OPEN Foundation

Depression

Psilocybin-Induced Decrease in Amygdala Reactivity Correlates with Enhanced Positive Mood in Healthy Volunteers

April 26, 2014 / Depression, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Psychopharmacology, Publications / By / , , , , , ,

Abstract

Background
The amygdala is a key structure in serotonergic emotion-processing circuits. In healthy volunteers, acute administration of the serotonin 1A/2A/2C receptor agonist psilocybin reduces neural responses to negative stimuli and induces mood changes toward positive states. However, it is little-known whether psilocybin reduces amygdala reactivity to negative stimuli and whether any change in amygdala reactivity is related to mood change.

Methods
This study assessed the effects of acute administration of the hallucinogen psilocybin (.16 mg/kg) versus placebo on amygdala reactivity to negative stimuli in 25 healthy volunteers using blood oxygen level-dependent functional magnetic resonance imaging. Mood changes were assessed using the Positive and Negative Affect Schedule and the state portion of the State-Trait Anxiety Inventory. A double-blind, randomized, cross-over design was used with volunteers counterbalanced to receive psilocybin and placebo in two separate sessions at least 14 days apart.

Results
Amygdala reactivity to negative and neutral stimuli was lower after psilocybin administration than after placebo administration. The psilocybin-induced attenuation of right amygdala reactivity in response to negative stimuli was related to the psilocybin-induced increase in positive mood state.

Conclusions
These results demonstrate that acute treatment with psilocybin decreased amygdala reactivity during emotion processing and that this was associated with an increase of positive mood in healthy volunteers. These findings may be relevant to the normalization of amygdala hyperactivity and negative mood states in patients with major depression.

Kraehenmann, R., Preller, K. H., Scheidegger, M., Pokorny, T., Bosch, O. G., Seifritz, E., & Vollenwieder, F. X. (2014). Psilocybin-Induced Decrease in Amygdala Reactivity Correlates with Enhanced Positive Mood in Healthy Volunteers. Biological Psychiatry. http://dx.doi.org/10.1016/j.biopsych.2014.04.010
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Classical hallucinogens as antidepressants? A review of pharmacodynamics and putative clinical roles

March 17, 2014 / Anxiety disorders / PTSD, Depression, Mushrooms / Psilocybin, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Psychotherapy, Publications / By / , , ,

Abstract

Hallucinogens have been part of spiritual practice for millennia, but controversy surrounding their mind-manifesting effects led to their proscription by the mid-20th century, largely without evidence of harm or toxicity and despite nascent data suggesting therapeutic utility in treating depressive illnesses. This review explores their pharmacodynamic actions and the current limited data on their clinic effectiveness. These drugs appear to exert their psychedelic effects through their agonist or partial agonist activity at the serotonergic 5-HT2A receptor, though they also have affinity for other metabotropic serotonin receptors. Hallucinogen binding affects a wide range of intracellular signalling pathways, the precise nature of which remains incompletely understood. They alter the serotonergic tone of brainstem raphe nuclei that project through the brain; they interact with receptors in the prefrontal cortex altering connectivity patterns and intracellular functioning; and they disrupt inhibitory control of sensory input via the thalamus to the cortex. The serotonergic system has long been implicated in anxiety and depressive disorders, and is a major target of most existing antidepressants. Classical hallucinogens alter the functioning of this system, but not in the same way current medications do: whilst there are identified receptors and neurotransmitter pathways through which hallucinogens could therein produce therapeutic effects, the neurobiology of this remains speculative at this time. There is currently an extremely limited but growing literature on hallucinogen safety and clinical application. The drugs appear well tolerated by healthy controls and clinical populations, and the rapid tolerance to repeated administration might reduce the possibility of dependency. Clinical trials reported over the past decade have generally shown positive therapeutic potential, but they are notably few in number. Legislative policy has had a freezing effect on evaluation of these compounds, a better understanding of which might improve our knowledge of the processes involved in consciousness, the neuropathology of depression, and potentially open up new pharmacological therapies.

Baumeister, D., Barnes, G., Giaroli, G., & Tracy, D. (2014). Classical hallucinogens as antidepressants? A review of pharmacodynamics and putative clinical roles. Therapeutic Advances in Psychopharmacology, 4(4), 156-159. http://dx.doi.org/10.1177/2045125314527985
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Why Psychiatry Needs Psychedelics and Psychedelics Need Psychiatry

March 11, 2014 / Addiction, Anxiety disorders / PTSD, Depression, LSD, MDMA, Mushrooms / Psilocybin, Papers, Psychiatry, Psychology, Psychotherapy, Publications / By /

Abstract

Without researching psychedelic drugs for medical therapy, psychiatry is turning its back on a group of compounds that could have great potential. Without the validation of the medical profession, the psychedelic drugs, and those who take them off-license, remain archaic sentiments of the past, with the users maligned as recreational drug abusers and subject to continued negative opinion. These two disparate groups—psychiatrists and recreational psychedelic drug users—are united by their shared recognition of the healing potential of these compounds. A resolution of this conflict is essential for the future of psychiatric medicine and psychedelic culture alike. Progression will come from professionals working in the field adapting to fit a conservative paradigm. In this way, they can provide the public with important treatments and also raise the profile of expanded consciousness in mainstream society.

Sessa, B. (2014). Why Psychiatry Needs Psychedelics and Psychedelics Need Psychiatry. Journal of Psychoactive Drugs, 46(1), 57–62. http://dx.doi.org/10.1080/02791072.2014.877322
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Do the dissociative side effects of ketamine mediate its antidepressant effects?

February 18, 2014 / Depression, Ketamine, Medicine, Neuroscience, Other subjects, Papers, Psychiatry, Psychology, Psychopharmacology, Psychotherapy, Publications / By / , , , , , , ,

Abstract

Background

The N-methyl-d-aspartate receptor antagonist ketamine has rapid antidepressant effects in major depression. Psychotomimetic symptoms, dissociation and hemodynamic changes are known side effects of ketamine, but it is unclear if these side effects relate to its antidepressant efficacy.

Methods

Data from 108 treatment-resistant inpatients meeting criteria for major depressive disorder and bipolar disorder who received a single subanesthetic ketamine infusion were analyzed. Pearson correlations were performed to examine potential associations between rapid changes in dissociation and psychotomimesis with the Clinician-Administered Dissociative States Scale (CADSS) and Brief Psychiatric Rating Scale (BPRS), respectively, manic symptoms with Young Mania Rating Scale (YMRS), and vital sign changes, with percent change in the 17-item Hamilton Depression Rating scale (HDRS) at 40 and 230 min and Days 1 and 7.

Results

Pearson correlations showed significant association between increased CADSS score at 40 min and percent improvement with ketamine in HDRS at 230 min (r=−0.35, p=0.007) and Day 7 (r=−0.41, p=0.01). Changes in YMRS or BPRS Positive Symptom score at 40 min were not significantly correlated with percent HDRS improvement at any time point with ketamine. Changes in systolic blood pressure, diastolic blood pressure, and pulse were also not significantly related to HDRS change.

Limitations

Secondary data analysis, combined diagnostic groups, potential unblinding.

Conclusions

Among the examined mediators of ketamine׳s antidepressant response, only dissociative side effects predicted a more robust and sustained antidepressant. Prospective, mechanistic investigations are critically needed to understand why intra-infusion dissociation correlates with a more robust antidepressant efficacy of ketamine.

Luckenbaugh, D. A., Niciu, M. J., Ionescu, D. F., Nolan, N. M., Richards, E. M., Brutsche, N. E., … & Zarate, C. A. (2014). Do the dissociative side effects of ketamine mediate its antidepressant effects?. Journal of affective disorders, 159, 56-61. http://dx.doi.org/10.1016/j.jad.2014.02.017

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IJTS Special Topic Section: Ketamine ● Making Ketamine Work in the Long Run

January 1, 2014 / Depression, History, Ketamine, Medicine, Other disciplines, Other subjects, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By /

Abstract

Treatments such as ketamine psychotherapy face substantial financial and regulatory obstacles to dissemination into widespread use. Newly patented medications are able to generate enough capital to pay for studies required for FDA approval, personnel to apply for coverage on insurance plans, and marketing to establish a successful launch. Ketamine is an older drug with considerable evidence of efficacy for treatment resistant depression, and almost 50 years of data concerning safety as an anesthetic agent. However, it can no longer be patented, so there is no incentive for pharmaceutical companies to help get it into widespread use. In this paper we discuss some of the complex issues surrounding use of ketamine in the outpatient setting and share information and practice pearls that have been gathered through communication with other practitioners and through direct experience with over 1000 treatments involving 120 patients in the last eight years. The safety and appropriateness of intramuscular ketamine treatment in the outpatient psychiatric office is discussed. We hope to help proponents of effective mental health interventions navigate the actual and potential challenges involved in safe application of this treatment option outside of hospital-based programs.

Early, T. S. (2014). Making Ketamine Work in the Long Run. International Journal of Transpersonal Studies, 33(2).
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IJTS Special Topic Section: Ketamine ● Ketamine for Depression: A Mixed-Methods Study

January 1, 2014 / Depression, Ketamine, Medicine, Other subjects, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By /

Abstract

Prior studies have reported variously on the presence or absence of dissociative effects at subanesthtetic doses of ketamine administered for treatment-resistant depression. This mixedmethods study emulated the protocol used for the studies in question, with IV administration of 0.5mg/kg over 40 minutes with eight experienced ketamine users. Quantitative measures were generally insignificant since this was not a population reporting depression; blood pressure increased as expected by 20-30mm systolic and 6-20mm diastolic, falling rapidly by 20 minutes after completion of the infusion. Individual qualitative reports reports of relaxation, pleasant sensation, decreased cognitive function, and some disabling of ordinary capacities. As experienced users, subjects commented freely on what was characterized as the triviality of the experience, and typically expressed skepticism that ketamine could have antidepressant properties when administered at this dose or in this manner, as well as disbelief that it could be beneficial except perhaps as a period of relaxation, or as a partial break from ordinary states of mind in naïve subjects. Group discussion produced a consensus recommendation in favor of threshold- and higher-dosage transformative work beginning with a 40-50mg IM bolus, potentially in a series of sessions with higher dosages if indicated, with the number of sessions to be determined by clinical practice; such work should occur in a closely monitored psychotherapeutic setting.

Wolfson, P. E. (2014). Ketamine for Depression: A Mixed-Methods Study. International Journal of Transpersonal Studies, 33(2).
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IJTS Special Topic Section: Ketamine ● Ketamine and Depression: A Review

January 1, 2014 / Depression, Ketamine, Medicine, Other subjects, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / , ,

Abstract

Ketamine, via intravenous infusions, has emerged as a novel therapy for treatment-resistant depression, given rapid onset and demonstrable efficacy in both unipolar and bipolar depression. Duration of benefit, on the order of days, varies between these subtypes, but appears longer in unipolar depression. A unique property is reduction in suicidality although data are more limited. Strategies to extend duration, via multiple doses, maintenance treatment, or subsequent augmenting medications have yielded mixed results. There is a relative paucity of data regarding alternate methods of administration such as intramuscular, intranasal, and oral routes, though preliminary results are promising. Adverse effects most reliably include dissociative and sympathomimetic effects, both transient and mild, and suggest good tolerability. Ketamine’s unique effects may represent an opportunity for a paradigm shift in the pharmacologic treatment of depression.

Ryan, W. C., Marta, C. J., & Koek, R. J. (2014). Ketamine and depression: A review. International Journal of Transpersonal Studies, 33(2), 40-74.
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IJTS Special Topic Section: Ketamine ● Ketamine—Its History, Uses, Pharmacology, Therapeutic Practice, and an Exploration of its Potential as a Novel Treatment for Depression

January 1, 2014 / Depression, History, Ketamine, Other disciplines, Papers, Personal development, Psychiatry, Psychology, Psychopharmacology, Publications / By /

Introduction

The origins of this special section on ketamine and ketamine assisted psychotherapy and an overview and deliberately controversial discussion of depression and ketamine’s putative efficacy as an antidepressant arise from two sources. The first is a fairly widespread and historical appreciation of ketamine’s power as a transformative agent, especially when embedded in a psychotherapeutic context. Ketamine is after all the only legal psychedelic in use—as a Schedule III substance with an indication as a dissociative anesthetic and a long history of safe and effective use for anesthesia and analgesia, this without significant respiratory depression. Other uses have occurred, for example in the control of agitated, suicidal, and aggressively psychotic individuals in the ER setting, and as a transformational, psychedelic experience at low to moderate dosages—pre-anesthetic levels — inspired by the work of Roquet, Jansen, Krupitsky, and others [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][…]

Wolfson, P.E. (2014). Introduction to the Special Topic Section: Ketamine–Its History, Uses, Pharmacology, Therapeutic Practice, and an Exploration of its Potential as a Novel Treatment for Depression. The International Journal of Transpersonal Studies, 33(2), 33-39.
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Psilocybin – Summary of knowledge and new perspectives

December 17, 2013 / Addiction, Anxiety disorders / PTSD, Chemistry, Cluster headache, Depression, HPPD, Mushrooms / Psilocybin, Mystical experiences, Neuroscience, Papers, Personality, Phenomenology, Psychiatry, Psychology, Psychopharmacology, Psychosis, Psychotherapy, Publications, Safety, Spirituality, Toxicology / By / , ,

Abstract

Psilocybin, a psychoactive alkaloid contained in hallucinogenic mushrooms, is nowadays given a lot of attention in the scientific community as a research tool for modeling psychosis as well as due to its potential therapeutic effects. However, it is also a very popular and frequently abused natural hallucinogen. This review summarizes all the past and recent knowledge on psilocybin. It briefly deals with its history, discusses the pharmacokinetics and pharmacodynamics, and compares its action in humans and animals. It attempts to describe the mechanism of psychedelic effects and objectify its action using modern imaging and psychometric methods. Finally, it describes its therapeutic and abuse potential.

Tylš, F., Páleníček, T., & Horáček, J. (2014). Psilocybin – Summary of knowledge and new perspectives. European Neuropsychopharmacology, 24, 342-365. http://dx.doi.org/10.1016/j.euroneuro.2013.12.006

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Ketamine as the prototype glutamatergic antidepressant: pharmacodynamic actions, and a systematic review and meta-analysis of efficacy

October 22, 2013 / Depression, Ketamine, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / , , , ,

Abstract

The burden of depressive disorders and the frequent inadequacy of their current pharmacological treatments are well established. The anaesthetic and hallucinogenic drug ketamine has provoked much interest over the past decade or so as an extremely rapidly acting antidepressant that does not modify ‘classical’ monoaminergic receptors. Current evidence has shown several ways through which it might exert therapeutic antidepressant actions: blockade of glutamatergic NMDA receptors and relative upregulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtypes may alter cortical connectivity patterns; through intracellular changes in protein expression, including the proteins mammalian target of rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF); and alteration of intracellular signalling cascades. The clinical evidence demonstrates rapid improvements in mood and suicidal thinking in most participants, although study numbers have generally been small and many trials are unblinded and methodologically weak. There is a small body of work to suggest ketamine might also augment electroconvulsive therapy and potentially have a role as a surgical anaesthetic in depressed patients. A major problem is that the effects of ketamine appear temporary, disappearing after days to weeks (although longer benefits have been sustained in some), and attempts to circumvent this through pharmacological augmentation have been disappointing thus far. These exciting data are providing new insights into neurobiological models of depression, and potentially opening up a new class of antidepressants, but there are significant practical and ethical issues about any future mainstream clinical role it might have.

Caddy, C., Giaroli, G., White, T. P., Sukhwinder, S. S. & Tracy, D. K. (2014). Ketamine as the prototype glutamatergic antidepressant: pharmacodynamic actions, and a systematic review and meta-analysis of efficacy. Therapeutic Advances in Psychopharmacology, 4(2), 75-79. http://dx.doi.org/10.1177/2045125313507739
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14 May - Psychedelics & Psychosis with Phoebe Friesen, Dirk Corstens and Chelsea Rose

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