Efficacy evaluation and neurobiological mechanism of psychedelics based on looming model / 中国药理学与毒理学杂志

OBJECTIVE To investigate the effect of psychedelics on innate fear behavior of mice in Looming model(LM)and its neurobiological mechanism.METH-ODS ① Adult male C57BL/6J mice were randomly divid-ed into saline group,DOM group,psilocybin group and mescaline group.The drugs of the corresponding groups were given ip injecction 5 min in advance and LM were used to test the effect of them on freezing time in shelter of mice.② The mice were performing ip given DOM or psilocybin following 5-HT2A receptor antagonist M100907 ip 30 min later involved looming experiments.③Quan-tified the expression of EGR1 protein in mouse brains by immunofluorescence staining,then use ibotenic acid(IBO)damaged the mouse brain regions based on the result above and performed looming experiments.④ Specifically activate or inhibit CaMK Ⅱ,PV,VIP and SOM neurons of mice in saline or psilocybin groups respec-tively by chemical genetic methods and followed looming experiments.RESULTS ① In LM,the freezing time in shelter of mice in DOM,psilocybin and mescaline groups was significantly shorter compared to the saline group(P<0.05),and the dose-effect curves of above psyche-delics were U-shaped.② Compared with the vehicle + psilocybin/DOM groups,the freezing time in shelter of mice in M100907 + psilocybin/DOM groups was signifi-cantly prolonged(P<0.05),and there was no significant difference between the vehicle + saline group and the M100907 + psilocybin/DOM groups.③ Psilocybin signifi-cantly increased the expression of EGR1 protein in prelim-bic cortex(PrL)compared with saline,and the damage of PrL could effectively antagonized the effect of psilocybin shortening the freezing time in LM.④ Chemicalgenetic specific inhibition of CaMK Ⅱ,PV or VIP neurons in PrL could effectively antagonize the effect of psilocybin in LM,while chemicalgenetic specific activation of CaMK Ⅱneurons could significantly shorten the freezing time of saline-treated mice.CONCLUSION Psychedelics have capability to waken the innate fear behavior like freez-ing of mice in LM,and this effect is mediated by 5-HT2A receptor and CaMK Ⅱneuron in PrL.

Abriendo las puertas de la percepción: la psicoterapia asistida con psicodélicos como remedio de cuidados paliativos / Opening the gates of perception Psychedelic-assisted psychotherapy as a palliative care remedy

En tiempos en que los trastornos mentales han devenido una verdadera epidemia, la medicina paliativa se enfrenta a grandes desafíos sobre cómo abordar el sufrimiento al final de la vida, especialmente en aquellos pacientes cuyo mayor padecimiento no es de origen somático sino psicológico. A pesar de contar actualmente con vastas herramientas psicofarmacológicas, estas demuestran ir acompañadas de muchos efectos adversos y son ineficaces en muchos casos, lo que obliga a los expertos a estudiar métodos alternativos como la psicoterapia asistida por psicodélicos. Este documento aborda justamente tema de la psicoterapia asistida por psicodélicos y responde a las principales preocupaciones éticas que rodean a estas drogas. Teniendo en cuenta el estado legal de las drogas psicodélicas, se aplica un enfoque cuidadoso para garantizar que este nuevo método terapéutico, que está siendo seriamente estudiado, no cause daño a los pacientes y brinde beneficios sustanciales para el bienestar de los enfermos de acuerdo con principios éticos básicos. En conclusión, este trabajo destaca la importancia de da por psicodélicos como un tratamiento paliativo para los pacientes con enfermedades terminales, que sufren un duelo anticipado y a quienes se les debe ayudar a encontrar la paz durante los últimos meses de su vida

In the times of mental disorder epidemics palliative medicine is facing big challenges of how to tackle end of life distress in patients, whose biggest suffering is of not of somatic but rather psychological origins. Despite of having current psychopharmacological tools, these seem to be accompanied by many adverse effects and are ineffective in many patients, forcing the experts to study alternative methods such as psychedelic assisted psychotherapy. This paper is addressing the issues of such a novel approach as psychedelic assisted psychotherapy is and responding the major ethical concerns surrounding these drugs. Considering the legal status of psychedelic drug, careful approach is applied to ensure, that this new therapeutic method, which is now being studied, is of no harm to the patients, providing substantial benefits to the wellbeing of the ill in accordance with the basic ethical principles. In conclusion this paper is highlighting the importance of reexamining psychedelic assisted psychotherapy as a palliative treatment to the patients with terminal illness, who are suffering from anticipatory grief and to who it ought to be helped to come to peace during the last months of their lives

¿Es posible desarrollar investigaciones clínicas utilizando sustancias psicodélicas en Uruguay?: pasado y presente de las investigaciones sobre el potencial medicinal de los psicodélicos / Is it possible to develop clinical research using psychedelic substances in Uruguay ?: past and present of research on the medicinal potential of psychedelics

Los psicodélicos son sustancias capaces de alterar la conciencia, a través de su efecto sobre la transmisión serotoninérgica en el sistema nervioso central. En sus formas de ingesta tradicional son utilizados en rituales, con fines espirituales y medicinales. En el campo científico, dichas sustancias fueron estudiadas para posibles aplicaciones psicoterapéuticas en el período 1950-1970, y luego fueron excluidas de la investigación clínica durante las posteriores décadas. Sin embargo, desde 1990 asistimos a un «renacimiento de los estudios sobre psicodélicos¼, donde estas sustancias están siendo estudiadas en su potencial clínico para el tratamiento de distintos trastornos menta-les. El presente artículo describe y reflexiona sobre la historia de estas investigaciones en Uruguay y en el mundo, tanto en su primera etapa (1950-1970) como en su renacimiento posterior (1990-actualidad), dejando planteado un escenario en el que sea posible avanzar en el campo de las investigaciones clínicas con psicodélicos en nuestro país.

Psychedelics are substances capable of altering consciousness, through their effect on serotonergic transmission within the central nervous system. In their traditional uses, psychedelics are consumed during rituals, for spiritual and medicinal purposes. In the scientific field, these substances were studied because of their possible psychotherapeutic applications in the period 1950-1970. Afterwards, psychedelics were banned from clinical research for decades. Nevertheless, since 1990 we are witnessing a "renaissance of psychedelic studies", where these substances are being studied because of their clinical potential applications for the treatment of different mental disorders. The current article describes and analyzes the history of these research in Uruguay and in the world, both in its first stage (1950-1970) and in the present "renaissance" (1990-present). The article suggests a future scenario, where Uruguay could play a major role in the field of psychedelic research.

O renascimento dos psicodélicos como potenciais agentes psicoterapêuticos: trajetória, avanços recentes e perspectivas / The renaissance of psychedelics as potential psychotherapeutic agents: trajectory, recent advances and perspectives

Utilizados em vários contextos pela humanidade desde tempos imemoriais até os dias atuais, os psicodélicos despertaram a atenção dos pesquisadores na primeira metade do século passado. Desde então, mesmo com o longo período de restrições às pesquisas científicas devido à implementação da Controlled Substance Act em 1970, inúmeras investigações, principalmente nos últimos anos, vêm indicando o renascimento dos psicodélicos como importantes ferramentas em psicoterapia assistida. Esta revisão narrativa pretende divulgar a trajetória de pesquisa de psicodélicos selecionados (LSD, psilocibina, ayahuasca e MDMA), lançando luz sobre estudos clínicos que indicam a eficácia e a segurança médica dessas substâncias no tratamento de distúrbios mentais como depressão, ansiedade, dependência química e transtorno de estresse pós-traumático. Adicionalmente, também são apontados alguns eventos históricos e culturais relevantes que, de alguma forma, dialogam com esta trajetória.(AU)

Used in various contexts by mankind from immemorial time to nowadays, psychedelics aroused the attention of researchers in the first half of last century. Since then, even with the long period of restrictions on scientific research due to the implementation of the Controlled Substance Act in 1970, accumulated investigations, especially in recent years, have been indicating the renaissance of psychedelics as important tools in assisted psychotherapy. This narrative review intends to disclose the research trajectory of selected psychedelics (LSD, psilocybin, ayahuasca and MDMA) shedding light on clinical studies which support medical efficacy and safety of these substances to treat mental diseases such as depression, anxiety, substance use disorder and post-traumatic stress disorder. Additionally, some relevant historical and cultural events that somehow had dialogued with this trajectory are also approached.(AU)

Utilizados en diversos contextos por la humanidad desde tiempos inmemoriales hasta nuestros días, los psicodélicos despertaron la atención de los investigadores en la primera mitad del siglo pasado. Desde entonces, incluso con el largo período de restricciones en las investigaciones científicas debido a la implementación de la Controlled Substance Act en 1970, numerosas investigaciones, principalmente en los últimos años, han indicado el resurgimiento de los psicodélicos como herramientas importantes en la psicoterapia asistida. Esta revisión narrativa tiene como objetivo dar a conocer la trayectoria de investigación de psicodélicos seleccionados (LSD, psilocibina, ayahuasca y MDMA), arrojando luz sobre estudios clínicos que demuestran la eficacia médica y la seguridad de estas sustancias en el tratamiento de desordenes mentales como la depresión, la ansiedad, dependencia química y trastorno de estrés postraumático. Adicionalmente, también se señalan algunos hechos históricos y culturales relevantes que, de alguna manera, dialogan con esta trayectoria.(AU)

3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for victims of sexual abuse with severe post-traumatic stress disorder: an open label pilot study in Brazil

Objective: To conduct Brazil's first clinical trial employing 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder (PTSD), given its high prevalence resulting from epidemic violence. Methods: Of 60 volunteers, four matched the inclusion & exclusion criteria. Three patients with PTSD secondary to sexual abuse (diagnosed by the Structured Clinical Interview for DSM-IV and the Clinician Administered PTSD Scale for DSMV-4 [CAPS 4]) completed enrollment and treatment, following a standardized Multidisciplinary Association for Psychedelic Studies protocol consisting of 15 weekly therapy sessions: three with orally administered MDMA with concurrent psychotherapy and music, spaced approximately 1 month apart. CAPS-4 scores two months after the final MDMA session were the primary outcome. Results: No serious adverse events occurred. The most frequent adverse events were somatic pains and anguish. CAPS-4 reductions were always greater than 25 points. The final scores were 61, 27, and 8, down from baseline scores of 90, 78, and 72, respectively. All reductions were greater than 30%, which is indicative of clinically significant improvement. Secondary outcomes included lower Beck Depressive Inventory scores and higher Post-Traumatic Growth Inventory and Global Assessment of Functioning scores. Conclusions: Considering the current limitations in safe and efficacious treatments for PTSD and recent studies abroad with larger patient samples, MDMA-assisted psychotherapy could become a viable treatment in Brazil. Clinical trial registration: RBR-6sq4c9

Psicodélicos y muerte digna. Uso de sustancias psicodélicas al final de la vida / Psicodélicos e morte digna. O uso de psicodélicos no final da vida / Psychedelics and dignified death. Use of psychedelic substances at the end of life

Objetivo: repensar el potencial de los psicodélicos para la construcción de un marco psicoespiritual al final de la vida. Síntesis del contenido: con las recientes investigaciones que reconfirman el potencial de los psicodélicos para lograr experiencias místicas, estáticas y de trascendencia, los diferentes enfoques de atención al paciente moribundo se están enfrentando a una resurgente y revalidada terapia psicodélica y a un emergente paradigma psicoespiritual que procura una muerte digna, atendiendo trastornos psicológicos del final de la vida como la ansiedad, la depresión e incluso el miedo a la misma muerte. La terapia con psicodélicos favorece la construcción de un marco psicoespiritual en el moribundo, el cual está asociado a una mejor protección contra la depresión, la desesperanza, la desmoralización e incluso el deseo de una muerte acelerada. Conclusiones: entre las variables del marco de una muerte digna destaca la autonomía que tiene el moribundo para elegir qué hacer o no hacer con su cuerpo, su enfermedad o el final de su vida. Aquí se expone la necesidad de considerar el uso de psicodélicos para ayudar al moribundo a afrontar su deceso con paz, coraje y, sobre todo, dignidad.

Objetivo: repensar o potencial do uso de psicodélicos para a construção de uma estrutura psicoespiritual no final da vida. Síntese de conteúdo: com as pesquisas mais recentes que confirmam o potencial do uso de psicodélicos para atingir experiências místicas, estáticas e transcendentais, as diferentes abordagens para o cuidado do paciente moribundo trazem uma ressurgente e revalidada terapia com o uso de psicodélicos e um paradigma psicoespiritual emergente que procura uma morte digna, atendendo transtornos psicológicos no final da vida como a ansiedade, a depressão e, inclusive, o medo da própria morte. Essa terapia favorece a construção de uma estrutura psicoespiritual no paciente moribundo que está ligada a uma melhor proteção contra a depressão, a perda da esperança, a desmoralização e até o desejo de uma morte acelerada. Conclusões: entre as variáveis no contexto de uma morte digna destaca-se a autonomia do moribundo para eleger o que fazer ou não com seu corpo, com a doença e com o final da vida. Neste trabalho, é exposta a necessidade de considerar o uso de psicodélicos para ajudar o moribundo a encarar sua morte em paz, coragem e, principalmente, com dignidade.

Objective: To rethink the potential of psychedelics for the construction of a psycho-spiritual framework at the end of life. Content synthesis: With the recent studies that re-confirm the potential of psychedelics to get mystical, static and transcendent experiences, the different approaches to attention at dying patients are facing a resurgent and revalidated psychedelic therapy and an emerging psycho-spiritual paradigm that seeks a dignified death, attending psychological end-of-life disorders such as anxiety, depression and even fear of death itself. Psychedelic therapy favors the construction of a psycho-spiritual framework in the dying person, which is associated with a better protection against depression, despair, demoralization, and even the desire for an accelerated death. Conclusions: The autonomy of the dying person to choose what to do or not to do with his body, illness or the end of his life is a prominent issue among the variables in the framework of a dignified death. This work exposes the need to consider the use of psychedelics in orderto help the dying patient face their decease with peace, courage and, above all, dignity.

Ayahuasca no tratamento da farmacodependência à cocaína: possíveis intervenções terapêuticas? / Ayahuasca in the treatment of cocaine addiction: possible therapeutic interventions?

Alucinógenos (ALU) são substâncias psicoativas que não induzem o indivíduo à dependência, possuem perfil de segurança de uso mais alto quando comparado a outras drogas e baixa capacidade de causar tolerância ao uso. Estudos recentes propõem o uso de ALU como tratamento a algumas doenças e transtornos relacionados ao sistema nervoso central, como a depressão, ansiedade e dependência. Dentre os ALU, a ayahuasca (AYA), cujo princípio ativo é a dimetiltriptamina (DMT), é uma bebida psicoativa amplamente utilizada pelas populações indígenas em rituais religiosos. Existem evidências de que pode ser eficaz no tratamento de dependência relacionada ao álcool e nicotina. No entanto, para a cocaína, a segunda droga ilícita mais utilizada no Brasil e na Europa, não existem muitos estudos. O objetivo deste trabalho foi avaliar o potencial da AYA em prevenir a expressão da sensibilização comportamental (SC) induzida pela cocaína e as repercussões neuroquímicas do tratamento em camundongos C57Bl/6. Para tanto, foi avaliada a influência da administração aguda de AYA (1,76; 3,0; 17,6; 30,0 mg/kg de DMT v.o.) na atividade locomotora dos animais em campo aberto (CA). Como não houve diferença estatística na distância percorrida durante a análise, as duas menores doses (1,76 e 3,0 mg/kg de DMT v.o.) foram escolhidas como doses iniciais para a realização do protocolo de prevenção à expressão da SC induzida pela cocaína. Inicialmente, os animais foram habituados no CA durante 3 dias consecutivos após a administração de solução salina 0,9% i.p. No 4o dia experimental, os animais receberam, durante 10 dias alternados, cocaína 10 mg/kg ou salina 0,9% i.p. e foram submetidos diretamente à avaliação da atividade locomotora no CA por 30 minutos. Vinte e quatro horas depois, receberam, durante 8 dias consecutivos, água ou AYA (1,76 ou 3,0 mg/kg de DMT v.o.) e após 30 minutos da administração, foram colocados no CA por 30 minutos para análise da atividade locomotora. No dia seguinte, os camundongos foram desafiados com uma administração de salina. E, no último dia experimental, foi realizado um desafio com cocaína, sempre colocando o animal no CA por 30 minutos. Nessas doses, a AYA não foi eficaz em prevenir a expressão da SC induzida pela cocaína. Dessa forma, avaliamos doses superiores de AYA (15, 30 e 45 mg/kg de DMT v.o.), as quais foram capazes de prevenir a expressão da SC à cocaína. Assim, o protocolo experimental foi novamente realizado com a menor dose (15 mg/kg de DMT v.o.), ao término do protocolo experimental, os animais foram eutanasiados e tiveram seu córtex pré-frontal, estriado e hipocampo dissecados para análise por immunoblotting dos receptores serotoninérgicos 5-HT1A e 5-HT2A. No entanto, não foram não observadas diferenças significativas ao comparar o nível proteico dos receptores nos grupos experimentais. Dessa forma, esses resultados sugerem que a AYA pode ser uma boa estratégia terapêutica para a dependência em cocaína, abrindo caminho para novos estudos

Psychedelics (PSY) are psychoactive substances that do not induce the individual to addiction, have a higher use safety profile when compared to other drugs and low ability to cause tolerance to use. Recent studies propose the use of PSY as a treatment for some diseases and disorders related to the central nervous system, such as depression, anxiety and addiction. Among the PSY, ayahuasca (AYA), whose active component is dimethyltryptamine (DMT), is a psychoactive drink widely used by indigenous populations in religious rituals. There is evidence that it may be effective in treating alcohol and nicotine addiction. However, for cocaine, the second most widely used illicit drug in Brazil and Europe, there are not many studies. The aim of this study was to evaluate the potential of AYA in preventing cocaine-induced behavioral sensitization (BS) expression and the neurochemical repercussions of this treatment in C57Bl/6 mice. Thus, we evaluated the influence of acute administration of AYA (1.76; 3.0; 17.6; 30.0 mg/kg of DMT, orally) on the locomotor activity of animals in the open field (OF). As there was no statistical difference in the distance travelled during the analysis, the two lowest doses (1.76 and 3.0 mg/kg of DMT, orally) were chosen as initial doses to perform the cocaine-induced expression prevention protocol. First, animals were habituated to OF for 3 consecutive days following administration of saline 0.9% i.p. On the fourth experimental day, the animals received for 10 alternate days cocaine 10 mg/kg or saline 0,9% i.p. and were directly submitted to the evaluation of locomotor activity in OF for 30 minutes. Twenty-four hours later they received, for 8 consecutive days, water or AYA (1.76 or 3.0 mg/kg of DMT, orally), and 30 minutes after administration, they were placed in the OF for 30 minutes for analysis of locomotor activity. The next day, the mice were challenged with saline administration. On the last experimental day, a cocaine challenge was performed, always placing the animal in the OF for 30 minutes. At these doses, AYA was not effective in preventing cocaine-induced expression of BS. Thus, we evaluated higher doses of AYA (15, 30 and 45 mg/kg of DMT, orally), which were able to prevent the expression of cocaine-induced BS. Thus, the experimental protocol was again performed with the lowest dose (15 mg/kg of DMT, orally). At the end of the experimental protocol, the animals were euthanized and their prefrontal cortex, striatum and hippocampus were dissected for serotonergic receptor 5-HT1A and 5-HT2A by immunoblotting. However, no significant differences were observed when comparing receptor protein level in the experimental groups. Thus, these results suggest that AYA may be a good therapeutic strategy for cocaine addiction, paving the way for further studies

Long-term effects of ayahuasca in patients with recurrent depression: a 5-year qualitative follow-up

Background Ayahuasca is a botanical hallucinogenic preparation traditionally used by indigenous populations of Northwestern Amazonian countries for ritual and therapeutic purposes. It is rich in β-carboline alkaloids and N,N-dimethyltryptamine (DMT). Preclinical, observational, and experimental studies suggest that ayahuasca and its alkaloids have anxiolytic and antidepressive effects. We recently reported in an open-label trial that ayahuasca administration was associated with significant decreases in depression symptoms for 2-3 weeks after the experimental session in 17 patients with treatment-resistant major depressive disorder. Objectives To investigate if the experiment had any long-lasting effects on patients Methods Eight patients were interviewed 4 to 7 years after ayahuasca intake. Results Our results suggest that ayahuasca was well tolerated and that symptom reductions were limited to a few weeks. Importantly, most patients believed that the experience was among the most important of their lives, even 4-7 years later. Discussion To the best of our knowledge, this is the first long-term follow-up of a clinical sample that participated in an ayahuasca trial. Further studies with different and repeated dosing should be designed to further explore the antidepressive and anxiolytic effects of ayahuasca.