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Psilocybin and Mood Regulation

December 6, 2021 / Mushrooms / Psilocybin, Publications / By

With their recent publication, Kraehenmann et al. (2014) have increased our understanding of the mechanism that is thought to underlie the potential effectiveness of psychedelic–assisted psychotherapy in relieving mood and anxiety related symptomology. Their results elaborate on earlier findings that the administration of psychedelics [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”][1] in addition with psychotherapy reduces anxiety symptoms on a relatively short term (Gasser et al., 2014; Moreno, Wiegand, Taitano, & Delgado, 2006), with one study even showing a reduction of anxiety and an increase of positive mood six months after only a single dose of psilocybin (Grob et al., 2011).

These clinical observations are now complemented by the finding that psilocybin attenuates amygdala [2] reactivity in response to emotionally loaded pictures in healthy volunteers, and that these changes are associated with a positive mood change. The authors suggest that psilocybin might have the potential to normalize neurobiological systems that are dysregulated in individuals with a depressed mood state. In addition to the psychometric evidence and clinical observations that psilocybin-assisted psychotherapy improves mood within a clinical population, the results of the current study provide a possible neurobiological explanation for these effects. The questions that arise from this study relate to the degree to which these results can be generalized to a clinical population, and if and to what extent the acute changes in amygdala reactivity by themselves may account for long term changes in the processing of emotions.

According to the Trimbos Institute (2014) [3] there is a current prevalence of 4 – 10 % of people suffering from depression in Western society. Because of its high prevalence and devastating individual and societal consequences, depression is considered a major public health problem (Spijker, van Straten, Bockting, Meeuwissen, & van Balkom, 2013). The regular treatment options include psychotherapy, pharmacotherapy or a combination of the two, of which the latter is thought to establish the most favorable outcome. One of the added values of the study of Kraehenmann (2014) is the finding that psilocybin – with its pharmacological effect on amygdala reactivity – shares a neurobiological mechanism of action with selective serotonin reuptake inhibitors (SSRI’s), which are prescription drugs that are commonly deployed in the treatment of depression and other mood related disorders. What then, might be the necessity of exploring these psychedelic compounds as alternatives for customary treatment options?

The treatment of mood disorders with SSRI’s has several disadvantages, with probably the most prominent criticism being the modest response (47%) and remission rates (between 28 – 33%; Trivedi et al., 2006). Other disadvantages include a delayed therapeutic action (Stahl, 1998), withdrawal difficulties (Schatzberg, 1997), and the daily pharmacological treatment routine. Results from the psychedelic-assisted treatment sessions imply a prolonged uplift of mood after the pharmacological intervention, which is only implemented occasionally. These results are far too preliminary to abandon the extensively reviewed prescription drugs in the treatment of mood disorders and switch to less scientifically studied compounds that share some of the same neurobiological features, but it might be valuable to elucidate upon their therapeutical potential. What is it that psychologically distinguishes one type of drug with antidepressant properties from the other, and who are the people that might benefit from making this distinction? With one out of ten people suffering from depressive symptoms [4], the need for this kind of knowledge may not be underestimated.

 
[1] Red. classical psychedelics, which are isolated from a broader categorization of psychedelics by their pharmacological manifestation as serotonin 5-HT2A receptor agonists
[2] The amygdala is a structure in the limbic system that plays a major role in the processing of emotions and is therefore a key target for psychopharmacological interventions to treat mood and anxiety disorders (Phelps & LeDoux, 2005)
[3] The Trimbos Institute is a Dutch organization that serves as an information centre for matters related to mental health
[4] In Western societies (Trimbos Institute, 2014)
 
References
Gasser, P., Holstein, D., Michel, Y., Doblin, R., Yazar-Klosinski, B., Passie, T., & Brenneisen, R. (2014). Safety and Efficacy of Lysergic Acid Diethylamide-Assisted Psychotherapy for Anxiety Associated With Life-threatening Diseases. The Journal of Nervous and Mental Disease, 00(00), 1. doi:10.1097/NMD.0000000000000113
Grob, C. S., Danforth, A. L., Chopra, G. S., Hagerty, M., McKay, C. R., Halberstadt, A. L., & Greer, G. R. (2011). Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Archives of General Psychiatry, 68(1), 71–8. doi:10.1001/archgenpsychiatry.2010.116
Kraehenmann, R., Preller, K. H., Scheidegger, M., Pokorny, T., Bosch, O. G., Seifritz, E., & Vollenweider, F. X. (2014). Psilocybin-Induced Decrease in Amygdala Reactivity Correlates with Enhanced Positive Mood in Healthy Volunteers. Biological Psychiatry, 1–9. doi:10.1016/j.biopsych.2014.04.010
Moreno, F. A., Wiegand, C. B., Taitano, E. K., & Delgado, P. L. (2006). Safety, Tolerability, and Efficacy of Psilocybin in 9 Patients With Obsessive-Compulsive Disorder. The Journal of Clinical Psychiatry, 67(11), 1735–1740. doi:10.4088/JCP.v67n1110
Moreno, F. A., Wiegand, C. B., Taitano, E. K., & Delgado, P. L. (2006). Safety, Tolerability, and Efficacy of Psilocybin in 9 Patients With Obsessive-Compulsive Disorder. The Journal of Clinical Psychiatry, 67(11), 1735–1740. doi:10.4088/JCP.v67n1110
Spijker, J., van Straten, A., Bockting, C. L. H., Meeuwissen, J. a C., & van Balkom, A. J. L. M. (2013). Psychotherapy, antidepressants, and their combination for chronic major depressive disorder: a systematic review. Canadian Journal of Psychiatry. Revue Canadienne de Psychiatrie, 58(7), 386–92. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/23870720
Stahl, S. M. (1998). Mechanism of action of serotonin selective reuptake inhibitors. Serotonin receptors and pathways mediate therapeutic effects and side effects. Journal of Affective Disorders, 51(3), 215–35. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10333979
Trimbos Instituut (2014). Feiten en cijfers depressie. Reviewed on July 12, 2014 at http://www.trimbos.nl/onderwerpen/psychische-gezondheid/depressie/feiten-en-cijfers
Trivedi, M. H., Rush, a J., Wisniewski, S. R., Nierenberg, A. a, Warden, D., Ritz, L., … Fava, M. (2006). Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. The American Journal of Psychiatry, 163(1), 28–40. doi:10.1176/appi.ajp.163.1.28[/fusion_builder_column][/fusion_builder_row][/fusion_builder_container]

Psilocybine en stemmingsregulatie

December 6, 2021 / Mushrooms / Psilocybin / By

De resultaten van een recent gepubliceerde studie van Kraehenmann et al. (2014), bieden mogelijk een verklaring voor het mechanisme wat ten grondslag zou kunnen liggen aan het gunstige effect dat een psychotherapeutische behandeling in combinatie met een psychedelicum [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”][1] lijkt te kunnen hebben op stemmings- en angstklachten. De resultaten vullen de bevindingen van enkele klinische studies aan, waaruit is gebleken dat het gebruik van een psychedelicum binnen een psychotherapeutische behandeling angstklachten kan reduceren (Gasser et al., 2014; Grob et al., 2011; Moreno, Wiegand, Taitano, & Delgado, 2006). Binnen één studie werd zelfs gevonden dat mensen die als aanvulling op hun behandeling eenmalig psilocybine kregen toegediend, naast een verminderde angst, zes maanden later ook een significant positievere stemming hadden ten opzichte van mensen die geen psilocybine kregen toegediend (Grob et al., 2011).

Deze klinische observaties worden nu aangevuld met de bevinding dat psilocybine bij gezonde proefpersonen de reactiviteit van de amygdala [2] verzwakt in reactie op emotioneel beladen afbeeldingen, en dat deze verandering wordt geassocieerd met een positieve verandering van de stemming. De auteurs van het artikel opperen dat psilocybine mogelijk de potentie heeft om gedereguleerde neurobiologische systemen te normaliseren bij mensen die kampen met een depressieve stemmingsstoornis.

In aanvulling op het psychometrische bewijs en de klinische observaties dat de combinatie van psilocybine met psychotherapie stemmingsklachten lijkt te kunnen verminderen in een klinische populatie, levert de huidige studie een mogelijke neurobiologische verklaring voor dit effect. De vraag is echter wel in hoeverre deze bevinding gegeneraliseerd kan worden naar een klinische populatie, en of de acute veranderingen in de reactiviteit van de amygdala een verandering in de verwerking van emoties op langere termijn kan verklaren.

Volgens het Trimbos Instituut [3] (2014) ligt de huidige prevalentie van mensen die lijden onder een depressie in de Westerse maatschappij tussen de 4 en 10%. Vanwege dit hoge percentage en de vernietigende consequenties op individueel en maatschappelijk niveau, wordt depressiviteit beschouwd als een groot volksgezondheidsprobleem (Spijker, van Straten, Bockting, Meeuwissen, & van Balkom, 2013). Reguliere behandelmethoden bestaan uit psychotherapie, medicatie of een combinatie daarvan, en over het algemeen wordt er vanuit gegaan dat de combinatie het meest gunstige effect heeft. Een interessante toevoeging van de studie van Kraehenmann (2014) is dat psilocybine – met zijn farmacologische effect op amygdala reactiviteit – een neurobiologisch werkingsmechanisme deelt met selectieve serotonine-heropname remmers (SSRI’s), een klasse medicijnen die vaak wordt ingezet bij de behandeling van depressie en andere stemmingsgerelateerde stoornissen. Dit in beschouwing genomen, kan men zich afvragen wat de toegevoegde waarde zou kunnen zijn van verder onderzoek naar de mogelijkheid om deze psychedelische substanties in te zetten als alternatief op de reguliere behandelmethoden. Het antwoord schuilt in het vaak langdurige, moeizame behandeltraject met de momenteel beschikbare medicatie, waarvan de uitkomst ver van zeker is.

De behandeling van stemmingsstoornissen met SSRI’s heeft verschillende nadelen, waarvan de bescheiden percentages van patiënten waarbij de medicatie aanslaat (47%) en het aantal mensen dat (tijdelijk) herstelt (28 – 33%) waarschijnlijk tot de meest uitgesproken behoren. Andere nadelen zijn de vertraagde therapeutische werking (Stahl, 1998), ontwenningsproblematiek (Schatzberg, 1997), en het dagelijks moet innemen van medicatie met diverse vervelende bijwerkingen. In tegenstelling tot een behandeling met SSRI’s, wijzen de resultaten van de eerder besproken studies uit dat een sporadische sessie met een psychedelicum ter aanvulling op de gebruikelijke psychotherapie, mogelijk kan leiden tot een langdurige verbetering van de stemming. Gezien het hier echter om enkele kleinschalige studies gaat is het uiteraard nog veel te voorbarig om definitieve conclusies te trekken en het gebruik van de uitgebreid onderzochte SSRI’s te staken. Desalniettemin zou een verkenning van het therapeutisch potentieel van het brede scala aan psychedelische middelen waardevolle informatie op kunnen leveren. Wat onderscheidt psychologisch gezien het ene middel met antidepressieve eigenschappen van het ander, en welke mensen zijn er mogelijk bij gebaat dat dit onderscheid wordt gemaakt? Met één op de tien mensen [4] die dagelijks kampt met depressieve symptomen mag het belang van dit soort kennis niet worden onderschat.

 
[1] Red. klassieke psychedelica, welke kunnen worden geïsoleerd van een bredere categorisatie van psychedelica op basis van de farmacologische manifestatie als 5-HT2A receptor agonisten
[2] De amygdala is een structuur in het limbische systeem die een belangrijke rol speelt bij het verwerken van emoties en is daarom een belangrijk doel van psychofarmacologische interventies voor het behandelen van stemmings- en angststoornissen (Phelps & LeDoux, 2005)
[3] Het Trimbos Instituut is een Nederlands informatiecentrum dat zich bezighoud met kwesties omtrent geestelijke gezondheid
[4] In de Westerse maatschappij (Trimbos Instituut, 2014)
 
Referenties
Gasser, P., Holstein, D., Michel, Y., Doblin, R., Yazar-Klosinski, B., Passie, T., & Brenneisen, R. (2014). Safety and Efficacy of Lysergic Acid Diethylamide-Assisted Psychotherapy for Anxiety Associated With Life-threatening Diseases. The Journal of Nervous and Mental Disease, 00(00), 1. doi:10.1097/NMD.0000000000000113
Grob, C. S., Danforth, A. L., Chopra, G. S., Hagerty, M., McKay, C. R., Halberstadt, A. L., & Greer, G. R. (2011). Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Archives of General Psychiatry, 68(1), 71–8. doi:10.1001/archgenpsychiatry.2010.116
Kraehenmann, R., Preller, K. H., Scheidegger, M., Pokorny, T., Bosch, O. G., Seifritz, E., & Vollenweider, F. X. (2014). Psilocybin-Induced Decrease in Amygdala Reactivity Correlates with Enhanced Positive Mood in Healthy Volunteers. Biological Psychiatry, 1–9. doi:10.1016/j.biopsych.2014.04.010
Moreno, F. A., Wiegand, C. B., Taitano, E. K., & Delgado, P. L. (2006). Safety, Tolerability, and Efficacy of Psilocybin in 9 Patients With Obsessive-Compulsive Disorder. The Journal of Clinical Psychiatry, 67(11), 1735–1740. doi:10.4088/JCP.v67n1110
Moreno, F. A., Wiegand, C. B., Taitano, E. K., & Delgado, P. L. (2006). Safety, Tolerability, and Efficacy of Psilocybin in 9 Patients With Obsessive-Compulsive Disorder. The Journal of Clinical Psychiatry, 67(11), 1735–1740. doi:10.4088/JCP.v67n1110
Spijker, J., van Straten, A., Bockting, C. L. H., Meeuwissen, J. a C., & van Balkom, A. J. L. M. (2013). Psychotherapy, antidepressants, and their combination for chronic major depressive disorder: a systematic review. Canadian Journal of Psychiatry. Revue Canadienne de Psychiatrie, 58(7), 386–92. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/23870720
Stahl, S. M. (1998). Mechanism of action of serotonin selective reuptake inhibitors. Serotonin receptors and pathways mediate therapeutic effects and side effects. Journal of Affective Disorders, 51(3), 215–35. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10333979
Trimbos Instituut (2014). Feiten en cijfers depressie. Reviewed on July 12, 2014 at http://www.trimbos.nl/onderwerpen/psychische-gezondheid/depressie/feiten-en-cijfers
Trivedi, M. H., Rush, a J., Wisniewski, S. R., Nierenberg, A. a, Warden, D., Ritz, L., … Fava, M. (2006). Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. The American Journal of Psychiatry, 163(1), 28–40. doi:10.1176/appi.ajp.163.1.28[/fusion_builder_column][/fusion_builder_row][/fusion_builder_container]

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

July 20, 2014 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , , , , , , , , , , , ,

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

July 15, 2014 / DMT, LSD, Mescaline / Cacti, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / By /

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

July 14, 2014 / Ayahuasca, Papers, Psychology, Publications / By /

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

July 3, 2014 / Neuroscience, Papers, Publications / By / , , , , ,

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

July 2, 2014 / Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / By / , , , ,

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

July 1, 2014 / Depressive Disorders, Ketamine, Neuroscience, Papers, Publications / By / , , , , , ,

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

July 1, 2014 / Mushrooms / Psilocybin, Papers, Psychology, Publications, Substance Use Disorder / By / , ,

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

June 30, 2014 / Depressive Disorders, Humanities & Art, Papers, Psychiatry & Medicine, Psychology, Publications / By / , ,

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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