read social cues and to know how to integrate into a group conversation or initiate a friendship is what they needed help with. That’s how working with social anxiety as an indication came about.
So with hindsight, yes, you could say that anxiety is a thread that has run through most of the clinical work that I’ve been involved with. Anxiety disorders are the most common mental health diagnoses in the United States, and they have been a good match so far with psychedelics-assisted therapy.
Your latest research with psychedelics is about psychological distress in long-term AIDS/HIV survivors. Can you tell us more about this new study?
I want to clarify that I’m not one of the investigators on this study, I’m a lead clinician. I co-facilitated the therapy groups and the psilocybin treatment sessions. Dr. Brian Anderson initiated this study at UCSF. San Francisco has been a hub of HIV medicine, and Brian became aware that there’s an underserved population of long-term survivors who acquired the HIV virus back in the 1980’s or early 1990’s. As a result of losing so many of their friends and because of the impact of HIV on their lives and on the community, they were living with a high degree of demoralization.
Dr. Anderson wanted to explore if treatment with psilocybin-assisted therapy could help improve overall quality of life and reduce anxiety and depression symptoms. The first phase has been completed, the data are analyzed, and a manuscript has been prepared. All I can say right now is that the outcomes were encouraging.
One way in which this study was very innovative is that we worked with a group therapy model, where the participants prepared as a group, and then each one had an individual psilocybin-assisted therapy session, and they came back together to do their integration work as a group. We’re frequently asked if everyone took the psilocybin all together, and they did not. I don’t think we’re quite there yet, but I couldn’t help but wonder what that might be like someday.
At the upcoming ICPR 2020 conference in April, you’ll speak about ethical challenges within psychedelic medicine. Can you explain its importance?
It’s no secret that psychedelics present unique challenges when it comes to ethical considerations and boundaries. These substances place people in profound altered states of consciousness, and with that shift can come increased suggestibility and vulnerability. We’re working with such novel treatment paradigms that we need novel approaches to how the individuals who are entrusted with the roles of therapist or guide should be vetted, trained, and supervised.
Could you elaborate?
Well, it became very apparent to me that there are certain personality types that are drawn to situations in which they’re in close proximity to people who are vulnerable and open. They seek to manipulate and have a very unhealthy relationship with power. Back in the 60’s and early 70’s, when people were working with these substances in controlled and uncontrolled settings, there were problems with individuals who would transgress boundaries. And today, we’re plunging headlong into a new era where billions of dollars are accruing to throw money at this enterprise; there’s such a rush to do it quickly.
But, we don’t have the structures in place to keep the participants in research settings -and eventually customers in commercial settings- safe from abuses of power. So, I’ve started proposing that we need to look at other medical professions where they have to accommodate similar levels of vulnerability, such as anesthesiologists, pediatricians and gerontologists. We need to agree on which methods we’re going to have to employ to train and supervise peers. We don’t have a good system for winnowing out individuals who seek to do this work who have clinically significant narcissistic traits or psychopathy. How are we going to gatekeep? If we don’t talk about this responsibility and address it, we’re at risk of running into trouble again.
Alicia Danforth’s talk at ICPR 2020 will be entitled: “Getting Our House in Order: Advancing the Ethics of Psychedelic Medicine and Psychotherapy from Storming to Norming

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Psilocybin Therapeutic Research: The Present and Future Paradigm

Abstract

Psilocybin, an active component in “magic mushroom”, may have the potential to meet the therapeutic needs for a number of indications without the addictiveness and overdose risk of other mind-altering drugs, such as cocaine, heroin, alcohol, methamphetamine, and so forth. The need for new therapies is urgent because addiction, overdose, and suicide deaths have risen throughout the United States and around the world. Anecdotal and contemporary pharmacological reports have provided some indication about the therapeutic use of psilocybin for the treatment of mental health disorders such as major depressive disorder and addiction disorders. In this Viewpoint, I summarize the current state of psilocybin therapeutic research and attempt to provide some insight into future directions on which the scientific community may wish to focus.

Kargbo, R. B. (2020). Psilocybin Therapeutic Research: The Present and Future Paradigm. ACS Medicinal Chemistry Letters11(4), 399-402.; 10.1021/acsmedchemlett.0c00048

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Psychedelics and Dying Care: A Historical Look at the Relationship Between Psychedelics and Palliative Care

Abstract

This article examines the historical relationship between psychedelics and palliative care. Historians have contributed to a growing field of studies about how psychedelics have been used in the past, but much of that scholarship focused on interrogating questions of legitimacy or proving that psychedelics had therapeutic potential. Palliative care had not yet developed as medical sub-specialty, more often leaving dying care on the margins of modern, pharmaceutical-based treatments. As psychedelic researchers in the 1950s began exploring different applications for psychoactive substances such as LSD and mescaline, however, dying care came into clearer focus as a potential avenue for psychedelics. Before that application gained momentum in clinical or philosophical discussions, psychedelics were criminalized and some of those early discussions were lost. This article looks back at historical discussions about LSD’s potential for easing the anxiety associated with dying, and considers how those early conversations might offer insights into today’s more articulated discussions about psychedelics in palliative care.
Dyck, E. (2019). Psychedelics and dying care: A historical look at the relationship between psychedelics and palliative care. Journal of psychoactive drugs51(2), 102-107., https://doi.org/10.1080/02791072.2019.1581308
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Microdosing psychedelics: Demographics, practices, and psychiatric comorbidities.

Abstract

RATIONALE:
Microdosing psychedelics – the practice of consuming small, sub-hallucinogenic doses of substances such as LSD or psilocybin – is gaining attention in popular media but remains poorly characterized. Contemporary studies of psychedelic microdosing have yet to report the basic psychiatric descriptors of psychedelic microdosers.
OBJECTIVES:
To examine the practices and demographics of a population of psychedelic microdosers – including their psychiatric diagnoses, prescription medications, and recreational substance use patterns – to develop a foundation on which to conduct future clinical research.
METHODS:
Participants (n = 909; Mage = 26.9, SD = 8.6; male = 83.2%; White/European = 79.1%) recruited primarily from the online forum Reddit completed an anonymous online survey. Respondents who reported using LSD, psilocybin, or both for microdosing were grouped and compared with non-microdosing respondents using exploratory odds ratio testing on demographic variables, rates of psychiatric diagnoses, and past-year recreational substance use.
RESULTS:
Of microdosers, most reported using LSD (59.3%; Mdose = 13 mcg, or 11.3% of one tab) or psilocybin (25.9%; Mdose = 0.3 g of dried psilocybin mushrooms) on a one-day-on, two-days-off schedule. Compared with non-microdosers, microdosers were significantly less likely to report a history of substance use disorders (SUDs; OR = 0.17 (95% CI: 0.05-0.56)) or anxiety disorders (OR = 0.61 (95% CI: 0.41-0.91)). Microdosers were also more likely to report recent recreational substance use compared with non-microdosers (OR = 5.2 (95% CI: 2.7-10.8)).
CONCLUSIONS:
Well-designed randomized controlled trials are needed to evaluate the safety and tolerability of this practice in clinical populations and to test claims about potential benefits.
Rosenbaum, D., Weissman, C., Anderson, T., Petranker, R., Dinh-Williams, L. A., Hui, K., & Hapke, E. (2020). Microdosing psychedelics: Demographics, practices, and psychiatric comorbidities. Journal of Psychopharmacology, 0269881120908004., https://doi.org/10.1177/0269881120908004
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Self-reported negative outcomes of psilocybin users: A quantitative textual analysis

Abstract

Psilocybin, a substance mainly found in mushrooms of the genus psilocybe, has been historically used for ritualistic, recreational and, more recently, medicinal purposes. The scientific literature suggests low toxicity, low risk of addiction, overdose, or other causes of injury commonly caused by substances of abuse, with growing interest in the use of this substance for conditions such as treatment-resistant depression. However, the presence of negative outcomes linked to psilocybin use is not clear yet. The objective of this study is to investigate the negative effects of psilocybin consumption, according to the users’ own perception through self-reports extracted from an online platform. 346 reports were analyzed with the assistance of the IRAMUTEQ textual analysis software, adopting the procedures of Descending Hierarchical Classification, Correspondence Factor Analysis and Specificities Analysis. The text segments were grouped in 4 main clusters, describing thinking distortions, emergencies, perceptual alterations and the administration of the substance. Bad trips were more frequent in female users, being associated with thinking distortions. The use of multiple doses of psilocybin in the same session or its combination with other substances was linked to the occurrence of long-term negative outcomes, while the use of mushrooms in single high doses was linked to medical emergencies. These results can be useful for a better understanding of the effects of psilocybin use, guiding harm-reduction initiatives.

 
Bienemann, B., Ruschel, N. S., Campos, M. L., Negreiros, M. A., & Mograbi, D. C. (2020). Self-reported negative outcomes of psilocybin users: A quantitative textual analysis. Plos one15(2), e0229067., https://doi.org/10.1371/journal.pone.0229067
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Subacute Effects of the Psychedelic Ayahuasca on the Salience and Default Mode Networks

Abstract

Background: Neuroimaging studies have just begun to explore the acute effects of psychedelics on large-scale brain networks’ functional organization. Even less is known about the neural correlates of subacute effects taking place days after the psychedelic experience. This study explores the subacute changes of primary sensory brain networks and networks supporting higher-order affective and self-referential functions 24 hours after a single session with the psychedelic ayahuasca.
Methods: We leveraged task-free functional magnetic resonance imaging data 1 day before and 1 day after a randomized placebo-controlled trial exploring the effects of ayahuasca in naïve healthy participants (21 placebo/22 ayahuasca). We derived intra- and inter-network functional connectivity of the salience, default mode, visual, and sensorimotor networks, and assessed post-session connectivity changes between the ayahuasca and placebo groups. Connectivity changes were associated with Hallucinogen Rating Scale scores assessed during the acute effects.
Results: Our findings revealed increased anterior cingulate cortex connectivity within the salience network, decreased posterior cingulate cortex connectivity within the default mode network, and increased connectivity between the salience and default mode networks 1 day after the session in the ayahuasca group compared to placebo. Connectivity of primary sensory networks did not differ between groups. Salience network connectivity increases correlated with altered somesthesia scores, decreased default mode network connectivity correlated with altered volition scores, and increased salience default mode network connectivity correlated with altered affect scores.
Conclusion: These findings provide preliminary evidence for subacute functional changes induced by the psychedelic ayahuasca on higher-order cognitive brain networks that support interoceptive, affective, and self-referential functions.

Pasquini, L., Palhano-Fontes, F., & de Araujo, D. B. (2019). Subacute effects of the psychedelic ayahuasca on the salience and default mode networks. medRxiv, 19007542., https://doi.org/10.1177/0269881120909409
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Learning to Let Go: A Cognitive-Behavioral Model of How Psychedelic Therapy Promotes Acceptance

Abstract

The efficacy of psychedelic-assisted therapies for mental disorders has been attributed to the lasting change from experiential avoidance to acceptance that these treatments appear to facilitate. This article presents a conceptual model that specifies potential psychological mechanisms underlying such change, and that shows substantial parallels between psychedelic therapy and cognitive behavioral therapy: We propose that in the carefully controlled context of psychedelic therapy as applied in contemporary clinical research, psychedelic-induced belief relaxation can increase motivation for acceptance via operant conditioning, thus engendering episodes of relatively avoidance-free exposure to greatly intensified private events. Under these unique learning conditions, relaxed avoidance-related beliefs can be exposed to corrective information and become revised accordingly, which may explain long-term increases in acceptance and corresponding reductions in psychopathology. Open research questions and implications for clinical practice are discussed.

Wolff, M., Evens, R., Mertens, L. J., Koslowski, M., Betzler, F., Gründer, G., & Jungaberle, H. (2020). Learning to Let Go: A Cognitive-Behavioral Model of How Psychedelic Therapy Promotes Acceptance. Frontiers in Psychiatry11, 5.; 10.3389/fpsyt.2020.00005
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Posttraumatic Growth After MDMA-Assisted Psychotherapy for Posttraumatic Stress Disorder

Abstract

3,4-Methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for posttraumatic stress disorder (PTSD) has been shown to significantly reduce clinical symptomatology, but posttraumatic growth (PTG), which consists of positive changes in self-perception, interpersonal relationships, or philosophy of life, has not been studied with this treatment. Participant data (n = 60) were pooled from three Phase 2 clinical studies employing triple-blind crossover designs. Participants were required to meet DSM-IV-R criteria for PTSD with a score higher than 50 on the Clinician-Administered PTSD Scale (CAPS-IV) as well as previous inadequate response to pharmacological and/or psychotherapeutic treatment. Data were aggregated into two groups: an active MDMA dose group (75-125 mg of MDMA; n = 45) or placebo/active control (0-40 mg of MDMA; n = 15). Measures included the Posttraumatic Growth Inventory (PTGI) and the CAPS-IV, which were administered at baseline, primary endpoint, treatment exit, and 12-month follow-up. At primary endpoint, the MDMA group demonstrated more PTG, Hedges’ g = 1.14, 95% CI [0.49, 1.78], p < .001; and a larger reduction in PTSD symptom severity, Hedges’ g = 0.88, 95% CI [-0.28, 1.50], p < .001, relative to the control group. Relative to baseline, at the 12-month follow-up, within-subject PTG was higher, p < .001; PTSD symptom severity scores were lower, p < .001; and two-thirds of participants (67.2%) no longer met criteria for PTSD. MDMA-assisted psychotherapy for PTSD resulted in PTG and clinical symptom reductions of large-magnitude effect sizes. Results suggest that PTG may provide a new mechanism of action warranting further study.

Gorman, I., Belser, A. B., Jerome, L., Hennigan, C., Shechet, B., Hamilton, S., Yazar-Klosinski, B., Emerson, A., & Feduccia, A. A. (2020). Posttraumatic Growth After MDMA-Assisted Psychotherapy for Posttraumatic Stress Disorder. Journal of traumatic stress, 33(2), 161–170. https://doi.org/10.1002/jts.22479

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Posttraumatic Growth After MDMA‐Assisted Psychotherapy for Posttraumatic Stress Disorder

Abstract

3,4‐Methylenedioxymethamphetamine (MDMA)–assisted psychotherapy for posttraumatic stress disorder (PTSD) has been shown to significantly reduce clinical symptomatology, but posttraumatic growth (PTG), which consists of positive changes in self‐perception, interpersonal relationships, or philosophy of life, has not been studied with this treatment. Participant data (n = 60) were pooled from three Phase 2 clinical studies employing triple‐blind crossover designs. Participants were required to meet DSM‐IV‐R criteria for PTSD with a score higher than 50 on the Clinician‐Administered PTSD Scale (CAPS‐IV) as well as previous inadequate response to pharmacological and/or psychotherapeutic treatment. Data were aggregated into two groups: an active MDMA dose group (75–125 mg of MDMA; n = 45) or placebo/active control (0–40 mg of MDMA; n = 15). Measures included the Posttraumatic Growth Inventory (PTGI) and the CAPS‐IV, which were administered at baseline, primary endpoint, treatment exit, and 12‐month follow‐up. At primary endpoint, the MDMA group demonstrated more PTG, Hedges’ g = 1.14, 95% CI [0.49, 1.78], p < .001; and a larger reduction in PTSD symptom severity, Hedges’ g = 0.88, 95% CI [−0.28, 1.50], p < .001, relative to the control group. Relative to baseline, at the 12‐month follow‐up, within‐subject PTG was higher, p < .001; PTSD symptom severity scores were lower, p < .001; and two‐thirds of participants (67.2%) no longer met criteria for PTSD. MDMA‐assisted psychotherapy for PTSD resulted in PTG and clinical symptom reductions of large‐magnitude effect sizes. Results suggest that PTG may provide a new mechanism of action warranting further study.
Gorman, I., Belser, A. B., Jerome, L., Hennigan, C., Shechet, B., Hamilton, S., … & Feduccia, A. A. (2020). Posttraumatic Growth After MDMA‐Assisted Psychotherapy for Posttraumatic Stress Disorder. Journal of Traumatic Stress., https://doi.org/10.1002/jts.22479

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N,N-dimethyltryptamine reduces infarct size and improves functional recovery following transient focal brain ischemia in rats

Abstract

Background and purpose: N,N-dimethyltryptamine (DMT) is an endogenous ligand of the Sigma 1 receptor (Sig-1R) with documented in vitro cytoprotective properties against hypoxia. Our aim was to demonstrate the in vivo neuroprotective effect of DMT following ischemia-reperfusion injury in the rat brain.

Methods: Transient middle cerebral occlusion (MCAO) was induced for 60 min in male Wistar rats using the filament occlusion model under general anaesthesia. Before the removal of the filament the treatment group (n = 10) received an intra-peritoneal (IP) bolus of 1 mg/kg-body weight (bw) DMT dissolved in 1 ml 7% ethanol/saline vehicle, followed by a maintenance dose of 2 mg/Kg-bw/h delivered over 24 h via osmotic minipumps. Controls (n = 10) received a vehicle bolus only. A third group (n = 10) received a Sig-1R antagonist (BD1063, 1 mg/kg-bw bolus +2 mg/kg-bw/h maintenance) in parallel with the DMT. Lesion volume was measured by MRI 24 h following the MCAO. Shortly after imaging the animals were terminated, and the native brains and sera were removed. Four rats were perfusion fixed. Functional recovery was studied in two separate group of pre-trained animals (n = 8-8) using the staircase method for 30 days. The expression levels of proteins involved in apoptosis, neuroplasticity and inflammatory regulation were assessed by real-time qPCR and ELISA.

Results: DMT treated rats were characterized by lower ischemic lesion volume (p = .0373), and better functional recovery (p = .0084) compared to the controls. Sig-1R was expressed both in neurons and in microglia in the peri-infarct cortex, and the DMT induced change in the lesion volume was hindered by BD1063. Lower APAF1 expression (mRNA and protein) and higher BNDF levels were documented on DTM, while decreased TNF-α, IL1-β, IL-6 and increased IL-10 expressions indicated the compound’s anti-inflammatory potential.

Conclusion: Our results indicate a Sig-1R dependent reduction of the ischemic brain injury following exogenous DMT administration in rats, presumably through a combined anti-apoptotic, pro-neurotrophic and anti-inflammatory treatment effect.

Nardai, S., László, M., Szabó, A., Alpár, A., Hanics, J., Zahola, P., Merkely, B., Frecska, E., & Nagy, Z. (2020). N,N-dimethyltryptamine reduces infarct size and improves functional recovery following transient focal brain ischemia in rats. Experimental neurology, 327, 113245. https://doi.org/10.1016/j.expneurol.2020.113245

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