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Ketamine administration in depressive disorders: a systematic review and meta-analysis

/ Depressive Disorders, Ketamine, Papers, Psychology, Publications / / , , , , , , , , , , , ,

Abstract

Introduction
Ketamine’s efficacy in depressive disorders has been established in several controlled trials. The aim of the present study was to determine whether or not ketamine administration significantly improves depressive symptomatology in depression and more specifically in major depressive disorder (MDD), bipolar depression, resistant depression (non-ECT studies), and as an anesthetic agent in electroconvulsive therapy (ECT) for resistant depression (ECT studies). Secondary outcomes were the duration of ketamine’s effect, the efficacy on suicidal ideations, the existence of a dose effect, and the safety/tolerance of the treatment.

Methods
Studies were included if they met the following criteria (without any language or date restriction): design: randomized controlled trials, intervention: ketamine administration, participants: diagnosis of depression, and evaluation of severity based on a validated scale. We calculated standardized mean differences (SMDs) with 95 % confidence intervals (CIs) for each study. We used fixed and random effects models. Heterogeneity was assessed using the I2 statistic.

Results
We included nine non-ECT studies in our quantitative analysis (192 patients with major depressive disorder and 34 patients with bipolar depression). Overall, depression scores were significantly decreased in the ketamine groups compared to those in the control groups (SMD = −0.99; 95 % CI −1.23, −0.75; p < 0.01). Ketamine’s efficacy was confirmed in MDD (resistant to previous pharmacological treatments or not) (SMD = −0.91; 95 % CI −1.19,−0.64; p < 0.01), in bipolar depression (SMD = −1.34; 95 % CI −1.94, −0.75), and in drug-free patients as well as patients under medication. Four ECT trials (118 patients) were included in our quantitative analysis. One hundred and three patients were diagnosed with major depressive disorder and 15 with bipolar depression. Overall, depression scores were significantly improved in the 58 patients receiving ketamine in ECT anesthesia induction compared to the 60 patients (SMD = −0.56; 95 % CI −1.10, −0.02; p = 0.04; I2 = 52.4 %). The duration of ketamine’s effects was assessed in only two non-ECT studies and seemed to persist for 2–3 days; this result needs to be confirmed. Three of four studies found significant decrease of suicidal thoughts and one found no difference between groups, but suicidal ideations were only studied by the suicide item of the depressive scales. It was not possible to determine a dose effect; 0.5 mg/kg was used in the majority of the studies. Some cardiovascular events were described (mostly transient blood pressure elevation that may require treatment), and ketamine’s use should remain cautious in patients with a cardiovascular history.

Conclusion
The present meta-analysis confirms ketamine’s efficacy in depressive disorders in non-ECT studies, as well as in ECT studies. The results of this first meta-analysis are encouraging, and further studies are warranted to detail efficacy in bipolar disorders and other specific depressed populations. Middle- and long-term efficacy and safety have yet to be explored. Extrapolation should be cautious: Patients included had no history of psychotic episodes and no history of alcohol or substance use disorders, which is not representative of all the depressed patients that may benefit from this therapy.

Fond, G., Loundou, A., Rabu, C., Macgregor, A., Lançon, C., Brittner, M. … Boyer, L. (2014). Ketamine administration in depressive disorders: a systematic review and meta-analysis. Psychopharmacology, 231, 3663-3676. http://dx.doi.org/10.1007/s00213-014-3664-5
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Recent advances in the neuropsychopharmacology of serotonergic hallucinogens

/ DMT, LSD, Mescaline / Cacti, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / /

Abstract

Serotonergic hallucinogens, such as (+)-lysergic acid diethylamide, psilocybin, and mescaline, are somewhat enigmatic substances. Although these drugs are derived from multiple chemical families, they all produce remarkably similar effects in animals and humans, and they show cross-tolerance. This article reviews the evidence demonstrating the serotonin 5-HT2A receptor is the primary site of hallucinogen action. The 5-HT2A receptor is responsible for mediating the effects of hallucinogens in human subjects, as well as in animal behavioral paradigms such as drug discrimination, head twitch response, prepulse inhibition of startle, exploratory behavior, and interval timing. Many recent clinical trials have yielded important new findings regarding the psychopharmacology of these substances. Furthermore, the use of modern imaging and electrophysiological techniques is beginning to help unravel how hallucinogens work in the brain. Evidence is also emerging that hallucinogens may possess therapeutic efficacy.

Halberstadt, A. L. (2014). Recent advances in the neuropsychopharmacology of serotonergic hallucinogens. Behavioural Brain Research, 277, 99-120. http://dx.doi.org/10.1016/j.bbr.2014.07.016
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The Effects of Ayahuasca Ritual Participation on Gay and Lesbian Identity

/ Ayahuasca, Papers, Psychology, Publications / /

Abstract

The practice of drinking ayahuasca—a psychoactive brew indigenous to the Amazon—has been investigated in several studies and shown to have positive long-term effects on mental states, and a particularly strong positive effect on perceptions of identity. This article discusses if these previous findings can be found in the experience of gay people, who are often taught by their culture and religion that their lifestyles, values, and sexual orientation are unacceptable. The qualitative study examined the interview responses of 17 self-identified gay and lesbian participants who had drunk ayahuasca in a ceremonial context within the past three years, regarding their self-perceptions and integration of group beliefs. Participants drank either in shamanic or Santo Daime ceremonies or, in the case of one participant, with an Afro-Brazilian group that used ayahuasca. Participants reported affirmation of their sexual orientation, and no participants reported negative effects on perception of identity. Additional positive effects in other areas of their lives, which they attributed to ayahuasca sessions, contributed to the overall positive outcomes that were reported by this group as a result of their ritual participation.

Cavnar, C. (2014). The effects of ayahuasca ritual participation on gay and lesbian identity. Journal of psychoactive drugs, 46(3), 252-260. https://dx.doi.org/10.1080/02791072.2014.920117

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The role of 5-HT2A, 5-HT2C and mGlu2 receptors in the behavioral effects of tryptamine hallucinogens N,N-dimethyltryptamine and N,N-diisopropyltryptamine in rats and mice

/ Neuroscience, Papers, Publications / / , , , , ,

Abstract

Rationale

Serotonin 5-HT2A and 5-HT2C receptors are thought to be the primary pharmacological mechanisms for serotonin-mediated hallucinogenic drugs, but recently there has been interest in metabotropic glutamate (mGluR2) receptors as contributors to the mechanism of hallucinogens.

Objective

The present study assesses the role of these 5-HT and glutamate receptors as molecular targets for two tryptamine hallucinogens, N,N-dimethyltryptamine (DMT) and N,N-diisopropyltryptamine (DiPT).

Methods

Drug discrimination, head twitch, and radioligand binding assays were used. A 5-HT2AR inverse agonist (MDL100907), 5-HT2CR antagonist (SB242084), and mGluR2/3 agonist (LY379268) were tested for their ability to attenuate the discriminative stimulus effects of DMT and DiPT; an mGluR2/3 antagonist (LY341495) was tested for potentiation. MDL100907 was used to attenuate head twitches induced by DMT and DiPT. Radioligand binding studies and inosital-1-phosphate (IP-1) accumulation were performed at the 5-HT2CR for DiPT.

Results

MDL100907 fully blocked the discriminative stimulus effects of DMT, but only partially blocked DiPT. SB242084 partially attenuated the discriminative stimulus effects of DiPT, but produced minimal attenuation of DMT’s effects. LY379268 produced potent, but only partial blockade of the discriminative stimulus effects of DMT. LY341495 facilitated DMT- and DiPT-like effects. Both compounds elicited head twitches (DiPT>DMT) which were blocked by MDL1000907. DiPT was a low-potency full agonist at 5-HT2CR in vitro.

Conclusions

The 5-HT2AR likely plays a major role in mediating the effects of both compounds. 5-HT2C and mGluR2 receptors likely modulate the discriminative stimulus effects of both compounds to some degree.

Carbonaro, T. M., Eshleman, A. J., Forster, M. J., Cheng, K., Rice, K. C., & Gatch, M. B. (2014). The role of 5-HT2A, 5-HT2C and mGlu2 receptors in the behavioral effects of tryptamine hallucinogens N, N-dimethyltryptamine and N, N-diisopropyltryptamine in rats and mice. Psychopharmacology, 1-10. https://dx.doi.org/10.1007/s00213-014-3658-3

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Enhanced repertoire of brain dynamical states during the psychedelic experience

/ Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / / , , , ,

Abstract

The study of rapid changes in brain dynamics and functional connectivity (FC) is of increasing interest in neuroimaging. Brain states departing from normal waking consciousness are expected to be accompanied by alterations in the aforementioned dynamics. In particular, the psychedelic experience produced by psilocybin (a substance found in `magic mushrooms`) is characterized by unconstrained cognition and profound alterations in the perception of time, space and selfhood. Considering the spontaneous and subjective manifestation of these effects, we hypothesize that neural correlates of the psychedelic experience can be found in the dynamics and variability of spontaneous brain activity fluctuations and connectivity, measurable with functional Magnetic Resonance Imaging (fMRI). Fifteen healthy subjects were scanned before, during and after intravenous infusion of psilocybin and an inert placebo. Blood-Oxygen Level Dependent (BOLD) temporal variability was assessed computing the variance and total spectral power, resulting in increased signal variability bilaterally in the hippocampi and anterior cingulate cortex. Changes in BOLD signal spectral behavior (including spectral scaling exponents) affected exclusively higher brain systems such as the default mode, executive control and dorsal attention networks. A novel framework enabled us to track different connectivity states explored by the brain during rest. This approach revealed a wider repertoire of connectivity states post-psilocybin than during control conditions. Together, the present results provide a comprehensive account of the effects of psilocybin on dynamical behaviour in the human brain at a macroscopic level and may have implications for our understanding of the unconstrained, hyper-associative quality of consciousness in the psychedelic state.

Tagliazucchi, E., Carhart-Harris, R. L., Leech, R., Nutt, D., & Chialvo, D. R. (2014). Enhanced repertoire of brain dynamical states during the psychedelic experience. Human Brain Mapping, 35(11), 5442-5456. http://dx.doi.org/10.1002/hbm.22562
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(R,S)-Ketamine metabolites (R,S)-norketamine and (2S,6S)-hydroxynorketamine increase the mammalian target of rapamycin function

/ Depressive Disorders, Ketamine, Neuroscience, Papers, Publications / / , , , , , ,

Abstract

BACKGROUND: Subanesthetic doses of (R,S)-ketamine are used in the treatment of neuropathic pain and depression. In the rat, the antidepressant effects of (R,S)-ketamine are associated with increased activity and function of mammalian target of rapamycin (mTOR); however, (R,S)-ketamine is extensively metabolized and the contribution of its metabolites to increased mTOR signaling is unknown.

METHODS: Rats (n = 3 per time point) were given (R,S)-ketamine, (R,S)-norketamine, and (2S,6S)-hydroxynorketamine and their effect on the mTOR pathway determined after 20, 30, and 60 min. PC-12 pheochromocytoma cells (n = 3 per experiment) were treated with escalating concentrations of each compound and the impact on the mTOR pathway was determined.

RESULTS: The phosphorylation of mTOR and its downstream targets was significantly increased in rat prefrontal cortex tissue by more than ~2.5-, ~25-, and ~2-fold, respectively, in response to a 60-min postadministration of (R,S)-ketamine, (R,S)-norketamine, and (2S,6S)-hydroxynorketamine (P < 0.05, ANOVA analysis). In PC-12 pheochromocytoma cells, the test compounds activated the mTOR pathway in a concentration-dependent manner, which resulted in a significantly higher expression of serine racemase with ~2-fold increases at 0.05 nM (2S,6S)-hydroxynorketamine, 10 nM (R,S)-norketamine, and 1,000 nM (R,S)-ketamine. The potency of the effect reflected antagonistic activity of the test compounds at the α7-nicotinic acetylcholine receptor.

CONCLUSIONS: The data demonstrate that (R,S)-norketamine and (2S,6S)-hydroxynorketamine have potent pharmacological activity both in vitro and in vivo and contribute to the molecular effects produced by subanesthetic doses of (R,S)-ketamine. The results suggest that the determination of the mechanisms underlying the antidepressant and analgesic effects of (R,S)-ketamine requires a full study of the parent compound and its metabolites.

Paul, R. K., Singh, N. S., Khadeer, M., Moaddel, R., Sanghvi, M., Green, C. E., … & Wainer, I. W. (2014). (R, S)-Ketamine metabolites (R, S)-norketamine and (2S, 6S)-hydroxynorketamine increase the mammalian target of rapamycin function. The Journal of the American Society of Anesthesiologists, 121(1), 149-159. http://dx.doi.org/10.1097/ALN.0000000000000285
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Examining the psychological mechanisms of psilocybin-assisted smoking cessation treatment: A pilot study

/ Mushrooms / Psilocybin, Papers, Psychology, Publications, Substance Use Disorder / / , ,

Abstract

Anthropological evidence and early experimental studies suggest that structured administration of 5-HT2A agonist hallucinogens (e.g., LSD, psilocybin) may have potential in treating addictions, including alcoholism and opioid dependence. Psilocybin administration has been recently linked to persisting effects including personality change (i.e., increased NEO Openness), mood enhancement, and behavior change. The association between mood, personality, and addiction has been well documented, and suggests that psilocybin may be useful in the treatment of addiction.

Garcia-Romeu, A. P., Johnson, M. W., & Griffiths, R. R. (2014). Examining the psychological mechanisms of psilocybin-assisted smoking cessation treatment: A pilot study. Drug & Alcohol Dependence, 140, e66. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.200
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Harmine for catatonic schizophrenia. A forgotten experiment

/ Depressive Disorders, Humanities & Art, Papers, Psychiatry & Medicine, Psychology, Publications / / , ,

Abstract

The purpose of this letter is to present a lesser-known experiment suggesting a positive response of catatonic schizophrenia to Harmine, a monoamine oxidase A inhibitor(MAO-A), a study conducted by Petre Tomescu, in the late 1920’s.

 

Hostiuc, S., Buda, O., & Ion, D. A. (2014). Harmine for catatonic schizophrenia. A forgotten experiment. Schizophrenia research, 1(159), 249-250. http://dx.doi.org/10.1016/j.schres.2014.08.006

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Ayahuasca Shamanism in the Amazon and Beyond

/ Publications /

Ayahuasca_shamanism

Beatriz Caiuby Labate and Clancy Cavnar offer an in-depth exploration of how Amerindian epistemology and ontology concerning indigenous shamanic rituals of the Amazon have spread to Western societies, and of how indigenous, mestizo, and cosmopolitan cultures have engaged with and transformed these forest traditions. The volume focuses on the use of ayahuasca, a psychoactive drink essential in many indigenous shamanic rituals of the Amazon. Ayahuasca use has spread far beyond its Amazonian origin, spurring a variety of legal and cultural responses in the countries to which it has spread. The essays in this volume look at how these responses have influenced ritual design and performance in traditional and non-traditional contexts, how displaced indigenous people and rubber tappers are engaged in the creative reinvention of rituals, and how these rituals help build ethnic alliances and cultural and political strategies for their marginalized position. Some essays explore important classic and contemporary issues in anthropology, including the relationship between the expansion of ecotourism and ethnic tourism and recent indigenous cultural revival and the emergence of new ethnic identities. The volume also examines trends in the commodification of indigenous cultures in post-colonial contexts, the combination of shamanism with a network of health and spiritually related services, and identity hybridization in global societies. The rich ethnographies and extensive analysis of these essays will allow deeper understanding of the role of ritual in mediating the encounter between indigenous traditions and modern societies.

Ayahuasca Shamanism in the Amazon and Beyond, door Beatriz Caiuby Labate & Clancy Cavnar (Editors), Oxford Ritual Studies reeks, Oxford University Press, 320 pagina’s.

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The Consumption of Psychoactive Plants in Ancient Global and Anatolian Cultures During Religious Rituals: The Roots of the Eruption of Mythological Figures and Common Symbols in Religions and Myths

/ Ayahuasca, Biology & Ethnobotany, DMT, Iboga / Ibogaine, Mescaline / Cacti, Mushrooms / Psilocybin, Papers, Publications, Salvia / Salvinorin A / /

Abstract

Psychoactive plants which contain hallucinogenic molecules that induce a form of altered states of consciousness (H-ASC) have been widely used during the religious rituals of many cultures throughout the centuries, while the consumption of these plants for spiritual and religious purposes is as old as human history. Some of those cultures were shaman and pagan subcultures; African native religions; Bwiti Cult; South American native religions; Amazon Cultures; Central American Cultures; Mexican subcultures; Aztec, Maya and Inca; Wiccan and witch subcultures; Satanists; American Indians; Greek and Hellenistic cultures; Sufis; Hassan Sabbah’s Hashissins; Hindu, Indian and Tibetan cultures; some of the Nordic subcultures etc. Some of the psychoactive ingredients of the plants that were used during these religious rituals were; narcotic analgesics (opium), THC (cannabis), psilocybin (magic mushrooms), mescaline (peyote), ibogaine (Tabernanthe iboga), DMT (Ayahuasca and phalaris species), Peganum harmala, bufotenin, muscimol (Amanita muscaria), thujone (absinthe, Arthemisia absinthium), ephedra, mandragora, star lotus, Salvia divinorum etc. The main purposes of the practice of these plants were: spiritual healing; to contact with spirits; to contact with the souls of ancestors; to reach enlightenment (Nirvana or Satori); to become a master shaman, pagan or witch; to reach so-called-other realities, etc. Such “psychedelic-philosophical plant rituals” changed participating persons’ psychology, philosophy and personality to a great degree. In these two successive articles, the consumption of psychedelic plants during religious rituals is reviewed and it is hypothesized that the images, Figures, illusions and hallucinations experienced during these “plant trips” had a great impact on the formation and creation of many Figures, characters, creatures, archetype images that exist not only in the mythology, but also in many religions, as well, such as angels, demons, Satan, mythological creatures, gods, goddesses etc. In the Middle East and Anatolia, within many hermetic and pagan religions, Greek and Hellenic cultures psychoactive plant use was a serious part of the religious rituals, such as Dionysian rituals or Witch’s’ Sabbaths. Although the impact of the “psychedelic experience and imagination” was enormous to the configuration of many religious and mythological characters, and archetypes, this fact has been underestimated and even unnoticed by many historians and anthropologists, because of the quasi-ethical trends of “anti-drug-brain-washed Western Societies”.
Sayin, H. U. (2014). The Consumption of Psychoactive Plants in Ancient Global and Anatolian Cultures During Religious Rituals: The Roots of the Eruption of Mythological Figures and Common Symbols in Religions and Myths. NeuroQuantology, 12(2), 276-296. https://dx.doi.org/10.14704/nq.2014.12.2.753
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