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Therapeutic Application

Capturing the different health conditions that PAP may adress

The relationship between subjective effects induced by a single dose of ketamine and treatment response in patients with major depressive disorder: A systematic review.

December 14, 2019 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , , ,

Abstract

OBJECTIVE:
The relationship between ketamine’s hallucinogenic- and dissociative-type effects and antidepressant mechanism of action is poorly understood. This paper reviewed the correlation between subjective effects defined by various psychometric scales and observed clinical outcomes in the treatment of patients with Major Depressive Disorder (MDD).
METHODS:
Based on PRISMA guidelines, we reviewed the dissociative and psychotomimetic mental state induced with ketamine during MDD treatment. Our selected studies correlated depression rating with validated scales collected at regular intervals throughout the study period such as the Clinician-Administered Dissociative States Scale (CADSS), Brief Psychiatric Rating Scale (BPRS), and the 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC). We excluded studies with bipolar depression or with repeated dosing and no single-dose phase. We included 8 of 556 screened reports.
RESULTS:
Two of five CADSS studies found significant negative correlations between increases in CADSS scores and depression scores. One of six BPRS studies demonstrated correlations between BPRS scores and depression scores. The 5D-ASC’s one study found no correlation with the MADRS.
CONCLUSIONS:
Ketamine’s dissociative and psychotomimetic effects were correlated with depression changes in 37.5% of studies, but most studies did not examine this relationship and future studies should consider this association since it appears important for MDMA and psilocybin therapies.
Mathai, D. S., Meyer, M. J., Storch, E. A., & Kosten, T. R. (2020). The relationship between subjective effects induced by a single dose of ketamine and treatment response in patients with major depressive disorder: A systematic review. Journal of Affective Disorders, 264, 123-129., https://doi.org/10.1016/j.jad.2019.12.023
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Neurotrophic mechanisms of psychedelic therapy

December 12, 2019 / Anxiety Disorders / PTSD, Depressive Disorders, Ketamine, LSD, MDMA, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications, Substance Use Disorder / By / ,

Abstract

Psychedelic drugs, often referred to as hallucinogens, are quite distinct from other classes of psychotropic drugs. Although the subjective and behavioral effects they induce are quite dramatic, they possess little addictive potential when compared to nicotine, alcohol or opiates. Since the discovery of ketamine antidepressant effects, there has been growing interest for these molecules. Serotonergic psychedelics such as psilocybin and lysergic acid diethylamide (LSD) are gaining attention as potential treatments for depression and addiction, similarly to 3,4-methylenedioxymethamphetamine (MDMA) for post-traumatic stress disorder (PTSD), and ibogaine for addiction. Although they possess distinct pharmacological profiles, their kinetics of action are quite similar: the therapeutic effects are felt within the hours following administration, and last well beyond drug elimination by the organism. This strongly suggests the induction of neurogenic and plastic mechanisms, including the involvement of trophic factors. This review will explore the literature dealing with the effects of psychedelics on neurotrophins, as well as the plastic adaptations that they induce, in an attempt to understand their surprising therapeutic potential. We will show that although ketamine and serotonergic psychedelics have affinity for very different receptors (NMDA, 5-HT2A), they ultimately initiate similar plastic adaptations in the prefrontal cortex through the involvement of the brain-derived neurotrophic factor (BDNF). We will see that although MDMA uses the same receptors as serotonergic psychedelics to alleviate PTSD symptoms, its effect on BDNF levels seem paradoxical and quite different. Finally, we show how ibogaine could exert its anti-addictive properties through a completely different neurotrophic factor than other psychedelic drugs, the glial cell line-derived neurotrophic factor (GDNF). While the current literature concerning the psychiatric applications of psychedelic therapy is encouraging, it remains to be determined whether their benefits could be obtained without their psychotomimetic effects, or concerns over potential toxicity.
Corne, R., & Mongeau, R. (2019). Neurotrophic mechanisms of psychedelic therapy. Biologie aujourd’hui, 213(3-4), 121., https://doi.org/10.1051/jbio/2019015
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4-MeO-PCP and 3-MeO-PCMo, new dissociative drugs, produce rewarding and reinforcing effects through activation of mesolimbic dopamine pathway and alteration of accumbal CREB, deltaFosB, and BDNF levels

December 11, 2019 / Neuroscience, Papers, Pharmacology & Chemistry, Psychiatry & Medicine, Publications, Substance Use Disorder / By / , , , , , ,

Abstract

Rationale: A high number of synthetic dissociative drugs continue to be available through online stores, leading to their misuse. Recent inclusions in this category are 4-MeO-PCP and 3-MeO-PCMo, analogs of phencyclidine. Although the dissociative effects of these drugs and their recreational use have been reported, no studies have investigated their abuse potential.

Objectives: To examine their rewarding and reinforcing effects and explore the mechanistic correlations.

Methods: We used conditioned place preference (CPP), self-administration, and locomotor sensitization tests to assess the rewarding and reinforcing effects of the drugs. We explored their mechanism of action by pretreating dopamine receptor (DR) D1 antagonist SCH23390 and DRD2 antagonist haloperidol during CPP test and investigated the effects of 4-MeO-PCP and 3-MeO-PCMo on dopamine-related proteins in the ventral tegmental area and nucleus accumbens. We also measured the levels of dopamine, phosphorylated cyclic-AMP response element-binding (p-CREB) protein, deltaFosB, and brain-derived neurotrophic factor (BDNF) in the nucleus accumbens. Additionally, we examined the effects of both drugs on brain wave activity using electroencephalography.

Results: While both 4-MeO-PCP and 3-MeO-PCMo induced CPP and self-administration, only 4-MeO-PCP elicited locomotor sensitization. SCH23390 and haloperidol inhibited the acquisition of drug CPP. 4-MeO-PCP and 3-MeO-PCMo altered the levels of tyrosine hydroxylase, DRD1, DRD2, and dopamine, as well as that of p-CREB, deltaFosB, and BDNF. All drugs increased the delta and gamma wave activity, whereas pretreatment with SCH23390 and haloperidol inhibited it.

Conclusion: Our results indicate that 4-MeO-PCP and 3-MeO-PCMo induce rewarding and reinforcing effects that are probably mediated by the mesolimbic dopamine system, suggesting an abuse liability in humans.

Abiero, A., Botanas, C. J., Custodio, R. J., Sayson, L. V., Kim, M., Lee, H. J., … & Cheong, J. H. (2020). 4-MeO-PCP and 3-MeO-PCMo, new dissociative drugs, produce rewarding and reinforcing effects through activation of mesolimbic dopamine pathway and alteration of accumbal CREB, deltaFosB, and BDNF levels. Psychopharmacology, 237(3), 757-772; 10.1007/s00213-019-05412-y

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Neuropharmacological modulation of the aberrant bodily self through psychedelics

December 6, 2019 / Depressive Disorders, DMT, LSD, Mushrooms / Psilocybin, Papers, Psychology, Publications / By / , ,

Abstract

As a continual source of sensory input and fundamental component of self-referential processing, the body holds an integral modulatory role in cognition. In a healthy state, predictive coding of multisensory integration promotes the construction of a coherent self. However, several psychiatric disorders comprise aberrant perceptions of the bodily self that are purported to involve discrepancies in the integration and updating of multisensory systems. Changes in functional connectivity of somatomotor and high-level association networks in these disorders could be successfully remediated through 5-HT2A receptor agonism via psychedelics. Reported alterations of bodily self-awareness during psychedelic experiences allude to a potentially central role of the bodily self. In this article, we bridge the domains of (aberrant) bodily self-awareness and psychedelics by discussing the predictive coding mechanisms underlying the bodily self and psychedelics. Furthermore, we propose that psychedelically-induced desynchronization of predictive coding might involve modulation of somatomotor, sensorimotor, and high-level association networks that could remediate aberrant perceptions of the bodily self.

Ho, J. T., Preller, K. H., & Lenggenhager, B. (2019). Neuropharmacological modulation of the aberrant bodily self through psychedelics. Neuroscience & Biobehavioral Reviews., https://doi.org/10.1016/j.neubiorev.2019.12.006
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Therapeutic use of serotoninergic hallucinogens: A review of the evidence and of the biological and psychological mechanisms.

December 3, 2019 / Anxiety Disorders / PTSD, Ayahuasca, Depressive Disorders, DMT, LSD, Mushrooms / Psilocybin, Papers, Psychology, Publications, Substance Use Disorder / By / ,

Abstract

Serotoninergic hallucinogens include drugs such as lysergic acid diethylamide (LSD), dimethyltryptamine (DMT) and psilocybin. Recent trials with single/few doses of these compounds show that they induce rapid and sustained antidepressive, anxiolytic, and antiaddictive effects. These effects are also observed in religious groups using the DMT-containing brew ayahuasca. The agonist action of these substances on 5-HT2A receptors expressed in frontal and limbic areas increase glutamatergic transmission and neuroplasticity. These neurochemical effects are associated with acute alterations on self-perception and increases in introspection and positive mood, and with subacute and long-term decreases in psychiatric symptoms, increases in some personality traits such as openness, improvements in emotional processing, and increases in empathy. These are preliminary but promising results that should be further explored in controlled trials with larger sample sizes, especially considering that these compounds could be beneficial in the treatment of treatment-resistant psychiatric disorders.
dos Santos, R. G., & Hallak, J. E. C. (2019). Therapeutic use of serotoninergic hallucinogens: a review of the evidence and of the biological and psychological mechanisms. Neuroscience & Biobehavioral Reviews., https://doi.org/10.1016/j.neubiorev.2019.12.001
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Embedding existential psychology within psychedelic science: reduced death anxiety as a mediator of the therapeutic effects of psychedelics.

November 29, 2019 / Anxiety Disorders / PTSD, Depressive Disorders, MDMA, Mushrooms / Psilocybin, Papers, Psychology, Publications / By / , , ,

Abstract

Psychedelic therapies can engender enduring improvements in psychological well-being. However, relatively little is known about the psychological mechanisms through which the salutary effects of psychedelics emerge. Through integrating extant research on psychedelics with contemporary existential psychology, we present a novel hypothesis that reduced death anxiety may be a key mechanism underpinning the therapeutic effects of psychedelics. In developing this hypothesis, we also provide a complementary review of mechanisms through which psychedelics may reduce death anxiety. We conclude that an awareness of the role of death anxiety in psychopathology has the potential to guide future research into psychedelic therapies.

Moreton, S. G., Szalla, L., Menzies, R. E., & Arena, A. F. (2019). Embedding existential psychology within psychedelic science: reduced death anxiety as a mediator of the therapeutic effects of psychedelics. 29, 1-12., https://doi.org/10.1007/s00213-019-05391-0
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Psychedelic studies on depression recruiting subjects in the Netherlands

December 6, 2021 / Depressive Disorders, Publications / By

Several clinical studies into psychedelics-assisted psychotherapy for treatment-resistant depression are currently going on at Dutch universities, and are still recruiting research subjects.
Three Dutch university medical centers – Groningen, Leiden and Utrecht – are participating in the largest research to date using psilocybin-assisted therapy for treatment-resistant depression. This study, a phase IIb dose-ranging study with 216 patients financed by Compass Pathways, is carried out in a number of sites across North America and Europe, including the Netherlands. If successful, it will be followed by phase III studies, paving the way for the use of psilocybin-assisted therapy as a standard treatment against depression.
These three research sites are still recruiting subjects over 18 years of age who will receive either 1mg, 10 mg or 25 mg of psilocybin in a single session following extensive preparation. Full details regarding study design and admission criteria can be found on the web pages of these research sites (Groningen, Leiden, Utrecht).
For this multisite study, Compass was granted Breakthrough Therapy designation by the FDA. The FDA designates a drug as a Breakthrough Therapy if preliminary clinical evidence shows that it may demonstrate substantial improvement over available therapy. This designation is intended to expedite the development and review of drugs for serious or life-threatening conditions, and it entails more intensive FDA guidance on an efficient drug development program.
More recently, the non-profit medical research organisation Usona Institute also obtained Breakthrough Therapy designation, this time for its psilocybin programme for major depressive disorder, an indication that is broader in scope than treatment-resistant depression. Adding the designation of MDMA as Breakthrough Therapy for post-traumatic stress disorder in 2017, this is the third time in as many years that the FDA gives a psychedelic treatment protocol this kind of organisational and administrative booster, feeding the hope of many that regular prescription of psychedelic treatments may be only a few years away.
In another study in the Netherlands, the department of Psychology and Neuroscience at Maastricht University is testing the effect of a single administration of  ‘a naturally occurring psychedelic substance’ on treatment-resistant depression. Previously, the same research team has tested the same compound on healthy volunteers, and the trial is now going into its clinical phase with subjects between 18 and 64 years of age presenting treatment-resistant depression. Full details are available on the Psychopharmacology in Maastricht website.
Elsewhere in Europe, other trials investigating the effects of therapy with psychedelics – mostly psilocybin – on depression, are still recruiting research subjects. In Zurich (Switzerland), dr. Franz Vollenweider’s team is conducting a randomised double-blind placebo-controlled study investigating the effects of psilocybin on major depressive disorder in 60 research subjects. In London, a team at Imperial College’s Centre for Psychedelic Research, led by David Nutt, is testing psilocybin against escitalopram, an SSRI antidepressant, on 50 research subjects with major depression. And also in London, the Centre for Affective Disorders was awarded a large grant from the National Institute for Health Research (NIHR) in 2017 to investigate the safety, feasibility and efficacy of psilocybin as a treatment for treatment-resistant depression. The Centre is starting recruitment of 60 participants for this randomised, placebo-controlled study, which will be led by Dr James Rucker.

Microdosing psychedelics: Motivations, subjective effects and harm reduction.

November 25, 2019 / Anxiety Disorders / PTSD, Depressive Disorders, LSD, Mushrooms / Psilocybin, Papers, Psychology, Publications / By / , , , ,

Abstract

BACKGROUND:
In recent years there has been growing media attention on microdosing psychedelics (e.g., LSD, psilocybin). This refers to people routinely taking small doses of psychedelic substances to improve mental health and wellbeing, or to enhance cognitive performance. Research evidence is currently limited. This paper examines microdosing motivations, dosing practices, perceived short-term benefits, unwanted effects, and harm reduction practices.
METHODS:
An international online survey was conducted in 2018 examining people’s experiences of using psychedelics. Eligible participants were aged 16 years or older, had used psychedelics and could comprehend written English. This paper focuses on 525 participants who were microdosing psychedelics at the time of the survey.
RESULTS:
Participants were primarily motivated to microdose to improve mental health (40%), for personal development (31%) and cognitive enhancement (18%). Most were microdosing with psilocybin (55%) or LSD/1P-LSD (48%). Principal components analysis generated three factors examining perceived short-term benefits of microdosing: improved mood and anxiety, enhanced connection to others and environment, and cognitive enhancement; and three factors examining negative and potentially unwanted effects: stronger-than-expected psychedelic effects, anxiety-related effects, and physical adverse effects. Most participants (78%) reported at least one harm reduction practice they routinely performed while microdosing.
CONCLUSION:
Our findings suggest that people microdosing are commonly doing so as a self-managed therapy for mental health, either as an alternative or adjunct to conventional treatments. This is despite psychedelics remaining prohibited substances in most jurisdictions. Recent findings from clinical trials with standard psychedelic doses for depression and anxiety suggest that a neurobiological effect beyond placebo is not unreasonable. Randomised controlled trials are needed, complemented by mixed methods social science research and the development of novel resources on microdosing harm reduction.

Lea, T., Amada, N., Jungaberle, H., Schecke, H., & Klein, M. (2020). Microdosing psychedelics: Motivations, subjective effects and harm reduction. International Journal of Drug Policy, 75, 102600., https://doi.org/10.1016/j.drugpo.2019.11.008
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Psilocybin-assisted therapy for depression: How do we advance the field?

November 22, 2019 / Depressive Disorders, Mushrooms / Psilocybin, Papers, Psychology, Publications / By / , , , , , ,

Abstract

In the quest for new treatment options for depression, attention is being paid to the potential role of psychedelic drugs. Psilocybin is of particular interest given its mechanism of action, its benefits in early trials and its relatively low side effects burden. This viewpoint outlines a number of key issues that remain to be elucidated about its potential use in the clinical environment, including clarification of the profile of people most likely to benefit and those who might experience adverse effects, longer-term outcomes and the role of psychotherapeutic input alongside the drug itself. There are also opportunities to understand better, the neurobiology underpinning its effects.

Meikle, S. E., Liknaitzky, P., Rossell, S. L., Ross, M., Strauss, N., Thomas, N., … & Castle, D. J. (2019). Psilocybin-assisted therapy for depression: How do we advance the field?. Australian & New Zealand Journal of Psychiatry, 0004867419888575., https://doi.org/10.1177/0004867419888575
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The Impact of Ayahuasca on Suicidality: Results From a Randomized Controlled Trial.

November 19, 2019 / Ayahuasca, Depressive Disorders, Papers, Psychology, Publications / By / , , , , ,

Abstract

Suicide is a major public health problem. Given increasing suicide rates and limitations surrounding current interventions, there is an urgent need for innovative interventions for suicidality. Although ayahuasca has been shown to target mental health concerns associated with suicidality (i.e., depression and hopelessness), research has not yet explored the impact of ayahuasca on suicidality. Therefore, we conducted secondary analyses of a randomized placebo-controlled trial in which individuals with treatment-resistant depression were administered one dose of ayahuasca (n = 14) or placebo (n = 15). Suicidality was assessed by a trained psychiatrist at baseline, as well as 1 day, 2 days, and 7 days after the intervention. A fixed-effects linear mixed model, as well as between and within-groups Cohen’s d effect sizes were used to examine changes in suicidality. Controlling for baseline suicidality, we found a significant effect for time (p < .05). The effect of the intervention (i.e., ayahuasca vs. placebo) trended toward significance (p = .088). At all time points, we found medium between-group effect sizes (i.e., ayahuasca vs. placebo; day 1 Cohen’s d = 0.58; day 2 d = 0.56; day 7 d = 0.67), as well as large within-group (ayahuasca; day 1 Cohen’s d = 1.33; day 2 d = 1.42; day 7 d = 1.19) effect sizes, for decreases in suicidality. Conclusions: This research is the first to explore the impact of ayahuasca on suicidality. The findings suggest that ayahuasca may show potential as an intervention for suicidality. We highlight important limitations of the study, potential mechanisms, and future directions for research on ayahuasca as an intervention for suicidality. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02914769.

Zeifman, R., Palhano-Fontes, F., Hallak, J., Nunes, E. A., Maia-de-Oliveira, J. P., & de Araujo, D. B. (2019). The Impact of Ayahuasca on Suicidality: Results From a Randomized Controlled Trial. Frontiers in Pharmacology, 10, 1325.
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