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Depressive Disorders

5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) used in a naturalistic group setting is associated with unintended improvements in depression and anxiety

March 1, 2019 / Anxiety Disorders / PTSD, Depressive Disorders, DMT, Neuroscience, Papers, Psychiatry & Medicine, Psychology, Publications / By / , , , ,

Abstract

BACKGROUND:

A recent epidemiological study suggested that 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) used for spiritual and recreational reasons is associated with subjective improvement in depression and anxiety. Further exploration of the potential psychotherapeutic effects of 5-MeO-DMT could inform future clinical trials.

OBJECTIVES:

We examined self-reported improvement in depression and anxiety among people who use 5-MeO-DMT in a group setting with structured procedures guiding dose and administration of 5-MeO-DMT. Such procedures also include activities for the preparation of, and support during/following sessions, which are similar to procedures used in clinical trials of hallucinogen administration. Next, we examined whether depression or anxiety were improved following use, and whether the acute subjective effects (mystical/challenging) or beliefs about the 5-MeO-DMT experience were associated with improvements in these conditions.

METHODS:

Respondents (n = 362; Mage = 47.7; Male = 55%; White/Caucasian = 84%) completed an anonymous web-based survey.

RESULTS:

Of those reporting having been diagnosed with depression (41%) or anxiety (48%), most reported these conditions were improved (depression = 80%; anxiety = 79%) following 5-MeO-DMT use, and fewer reported they were unchanged (depression = 17%; anxiety = 19%) or worsened (depression = 3%; anxiety = 2%). Improvement in depression/anxiety conditions were associated with greater intensity of mystical experiences and higher ratings of the spiritual significance and personal meaning of the 5-MeO-DMT experience. There were no associations between depression or anxiety improvement and the intensity of acute challenging physical/psychological effects during the 5-MeO-DMT experience.

CONCLUSIONS:

Future prospective controlled clinical pharmacology studies should examine the safety and efficacy of 5-MeO-DMT administration for relieving depression and anxiety.

Davis, A. K., So, S., Lancelotta, R., Barsuglia, J. P., & Griffiths, R. R. (2018). 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) used in a naturalistic group setting is associated with unintended improvements in depression and anxiety. The American journal of drug and alcohol abuse, 1-9., 10.1080/00952990.2018.1545024
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Sub-Acute Effects of Psilocybin on Empathy, Creative Thinking, and Subjective Well-Being

February 28, 2019 / Depressive Disorders, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology / By / , , ,

Abstract

Creative thinking and empathy are crucial for everyday interactions and subjective well-being. This is emphasized by studies showing a reduction in these skills in populations where social interaction and subjective well-being are significantly compromised (e.g., depression). Anecdotal reports and recent studies suggest that a single administration of psilocybin can enhance such processes and could therefore be a potential treatment. However, it has yet to be assessed whether effects outlast acute intoxication. The present study aimed to assess the sub-acute effects of psilocybin on creative thinking, empathy, and well-being. Participants attending a psilocybin retreat completed tests of creative (convergent and divergent) thinking and empathy, and the satisfaction with life scale on three occasions: before ingesting psilocybin (N = 55), the morning after (N = 50), and seven days after (N = 22). Results indicated that psilocybin enhanced divergent thinking and emotional empathy the morning after use. Enhancements in convergent thinking, valence-specific emotional empathy, and well-being persisted seven days after use. Sub-acute changes in empathy correlated with changes in well-being. The study demonstrates that a single administration of psilocybin in a social setting may be associated with sub-acute enhancement of creative thinking, empathy, and subjective well-being. Future research should test whether these effects contribute to the therapeutic effects in clinical populations.

Mason, N. L., Mischler, E., Uthaug, M. V., & Kuypers, K. P. (2019). Sub-Acute Effects of Psilocybin on Empathy, Creative Thinking, and Subjective Well-Being. Journal of psychoactive drugs, 1-12., 10.1080/02791072.2019.1580804
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Investigation of medical effect of multiple ketamine infusions on patients with major depressive disorder

February 21, 2019 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychiatry & Medicine, Publications / By / , , , , , ,

Abstract

OBJECTIVE::

Single-dose intravenous ketamine has rapid but time-limited antidepressant effects. We aimed to examine the sustained effects of six consecutive ketamine infusions in Chinese patients with major depressive disorder.

METHODS::

Seventy-seven patients with major depressive disorder were eligible to receive augmentation with six ketamine infusions (0.5 mg/kg over 40 min) administered over the course of 12 days (Monday-Wednesday-Friday). The coprimary outcome measures were the rates of response and remission as measured on the 10-item Montgomery-Asberg Depression Rating Scale. Psychotomimetic and dissociative symptoms were measured with the Brief Psychiatric Rating Scale-positive symptoms and the Clinician Administered Dissociative States Scale, respectively.

RESULTS::

After the first ketamine infusion, only 10 (13.0%) and 6 (7.8%) patients responded and remitted, respectively; after six ketamine infusions, 52 (67.5%) patients responded and 37 (48.1%) remitted. There was a significant mean decrease in Montgomery-Asberg Depression Rating Scale score at four hours after the first ketamine infusion (7.0±7.5, p<0.001), and this decrease was maintained for the duration of the infusion period. The response to ketamine treatment was positively associated with no history of psychiatric hospitalization (odds ratio=3.56, p=0.009). Suicidal ideation rapidly decreased across the entire study sample, even among the nonresponder group. No significant differences were found regarding Brief Psychiatric Rating Scale and Clinician Administered Dissociative States Scale scores from the first infusion at baseline to four hours post-infusion.

CONCLUSION::

Six ketamine infusions increased rates of response and remission when compared to a single-dose ketamine infusion in patients with major depressive disorder. Future controlled studies are warranted to confirm and expand these findings.

Zheng, W., Zhou, Y. L., Liu, W. J., Wang, C. Y., Zhan, Y. N., Li, H. Q., … & Ning, Y. P. (2019). Investigation of medical effect of multiple ketamine infusions on patients with major depressive disorder. Journal of Psychopharmacology, 0269881119827811., 10.1177/0269881119827811
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A systematic study of microdosing psychedelics

February 6, 2019 / Anxiety Disorders / PTSD, Ayahuasca, Depressive Disorders, DMT, Iboga / Ibogaine, Mescaline / Cacti, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications, Substance Use Disorder / By / ,

Abstract

The phenomenon of ‘microdosing’, that is, regular ingestion of very small quantities of psychedelic substances, has seen a rapid explosion of popularity in recent years. Individuals who microdose report minimal acute effects from these substances yet claim a range of long-term general health and wellbeing benefits. There have been no published empirical studies of microdosing and the current legal and bureaucratic climate makes direct empirical investigation of the effects of psychedelics difficult. In Study One we conducted a systematic, observational investigation of individuals who microdose. We tracked the experiences of 98 microdosing participants, who provided daily ratings of psychological functioning over a six week period. 63 of these additionally completed a battery of psychometric measures tapping mood, attention, wellbeing, mystical experiences, personality, creativity, and sense of agency, at baseline and at completion of the study. Analyses of daily ratings revealed a general increase in reported psychological functioning across all measures on dosing days but limited evidence of residual effects on following days. Analyses of pre and post study measures revealed reductions in reported levels of depression and stress; lower levels of distractibility; increased absorption; and increased neuroticism. To better understand these findings, in Study Two we investigated pre-existing beliefs and expectations about the effects of microdosing in a sample of 263 naïve and experienced microdosers, so as to gauge expectancy bias. All participants believed that microdosing would have large and wide-ranging benefits in contrast to the limited outcomes reported by actual microdosers. Notably, the effects believed most likely to change were unrelated to the observed pattern of reported outcomes. The current results suggest that dose controlled empirical research on the impacts of microdosing on mental health and attentional capabilities are needed.

Polito, V., & Stevenson, R. J. (2019). A systematic study of microdosing psychedelics. PloS one, 14(2), e0211023., 10.1371/journal.pone.0211023.
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Effects of Ketamine on Brain Activity During Emotional Processing: Differential Findings in Depressed Versus Healthy Control Participants.

January 25, 2019 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , , , , ,

Abstract

BACKGROUND:
In the search for novel treatments for depression, ketamine has emerged as a unique agent with rapid antidepressant effects. Experimental tasks involving emotional processing can be used during functional magnetic resonance imaging scanning to investigate ketamine’s effects on brain function in major depressive disorder (MDD). This study examined ketamine’s effects on functional magnetic resonance imaging activity during an emotional processing task.
METHODS:
A total of 33 individuals with treatment-resistant MDD and 24 healthy control participants (HCs) took part in this double-blind, placebo-controlled crossover study. Participants received ketamine and placebo infusions 2 weeks apart, and functional magnetic resonance imaging scans were conducted at baseline and 2 days after each infusion. Blood oxygen level-dependent signal was measured during an emotional processing task, and a linear mixed-effects model was used to analyze differences in activation among group, drug, and task-specific factors.
RESULTS:
A group-by-drug interaction was observed in several brain regions, including a right frontal cluster extending into the anterior cingulate cortex and insula. Participants with MDD had greater activity than HCs after placebo infusion but showed lower activity after ketamine infusion, which was similar to the activity in HCs after placebo. A group-by-drug-by-task condition interaction was also found, which showed further differences that varied between implicit and explicit emotional conditions.
CONCLUSIONS:
The main results indicate that ketamine had differential effects on brain activity in participants with MDD versus HCs. The pattern of activation in participants with MDD after ketamine infusion resembled the activation in HCs after placebo infusion, suggesting a normalization of function during emotional processing. The findings contribute to a better understanding of ketamine’s actions in the brain.
Reed, J. L., Nugent, A. C., Furey, M. L., Szczepanik, J. E., Evans, J. W., & Zarate Jr, C. A. (2019). Effects of ketamine on brain activity during emotional processing: differential findings in depressed versus healthy control participants. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging., 10.1016/j.bpsc.2019.01.005
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Effects of acute and repeated treatment with serotonin 5-HT2A receptor agonist hallucinogens on intracranial self-stimulation in rats

January 10, 2019 / Depressive Disorders, LSD, Mescaline / Cacti, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications, Substance Use Disorder / By / , , , , ,

Abstract

The prototype 5-HT2A receptor agonist hallucinogens LSD, mescaline, and psilocybin are classified as Schedule 1 drugs of abuse by the U.S. Drug Enforcement Administration. Accumulating clinical evidence has also suggested that acute or repeated “microdosing” with these drugs may have utility for treatment of some mental health disorders, including drug abuse and depression. The goal of the present study was to evaluate LSD, mescaline, and psilocybin effects on intracranial self-stimulation (ICSS), a procedure that has been used to evaluate abuse-related effects of other classes of abused drugs. Effects of repeated LSD were also examined to evaluate potential changes in its own effects on ICSS or changes in effects produced by the abused psychostimulant methamphetamine or the prodepressant kappa opioid receptor (KOR) agonist U69,593. Male Sprague-Dawley rats were implanted with microelectrodes targeting the medial forebrain bundle and trained to respond under a “frequency-rate” ICSS procedure, in which many drugs of abuse increase (or “facilitate”) ICSS. In acute dose-effect and time-course studies, evidence for abuse-related ICSS facilitation was weak and inconsistent; the predominant effect of all 3 drugs was dose- and time-dependent ICSS depression. Repeated LSD treatment failed to alter either its own ICSS depressant effects or the abuse-related effects of methamphetamine; however, repeated LSD did attenuate ICSS depression by U69,593. These results extend those of previous preclinical studies to suggest weak expression of abuse-related effects by 5-HT2A agonist hallucinogens and provide supportive evidence for therapeutic effects of repeated LSD dosing to attenuate KOR-mediated depressant effects but not abuse potential of psychostimulants.

Sakloth, F., Leggett, E., Moerke, M. J., Townsend, E. A., Banks, M. L., & Negus, S. S. (2019). Effects of acute and repeated treatment with serotonin 5-HT2A receptor agonist hallucinogens on intracranial self-stimulation in rats. Experimental and clinical psychopharmacology., 10.1037/pha0000253.
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Association of Combined Naltrexone and Ketamine With Depressive Symptoms in a Case series of Patients With Depression and Alcohol Use Disorder

January 9, 2019 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychiatry & Medicine, Publications, Substance Use Disorder / By / , ,

Abstract

Ketamine has rapid and robust antidepressant effects. However, there are concerns about the abuse liability of ketamine. This concern was heightened recently owing to a preliminary report suggesting that antidepressant effects of ketamine might be dependent on opiate receptor stimulation. Below, we present pilot data that indicate that the antidepressant effects of ketamine are not attenuated by naltrexone pretreatment. As a result, the combination of opiate receptor antagonism with ketamine might be a strategy to reduce addiction risk among patients with depression at risk for substance abuse.

Yoon, G., Petrakis, I. L., & Krystal, J. H. (2019). Association of Combined Naltrexone and Ketamine With Depressive Symptoms in a Case series of Patients With Depression and Alcohol Use Disorder. JAMA psychiatry., 10.1001/jamapsychiatry.2018.3990.
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Ketamine interactions with gut-microbiota in rats: relevance to its antidepressant and anti-inflammatory properties.

December 22, 2018 / Depressive Disorders, Ketamine, Papers, Psychiatry & Medicine, Psychology, Publications / By / , , , , ,

Abstract

BACKGROUND:
Appreciable evidence suggest that dysbiosis in microbiota, reflected in gut microbial imbalance plays a key role in the pathogenesis of neuropsychiatric disorders including depression and inflammatory diseases. Recently, the antidepressant properties of ketamine have gained prominence due to its fast and long lasting effects. Additional uses for ketamine in inflammatory disorders such as irritable bowel syndrome have been suggested. However, ketamine’s exact mechanism of action and potential effects on microbiome is not known. Here, we examined the effects of low dose ketamine, known to induce antidepressant effects, on stool microbiome profile in adult male Wistar rats. Animals (5/group) were injected intraperitoneally with ketamine (2.5 mg/kg) or saline, daily for 7 days and sacrificed on day 8 when intestinal stools were collected and stored at - 80 °C. DNA was extracted from the samples and the 16 S rRNA gene-based microbiota analysis was performed using 16S Metagenomics application.
RESULTS:
At genus-level, ketamine strikingly amplified Lactobacillus, Turicibacter and Sarcina by 3.3, 26 and 42 fold, respectively. Conversely, opportunistic pathogens Mucispirillum and Ruminococcus were reduced by approximately 2.6 and 26 fold, respectively, in ketamine group. Low levels of Lactobacillus and Turicibacter are associated with various disorders including depression and administration of certain species of Lactobacillus ameliorates depressive-like behavior in animal models. Hence, some of the antidepressant effects of ketamine might be mediated through its interaction with these gut bacteria. Additionally, high level of Ruminococcus is positively associated with the severity of irritable bowel syndrome (IBS), and some species of Mucispirillum have been associated with intestinal inflammation. Indirect evidence of anti-inflammatory role of Sarcina has been documented. Hence, some of the anti-inflammatory effects of ketamine and its usefulness in specific inflammatory diseases including IBS may be mediated through its interaction with these latter bacteria.
CONCLUSION:
Our data suggest that at least some of the antidepressant and anti-inflammatory effects of daily ketamine treatment for 7 days may be mediated via its interaction with specific gut bacteria. These findings further validate the usefulness of microbiome as a target for therapeutic intervention and call for more detailed investigation of microbiome interaction with central mediators of mood and/or inflammatory disorders.
Getachew, B., Aubee, J. I., Schottenfeld, R. S., Csoka, A. B., Thompson, K. M., & Tizabi, Y. (2018). Ketamine interactions with gut-microbiota in rats: relevance to its antidepressant and anti-inflammatory properties. BMC microbiology, 18(1), 222., 10.1186/s12866-018-1373-7
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Possible Interactions Between 5-HT2A Receptors and the Endocannabinoid System in Humans: Preliminary Evidence of Interactive Effects of Ayahuasca and Endocannabinoids in a Healthy Human Subject

December 1, 2018 / Ayahuasca, Depressive Disorders, Neuroscience, Papers, Psychiatry & Medicine, Publications / By / , , , , , ,

Excerpt

To the Editors

Ayahuasca is an ethnobotanical hallucinogenic preparation traditionally used for ritual and therapeutic purposes in the Northwestern Amazon Basin. It is prepared by the decoction of the bark of the vine Banisteriopsis caapi with the leaves of the shrub Psychotria viridis. Banisteriopsis caapi contains the β-carbolines harmine, tetrahydroharmine, and harmaline, which are reversible inhibitors of monoamine oxidase type A (MAO-A), whereas P. viridis contains N,N-dimethyltryptamine (DMT), an agonist at 5-HT1A/2A/2C receptors. Pure DMT is not active orally because it is metabolized by MAO-A, but the β-carbolines in ayahuasca inhibit peripheral MAO-A and allow DMT to reach the brain. The β-carbolines also reach the systemic circulation in humans, but their effects are poorly characterized.

A recent randomized controlled trial (RCT) with 29 patients with treatment-resistant depression showed that, compared with placebo, a single ayahuasca dose induced significant antidepressant effects 7 days after drug intake. The mechanisms behind these effects are not clear but seem to involve agonism at cortical 5-HT2A receptors in brain areas related to emotional processing. 5-HT2A receptor activation also leads to the formation and release of endocannabinoids (ECs), and both the production and release of the EC 2-arachidonoylglycerol (2-AG) are induced by 5-HT2A agonists. Considering that the 5-HT2Areceptor and the EC system (ECS) are coexpressed in brain regions related to emotional processing, they could be involved in the antidepressive effect of ayahuasca. To test the possible interaction between both systems, we administered in an open-label design a single oral ayahuasca dose (1 mL/kg) to a healthy 34-year-old man and assessed subjective effects (Visual Analog Mood Scale [VAMS], Bodily Symptoms Scale, Beck Anxiety Inventory [BAI]), tolerability (blood pressure and heart rate, self-report), and EC plasma levels (anandamide [AEA], 2-AG) at several time points: VAMS, Bodily Symptoms Scale, blood pressure, and heart rate at baseline and 40, 90, 120, 150, and 240 minutes after drug intake; BAI–baseline, 240 minutes after drug intake; AEA, 2-AG (blood samples) at baseline and 90 and 240 minutes after drug intake. Analysis of the ayahuasca sample using gas chromatography with nitrogen-phosphorus detection showed the following alkaloid content (in mg/mL): 0.702 DMT, 1.748 harmine, 0.780 tetrahydroharmine, and 0.039 harmaline. Analysis of plasma ECs was performed using ultrahigh-performance liquid chromatography–tandem mass spectrometry. Detailed information on subjective measures and ayahuasca and EC analyses is described in the Supplemental Digital Content, http://links.lww.com/JCP/A532

The volunteer was not taking any medication and was requested to abstain from alcohol, tobacco, and caffeinated drinks 12 hours before ayahuasca intake. He arrived in the laboratory at 7:00 AM under fasting conditions, and urinalysis for illicit drug use was performed before ayahuasca intake (the test measured cannabis and cocaine and was negative for both drugs). Afterward, a cannula was introduced in his arm for collecting blood samples. Ayahuasca was administered at approximately 8:00 AM, and the experimental session lasted 5 hours. The experimental session consisted in the administration of the drug followed by application of the scales and assessment of tolerability measures at the aforementioned time points. During measurements, the volunteer remained seated in a comfortable reclining chair in a quiet dimly lit room. There was no psychological intervention before, during, or after the session.The volunteer remained in the laboratory under observation to see if the effects had subsided and was discharged around 6 hours after drug intake, which is the approximate duration of the psychoactive effects of ayahuasca.

dos Santos, R. G., Crippa, J. A., de Lima Osório, F., Rocha, J. M., Rossi, G. N., Marchioni, C., … & Hallak, J. E. C. (2018). Possible Interactions Between 5-HT2A Receptors and the Endocannabinoid System in Humans: Preliminary Evidence of Interactive Effects of Ayahuasca and Endocannabinoids in a Healthy Human Subject. Journal of clinical psychopharmacology, 38(6), 644-646., 10.1097/JCP.0000000000000973
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