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Psilocybin with psychological support for treatment-resistant depression: six-month follow-up

November 8, 2017 / Depressive Disorders, Mushrooms / Psilocybin, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Rationale

Recent clinical trials are reporting marked improvements in mental health outcomes with psychedelic drug-assisted psychotherapy.

Objectives

Here, we report on safety and efficacy outcomes for up to 6 months in an open-label trial of psilocybin for treatment-resistant depression.

Methods

Twenty patients (six females) with (mostly) severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 and 25 mg, 7 days apart) in a supportive setting. Depressive symptoms were assessed from 1 week to 6 months post-treatment, with the self-rated QIDS-SR16 as the primary outcome measure.

Results

Treatment was generally well tolerated. Relative to baseline, marked reductions in depressive symptoms were observed for the first 5 weeks post-treatment (Cohen’s d = 2.2 at week 1 and 2.3 at week 5, both p < 0.001); nine and four patients met the criteria for response and remission at week 5. Results remained positive at 3 and 6 months (Cohen’s d = 1.5 and 1.4, respectively, both p < 0.001). No patients sought conventional antidepressant treatment within 5 weeks of psilocybin. Reductions in depressive symptoms at 5 weeks were predicted by the quality of the acute psychedelic experience.

Conclusions

Although limited conclusions can be drawn about treatment efficacy from open-label trials, tolerability was good, effect sizes large and symptom improvements appeared rapidly after just two psilocybin treatment sessions and remained significant 6 months post-treatment in a treatment-resistant cohort. Psilocybin represents a promising paradigm for unresponsive depression that warrants further research in double-blind randomised control trials.

Carhart-Harris, R. L., Bolstridge, M., Day, C. M. J., Rucker, J., Watts, R., Erritzoe, D. E., … & Rickard, J. A. (2017). Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology, 1-10. 10.1007/s00213-017-4771-x
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Double-blind comparison of the two hallucinogens psilocybin and dextromethorphan: similarities and differences in subjective experiences

November 7, 2017 / Mushrooms / Psilocybin, Papers, Psychology, Publications / By / , , ,

Abstract

Rationale

Although psilocybin and dextromethorphan (DXM) are hallucinogens, they have different receptor mechanisms of action and have not been directly compared.

Objective

This study compared subjective, behavioral, and physiological effects of psilocybin and dextromethorphan under conditions that minimized expectancy effects.

Methods

Single, acute oral doses of psilocybin (10, 20, 30 mg/70 kg), DXM (400 mg/70 kg), and placebo were administered under double-blind conditions to 20 healthy participants with histories of hallucinogen use. Instructions to participants and staff minimized expectancy effects. Various subjective, behavioral, and physiological effects were assessed after drug administration.

Results

High doses of both drugs produced similar increases in participant ratings of peak overall drug effect strength, with similar times to maximal effect and time-course. Psilocybin produced orderly dose-related increases on most participant-rated subjective measures previously shown sensitive to hallucinogens. DXM produced increases on most of these same measures. However, the high dose of psilocybin produced significantly greater and more diverse visual effects than DXM including greater movement and more frequent, brighter, distinctive, and complex (including textured and kaleidoscopic) images and visions. Compared to DXM, psilocybin also produced significantly greater mystical-type and psychologically insightful experiences and greater absorption in music. In contrast, DXM produced larger effects than psilocybin on measures of disembodiment, nausea/emesis, and light-headedness. Both drugs increased systolic blood pressure, heart rate, and pupil dilation and decreased psychomotor performance and balance.

Conclusions

Psilocybin and DXM produced similar profiles of subjective experiences, with psilocybin producing relatively greater visual, mystical-type, insightful, and musical experiences, and DXM producing greater disembodiment.

Carbonaro, T. M., Johnson, M. W., Hurwitz, E., & Griffiths, R. R. (2017). Double-blind comparison of the two hallucinogens psilocybin and dextromethorphan: similarities and differences in subjective experiences. Psychopharmacology, 1-14. 10.1007/s00213-017-4769-4
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Why MDMA therapy for alcohol use disorder? And why now?

November 7, 2017 / MDMA, Papers, Psychology, Publications, Substance Use Disorder / By /

Abstract

Alcohol use disorder represents a serious clinical, social and personal burden on its sufferers and a significant financial strain on society. Current treatments, both psychological and pharmacological are poor, with high rates of relapse after medical detoxification and dedicated treatment programs. The earliest historical roots of psychedelic drug-assisted psychotherapy in the 1950s were associated with Lysergic acid diethylamide (LSD)-assisted psychotherapy to treat what was then called, alcoholism. But results were varied and psychedelic therapy with LSD and other ‘classical’ psychedelics fell out of favour in the wake of socio-political pressures and cultural changes. A current revisiting of psychedelic clinical research is now targeting substance use disorders – and particularly alcohol use disorder – again. 3,4-Methylenedioxymethamphetamine (MDMA)-assisted psychotherapy has never been formally explored as a treatment for any form of substance use disorder. But in recent years MDMA has risen in prominence as an agent to treat posttraumatic stress disorder (PTSD). With its unique receptor profile and a relatively well-tolerated subjective experience of drug effects when used clinically, MDMA Therapy is ideally suited to allow a patient to explore and address painful memories without being overwhelmed by negative affect. Given that alcohol use disorder is so often associated with early traumatic experiences, the author is proposing in a current on-going UK-based study that patients with alcohol use disorder who have undergone a medical detoxification from alcohol might benefit from a course of MDMA-assisted psychotherapy.

Sessa, B. (2017). Why MDMA therapy for alcohol use disorder? And why now?. Neuropharmacology. 10.1016/j.neuropharm.2017.11.004
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Additive Effects of 3,4-Methylenedioxymethamphetamine (MDMA) and Compassionate Imagery on Self-Compassion in Recreational Users of Ecstasy

November 4, 2017 / MDMA, Papers, Psychology, Publications / By / , , , , , ,

Abstract

3,4-Methylenedioxymethylamphetamine (MDMA;‘ecstasy’) produces prosocial subjective effects that may extend to affiliative feelings towards the self. Behavioural techniques can produce similar self-directed affiliation. For example, compassionate imagery (CI) and ecstasy reduce self-criticism and increase self-compassion to a similar extent, with the effects of CI enhanced in the presence of ecstasy. Here, we examine self-compassion and self-criticism in recreational users who consumed chemically verified MDMA in a within-subjects crossover study. In a naturalistic setting, polydrug-using participants performed a self-focused CI exercise on two occasions separated by ≥6 days: once having consumed self-sourced MDMA and once not. Effects on state self-criticism, self-compassion and emotional empathy were assessed before and after MDMA use (or over an extended baseline period on the occasion that MDMA was not consumed) and reassessed after CI. In participants (n = 20; 8 women) whose ecstasy contained MDMA and no other drug, CI and MDMA appeared to separately increase emotional empathy (to critical facial expressions) and self-compassion. The effects of CI and MDMA on self-compassion also appeared to be additive. Establishing the observed effects in controlled studies will be critical for determining the combined utility of these approaches in fostering adaptive self-attitudes in a therapeutic context.

Kamboj, S. K., Walldén, Y. S., Falconer, C. J., Alotaibi, M. R., Blagbrough, I. S., Husbands, S. M., & Freeman, T. P. (2017). Additive Effects of 3, 4-Methylenedioxymethamphetamine (MDMA) and Compassionate Imagery on Self-Compassion in Recreational Users of Ecstasy. Mindfulness, 1-12. 10.1007/s12671-017-0849-0
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Dying to live: The power of transcendence in the treatment of existential anxiety

November 2, 2017 / Anxiety Disorders / PTSD, Depressive Disorders, Mushrooms / Psilocybin, Papers, Psychology, Publications / By /

Abstract

There is a notable lack of effective treatments and therapies available for the treatment of existential anxiety. There are, however, a number of avenues worthy of more attention, all experiential or using insights gained from experiences. Such experiences include near-death experiences (NDEs), out-of-body experiences (OBEs) and those yielded by classical psychedelics such as psilocybin. Of these, the psychedelics may have a particular utility when it comes to the treatment of existential anxiety. Psychedelics are currently undergoing a long-overdue scientific research renaissance, and there has been some highly promising research utilizing psilocybin in the treatment of existential anxiety and depression in terminally ill cancer patients, yielding compelling and robust findings. A single dose of psilocybin produced immediate and sustained decreases in anxiety and depression and improvements in outlook and life meaning in an overwhelming majority of study participants. At sufficient doses, psychedelics can occasion mystical-type experiences, and it appears this is intimately tied to their long-term psychotherapeutic efficacy. There is some intriguing overlap in aftereffects reported by those who have undergone mystical experiences via psychedelics, NDEs, and OBEs. An interesting property of the NDE is that the psychological changes appear to be mentally contagious, so that one may reap the benefits of the experience without incurring the risk of experiencing one. A common thread and apparently psychotherapeutic element linking these experiences is the experience of being disembodied and of transcending the limits of the body.
Gandy, S. (2017). Dying to live: The power of transcendence in the treatment of existential anxiety. Threshold: Journal of Interdisciplinary Consciousness Studies, 1(2), 25-36.
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Antidepressant Response and Dissociative Effects After Ketamine Treatment: Two Sides of the Same Coin?

November 1, 2017 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , ,

Abstract

In recent years, there has been growing interest in research on N-methyl-d-aspartate (NMDA) antagonists as rapid-acting agents for treating depression1 and related suicidal ideation.2 Ketamine has shown preliminary efficacy for the rapid treatment of both unipolar and bipolar depression, although it has been also associated with high rates of dissociative and psychotomimetic symptoms, especially within 60 minutes after the infusion.3 For this reason, we read with great interest the update recently published in JCP4 that synthesized issues related to efficacy, adverse effects, and mechanism of action of ketamine for treating depression. In particular, in analyzing ketamine-related adverse effects, this overview highlighted that subanesthetic doses of ketamine may induce dissociative and psychotomimetic symptoms, although these effects are often mild and short-lasting.4 In addition, the authors of a recent review5 suggest that intranasal route of administration and lower doses of ketamine, as well as alternative NMDA-modulating agents, all might mitigate dissociative and psychotomimetic effects.

However, ketamine-induced dissociative symptoms, whether therapeutic or side effects, may deserve additional insight. Findings from a randomized controlled trial6 showed that significant, though transient, dissociative effects can occur after ketamine infusion in about 1 out of 5 subjects with treatment-resistant depression. However, a significant correlation between dissociative symptoms 40 minutes after ketamine infusion and improvement in depressive symptoms (230 minutes and 7 days after infusion) has been reported in subjects with treatment-resistant major depressive or bipolar disorder.7 Among the potential mediators tested, only dissociative effects predicted a robust and sustained antidepressant response attributable to ketamine. This issue may well be supported by a biological rationale, since dissociative symptoms may be the consequence of the enhancement of glutamate release induced by ketamine.7 In addition, a recent study based on a retrospective chart review8 evaluating efficacy and safety of intravenous subanesthetic doses of esketamine in 27 subjects with treatment-resistant or bipolar depression found that mild to severe dissociative symptoms occurred in about one tenth of subjects. Nevertheless, 2 out of 3 subjects with dissociative symptoms remitted from depression within 3 weeks after esketamine infusion. Thus, also in this case, it seems that ketamine-related dissociation and therapeutic efficacy might be linked, possibly as “two sides of the same coin.” Nonetheless, available evidence is limited and not conclusive, since other studies, although based on small sample sizes, showed that dissociative symptoms were not correlated with changes in depression scores9 or could be even associated with suicidal ideation.10 Although a number of different factors involved in the efficacy of ketamine can be hypothesized,11 including induced psychotomimetic effects,12 the mechanisms of its antidepressant activity are far from being fully understood. In particular, it should be elucidated if transient dissociative effects induced by ketamine should be considered physiological conditions linked to antidepressant response, rather than intrinsic side effects that could decrease clinical confidence in terms of tolerability. Research should clarify strategies that can decrease ketamine-induced dissociative effects5 while not challenging its promising antidepressant properties.

Bartoli, F., Clerici, M., & Carrà, G. (2017). Antidepressant Response and Dissociative Effects After Ketamine Treatment: Two Sides of the Same Coin?. The Journal of clinical psychiatry, 78(9), e1318. 10.4088/JCP.17lr11789
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LSD modulates effective connectivity and neural adaptation mechanisms in an auditory oddball paradigm

October 31, 2017 / LSD, Neuroscience, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Under the predictive coding framework, perceptual learning and inference are dependent on the interaction between top-down predictions and bottom-up sensory signals both between and within regions in a network. However, how such feedback and feedforward connections are modulated in the state induced by lysergic acid diethylamide (LSD) is poorly understood. In this study, an auditory oddball paradigm was presented to healthy participants (16 males, 4 female) under LSD and placebo, and brain activity was recorded using magnetoencephalography (MEG). Scalp level Event Related Fields (ERF) revealed reduced neural adaptation to familiar stimuli, and a blunted neural ‘surprise’ response to novel stimuli in the LSD condition. Dynamic causal modelling revealed that both the presentation of novel stimuli and LSD modulate backward extrinsic connectivity within a task-activated fronto-temporal network, as well as intrinsic connectivity in the primary auditory cortex. These findings show consistencies with those of previous studies of schizophrenia and ketamine but also studies of reduced consciousness – suggesting that rather than being a marker of conscious level per se, backward connectivity may index modulations of perceptual learning common to a variety of altered states of consciousness, perhaps united by a shared altered sensitivity to environmental stimuli. Since recent evidence suggests that the psychedelic state may correspond to a heightened ‘level’ of consciousness with respect to the normal waking state, our data warrant a re-examination of the top-down hypotheses of conscious level and suggest that several altered states may feature this specific biophysical effector.
Timmermann, C., Spriggs, M. J., Kaelen, M., Leech, R., Nutt, D. J., Moran, R. J., … & Muthukumaraswamy, S. D. (2017). LSD modulates effective connectivity and neural adaptation mechanisms in an auditory oddball paradigm. Neuropharmacology. 10.1016/j.neuropharm.2017.10.039
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Psilocybin with psychological support improves emotional face recognition in treatment-resistant depression

October 30, 2017 / Depressive Disorders, Mushrooms / Psilocybin, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Rationale

Depressed patients robustly exhibit affective biases in emotional processing which are altered by SSRIs and predict clinical outcome.

Objectives

The objective of this study is to investigate whether psilocybin, recently shown to rapidly improve mood in treatment-resistant depression (TRD), alters patients’ emotional processing biases.

Methods

Seventeen patients with treatment-resistant depression completed a dynamic emotional face recognition task at baseline and 1 month later after two doses of psilocybin with psychological support. Sixteen controls completed the emotional recognition task over the same time frame but did not receive psilocybin.

Results

We found evidence for a group × time interaction on speed of emotion recognition (p = .035). At baseline, patients were slower at recognising facial emotions compared with controls (p < .001). After psilocybin, this difference was remediated (p = .208). Emotion recognition was faster at follow-up compared with baseline in patients (p = .004, d = .876) but not controls (p = .263, d = .302). In patients, this change was significantly correlated with a reduction in anhedonia over the same time period (r = .640, p = .010).

Conclusions

Psilocybin with psychological support appears to improve processing of emotional faces in treatment-resistant depression, and this correlates with reduced anhedonia. Placebo-controlled studies are warranted to follow up these preliminary findings.

Stroud, J. B., Freeman, T. P., Leech, R., Hindocha, C., Lawn, W., Nutt, D. J., … & Carhart-Harris, R. L. (2017). Psilocybin with psychological support improves emotional face recognition in treatment-resistant depression. Psychopharmacology, 1-8. 10.1007/s00213-017-4754-y
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Binding of Harmine Derivatives to DNA: A Spectroscopic Investigation

October 27, 2017 / Ayahuasca, Papers, Pharmacology & Chemistry, Publications / By / , , ,

Abstract

Harmine belongs to a group of β-carboline alkaloids endowed with antitumor properties. Harmine and its derivatives are thought to bind to DNA and interfere with topoisomerase activities. We investigated the base-dependent binding of harmine, and three of its synthetic anticancer-active derivatives to the genomic DNA from calf thymus and two synthetic 20-mer double helices, the poly(dG-dC)·poly(dG-dC) and the poly(dA-dT)·poly(dA-dT), by means of UV-Vis and circular dichroism (CD) spectroscopies. The data show that the DNA binding and stabilising properties of the investigated derivatives are base pair-dependent. These results could be used as a guide to design and develop further bioactive analogues.
Pagano, B., Caterino, M., Filosa, R., & Giancola, C. (2017). Binding of Harmine Derivatives to DNA: A Spectroscopic Investigation. Molecules, 22(11), 1831. 10.3390/molecules22111831
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Subjective effectiveness of ibogaine treatment for problematic opioid consumption: Short- and long-term outcomes and current psychological functioning

October 17, 2017 / Iboga / Ibogaine, Papers, Psychology, Publications, Substance Use Disorder / By / , , , ,

Abstract

Background and aims

Very few studies have reported the effectiveness of ibogaine as a treatment for chronic opioid use. Therefore, this study evaluated the acute subjective effects of ibogaine, outcomes on problematic opioid consumption, and the long-term associations with psychological functioning.

Methods

Using online data collection, 88 patients who received ibogaine treatment in Mexico between 2012 and 2015 completed our survey.

Results

Most participants (72%) had used opioids for at least 4 years and 69% reported daily use. Most (80%) indicated that ibogaine eliminated or drastically reduced withdrawal symptoms. Fifty percent reported that ibogaine reduced opioid craving, some (25%) reporting a reduction in craving lasting at least 3 months. Thirty percent of participants reported never using opioids again following ibogaine treatment. And over one half (54%) of these abstainers had been abstinent for at least 1 year, with 31% abstinent for at least 2 years. At the time of survey, 41% of all participants reported sustained abstinence (>6 months). Although 70% of the total sample reported a relapse following treatment, 48% reported decreased use from pretreatment levels and an additional 11% eventually achieved abstinence. Treatment responders had the lowest rates of depressive and anxious symptoms, the highest levels of subjective well-being and rated their ibogaine treatment as more spiritually meaningful compared with treatment non-responders.

Conclusion

The results suggest that ibogaine is associated with reductions in opioid use, including complete abstinence, and has long-term positive psychological outcomes. Future research should investigate the efficacy of ibogaine treatment using rigorous longitudinal and controlled designs.

Davis, A. K., Barsuglia, J. P., Windham-Herman, A. M., Lynch, M., & Polanco, M. (2017). Subjective effectiveness of ibogaine treatment for problematic opioid consumption: Short-and long-term outcomes and current psychological functioning. Journal of Psychedelic Studies, (0), 1-9. 10.1556/2054.01.2017.009
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