OPEN Foundation

Salvia / Salvinorin A

22-azidosalvinorin A exhibits antidepressant-like effect in mice

February 17, 2017 / Depression, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Publications, Salvia / Salvinorin A / By / , , , ,

Abstract

The increasing cases of depression has made the searches for new drugs and understanding of the underligning neurobiology of this psychiatric disorder a necessity. Here, we modified the structure of salvinorin A (a known halucinogen) and investigated antidepressant-like activity of its four derivatives; 22-methylsulfanylsalvinorin A(SA1), 2-O-cinnamoylsalvinorin B (CSB), 22-azidosalvinorin A (SA2), and 2-O-(4’-azidophenylsulfonyl)salvinorin B (SA3). Prior to behavioural tests (Irwin test, open field test – OFT, forced swimming test – FST and tail suspension test – TST), SA1 was prepared by reacting salvinorin B and methylthioacetic acid with 89% yield; CSB was obtained from the reaction of salvinorin B and cinnamic acid with 92% yield; SA2 was obtained from the reaction of salvinorin B and azidoacetic acid with 81% yield; and SA3 was prepared by reacting salvinorin B with 4-azidophenylsulfonyl chloride with 80% yield. Oral treatment of mice with these derivatives (1–1000 mg/kg) did not elicit toxic sign or death. Unlike SA, SA1, CSB and SA3, treatment with SA2 (5, 10 and 20 mg/kg) decreased the immobility (TST and FST) and swimming time (FST) without altering locomotor activity in OFT. A decrease in the immobility time in TST and FST confirmed antidepressant-like property of SA2. Although p-chlorophenylalanine (serotonin depletor) or WAY100635 (selective 5-HT1A receptor antagonist) did not attenuate effect of SA2, alpha-methyl-para-tyrosine (catecholamine depletor) and prazosin (selective α1-receptor antagonist) attenuated this effect. SA2 mildly inhibited monoamine oxidase and showed affinity for α1A, α1B, α1D and κ-opioid receptor subtypes. In summary, SA2 induced monoamine-mediated antidepressant-like effect.

Fajemiroye, J. O., Prabhakar, P. R., da Cunha, C. L., Costa, E. A., & Zjawiony, J. K. (2017). 22-Azidosalvinorin A exhibits antidepressant-like effect in mice. European Journal of Pharmacology. 10.1016/j.ejphar.2017.02.031
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A unique natural selective kappa-opioid receptor agonist, salvinorin A, and its roles in human therapeutics

February 10, 2017 / Other subjects, Papers, Psychology, Publications, Salvia / Salvinorin A / By / , , ,

Abstract

Until the mid-60s, only the Mazatecs, an indigenous group from Oaxaca, Mexico, used Salvia Divinorum (S. divinorum) due to its hallucinogen properties.

Later it was found that the hallucinogen effects of this plant were caused by the presence of a neoclerodane diterpene Salvinorin A (salvinorin A), which is a highly selective agonist of kappa-opioid receptor (KOR) that cause more intense hallucinations than the common hallucinogens as lysergic acid, mushrooms, ecstasy and others. In fact, smoking of only 200–500 μg of S. divinorum leaves is enough to produce these effects thus making it the most potent natural occurring hallucinogen known.

Due to its legal status in various countries, this compound has gained a worldwide popularity as a drug of abuse with an easy access through smartshops and internet.

Furthermore, salvinorin A gathered an increased interest in the scientific community thanks to its unique structure and properties, and various studies demonstrated that salvinorin A has antinociceptive, antidepressant, in some circumstances pro-depressant and anti-addictive effects that have yielded potential new avenues for research underlying salvinorin A and its semi-synthetic analogs as therapeutic agents.

Cruz, A., Domingos, S., Gallardo, E., & Martinho, A. (2017). A unique natural selective kappa-opioid receptor agonist, salvinorin A, and its roles in human therapeutics. Phytochemistry. 10.1016/j.phytochem.2017.02.001
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Biosynthesis of the psychotropic plant diterpene salvinorin A: Discovery and characterization of the Salvia divinorum clerodienyl diphosphate synthase

November 19, 2016 / Addiction, Chemistry, Neuroscience, Other subjects, Papers, Psychopharmacology, Publications, Salvia / Salvinorin A / By / , , , , , ,

Abstract

Salvia divinorum commonly known as diviner’s sage, is an ethnomedicinal plant of the mint family (Lamiaceae). S. divinorum is rich in clerodane-type diterpenoids, which accumulate predominantly in leaf glandular trichomes. The main bioactive metabolite, salvinorin A, is the first non-nitrogenous natural compound known to function as an opioid-receptor agonist, and is undergoing clinical trials for potential use in treating neuropsychiatric diseases and drug addictions. We report here the discovery and functional characterization of two S. divinorumditerpene synthases (diTPSs), the ent-copalyl diphosphate (ent-CPP) synthase SdCPS1, and the clerodienyl diphosphate (CLPP) synthase SdCPS2. Mining of leaf- and trichome-specific transcriptomes revealed five diTPSs, two of which are class II diTPSs (SdCPS1-2) and three are class I enzymes (SdKSL1-3). Of the class II diTPSs, transient expression in Nicotiana benthamianaidentified SdCPS1 as an ent-CPP synthase, which is prevalent in roots and, together with SdKSL1, exhibits a possible dual role in general and specialized metabolism. In vivo co-expression and in vitro assays combined with NMR analysis identified SdCPS2 as a CLPP synthase. A role of SdCPS2 in catalyzing the committed step in salvinorin A biosynthesis is supported by its biochemical function, trichome-specific expression and absence of additional class II diTPSs in S. divinorum. Structure-guided mutagenesis revealed four catalytic residues that enabled the re-programming of SdCPS2 activity to afford four distinct products, thus advancing our understanding of how neo-functionalization events have shaped the array of different class II diTPS functions in plants, and may promote synthetic biology platforms for a broader spectrum of diterpenoid bioproducts.

Pelot, K. A., Mitchell, R., Kwon, M., Hagelthorn, D. M., Wardman, J. F., Chiang, A., … & Zerbe, P. (2016). Biosynthesis of the psychotropic plant diterpene salvinorin A: Discovery and characterization of the Salvia divinorum clerodienyl diphosphate synthase. The Plant Journal. 10.1111/tpj.13427
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Chemogenomics knowledgebase and systems pharmacology for hallucinogen target identification-Salvinorin A as a case study

August 8, 2016 / Addiction, Neuroscience, Other subjects, Papers, Psychopharmacology, Publications, Salvia / Salvinorin A / By /

Abstract

Drug abuse is a serious problem worldwide. Recently, hallucinogens have been reported as a potential preventative and auxiliary therapy for substance abuse. However, the use of hallucinogens as a drug abuse treatment has potential risks, as the fundamental mechanisms of hallucinogens are not clear. So far, no scientific database is available for the mechanism research of hallucinogens. We constructed a hallucinogen-specific chemogenomics database by collecting chemicals, protein targets and pathways closely related to hallucinogens. This information, together with our established computational chemogenomics tools, such as TargetHunter and HTDocking, provided a one-step solution for the mechanism study of hallucinogens. We chose salvinorin A, a potent hallucinogen extracted from the plant Salvia divinorum, as an example to demonstrate the usability of our platform. With the help of HTDocking program, we predicted four novel targets for salvinorin A, including muscarinic acetylcholine receptor 2, cannabinoid receptor 1, cannabinoid receptor 2 and dopamine receptor 2. We looked into the interactions between salvinorin A and the predicted targets. The binding modes, pose and docking scores indicate that salvinorin A may interact with some of these predicted targets. Overall, our database enriched the information of systems pharmacological analysis, target identification and drug discovery for hallucinogens.

Xu, X. (2015). Chemogenomics Knowledgebase and Systems Pharmacology for Hallucinogen Target Identification-Salvinorin A as a Case Study (Doctoral dissertation, University of Pittsburgh). 10.1016/j.jmgm.2016.08.001
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Cytotoxic Effects of Salvinorin A, A Major Constituent of Salvia divinorum

August 1, 2016 / Papers, Safety, Salvia / Salvinorin A, Toxicology / By / , ,

Abstract

S. divinorum is a psychoactive plant that has been consumed as a recreational drug of abuse in the last years. Salvinorin A is its main constituent, and is responsible for the observed psychoactive effects. Both S. divinorum and salvinorin A have become controlled drugs in several countries, but they are not listed in the Schedules of the United Nations Drug Conventions. Regarding the effects of S. divinorum consumption, almost all studies are based on in vivo or on surveys, and there are no studies in vitro on its toxicity. Furthermore, all studies are focused on the acute toxicological effects of the plant. So, it is of utmost importance to further investigate the effects of S. divinorum and salvinorin A, particularly using in vitro models, after prolonged exposures. In this context, the present work evaluated the in vitro toxicity induced by S. divinorum or salvinorin A in six cell lines, through MTT assays and LC50 determination. Overall, results showed that both S. divinorum and salvinorin A are cytotoxic, dose- and time-dependent. Also, Hep G2 and Caco 2 (to a lesser extent) cells showed lower sensitivity to S. divinorum and salvinorin A when compared to the other studied cell lines. To our knowledge, this is the first work focused on the in vitro toxicity of S. divinorum and salvinorin A using a variety of cell lines, which are extensively described in literature and have been widely used in several in vitro studies.
Martinho, A., M Silva, S., & Gallardo, E. (2016). Cytotoxic Effects of Salvinorin A, A Major Constituent of Salvia divinorum. Medicinal Chemistry, 12(5), 432-440. 10.2174/1573406411666151005105617
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Clinical Applications of Hallucinogens: A Review

July 1, 2016 / Cacti / Mescaline, Iboga / Ibogaine, Ketamine, LSD, MDMA, Mushrooms / Psilocybin, Other substances, Papers, Psychiatry, Psychology, Psychotherapy, Publications, Salvia / Salvinorin A / By / , ,

Abstract

Hallucinogens fall into several different classes, as broadly defined by pharmacological mechanism of action, and chemical structure. These include psychedelics, entactogens, dissociatives, and other atypical hallucinogens. Although these classes do not share a common primary mechanism of action, they do exhibit important similarities in their ability to occasion temporary but profound alterations of consciousness, involving acute changes in somatic, perceptual, cognitive, and affective processes. Such effects likely contribute to their recreational use. However, a growing body of evidence indicates that these drugs may have therapeutic applications beyond their potential for abuse. This review will present data on several classes of hallucinogens with a particular focus on psychedelics, entactogens, and dissociatives, for which clinical utility has been most extensively documented. Information on each class is presented in turn, tracing relevant historical insights, highlighting similarities and differences between the classes from the molecular to the behavioral level, and presenting the most up-to-date information on clinically oriented research with these substances, with important ramifications for their potential therapeutic value.

Garcia-Romeu, A., Kersgaard, B., & Addy, P. H. (2016). Clinical applications of hallucinogens: A review. Experimental and clinical psychopharmacology, 24(4), 229. 10.1037/pha0000084
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Salvia divinorum: toxicological aspects and analysis in human biological specimens

June 9, 2016 / Ethnobotany, Other subjects, Papers, Publications, Salvia / Salvinorin A, Toxicology / By / , , ,

Abstract

The identification and quantitation of the main psychoactive component of Salvia divinorum (salvinorin A) in biological specimens are crucial in forensic and clinical toxicology. Despite all the efforts made, its uncontrolled abuse has increased quickly, exposing its users’ health to serious risks both in the short and long term. The use of alternative biological matrices in toxicological analyzes can be advantageous as complementary postmortem samples, or in situations when neither blood nor urine can be collected; they may be useful tools in those determinations, providing important information about prior exposure. The aim of this article is to present a brief summary of legal aspects of Salvia divinorum and salvinorin A, including the methods used for the determination of the latter in biological matrices.

Margalho, C., Corte-Real, F., López-Rivadulla, M., & Gallardo, E. (2016). Salvia divinorum: toxicological aspects and analysis in human biological specimens. Bioanalysis, (0). http://dx.doi.org/10.4155/bio-2016-0067

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"Quite a Profoundly Strange Experience": An Analysis of the Experiences of Salvia divinorum Users

May 13, 2016 / Anthropology, Other disciplines, Other subjects, Papers, Publications, Salvia / Salvinorin A, Sociology / By / , ,

Abstract

Salvia divnorum (an intense hallucinogen) is currently illegal in New Zealand under the 2014 Psychoactive Substances Amendment Act. Despite this, there is a scarcity of research surrounding Salvia divinorum and its effects in a New Zealand context. To explore the experiences of Salvia divinorum users, an anonymous questionnaire was advertised through flyers placed in locations where young adults congregate. A total of 393 people took part in the online questionnaire in 2010-2011, while salvia was legally available in New Zealand; 167 respondents had used salvia. Thematic analysis was used to analyze the resulting open-ended questionnaire data and three key themes were identified: the effects of salvia; the importance of set and setting; salvia use and pleasure/not-pleasure. Recreational use of salvia was situated within a broader drug landscape, with participants being drug experienced and “drug wise” (Measham, Aldridge, and Parker 2001). Use of salvia also appeared to be intermittent, with its use referred to as a novel experience. Thus, the recent criminalization of salvia under the 2014 Act may see a significant decline in use as experienced drug users look elsewhere for novel drug experiences.

Hutton, F., Kivell, B., & Boyle, O. (2016). “Quite a Profoundly Strange Experience”: An Analysis of the Experiences of Salvia divinorum Users. Journal of Psychoactive Drugs, 1-8. http://dx.doi.org/10.1080/02791072.2016.1179376

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“Quite a Profoundly Strange Experience”: An Analysis of the Experiences of Salvia divinorum Users

May 13, 2016 / Anthropology, Other disciplines, Other subjects, Papers, Publications, Salvia / Salvinorin A, Sociology / By / , ,

Abstract

Salvia divnorum (an intense hallucinogen) is currently illegal in New Zealand under the 2014 Psychoactive Substances Amendment Act. Despite this, there is a scarcity of research surrounding Salvia divinorum and its effects in a New Zealand context. To explore the experiences of Salvia divinorum users, an anonymous questionnaire was advertised through flyers placed in locations where young adults congregate. A total of 393 people took part in the online questionnaire in 2010-2011, while salvia was legally available in New Zealand; 167 respondents had used salvia. Thematic analysis was used to analyze the resulting open-ended questionnaire data and three key themes were identified: the effects of salvia; the importance of set and setting; salvia use and pleasure/not-pleasure. Recreational use of salvia was situated within a broader drug landscape, with participants being drug experienced and “drug wise” (Measham, Aldridge, and Parker 2001). Use of salvia also appeared to be intermittent, with its use referred to as a novel experience. Thus, the recent criminalization of salvia under the 2014 Act may see a significant decline in use as experienced drug users look elsewhere for novel drug experiences.

Hutton, F., Kivell, B., & Boyle, O. (2016). “Quite a Profoundly Strange Experience”: An Analysis of the Experiences of Salvia divinorum Users. Journal of Psychoactive Drugs, 1-8. http://dx.doi.org/10.1080/02791072.2016.1179376

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Depressant Effects of Salvia divinorum Involve Disruption of Physiological Sleep

April 1, 2016 / Papers, Psychopharmacology, Publications, Safety, Salvia / Salvinorin A / By / , , , , ,

Abstract

Although Salvia divinorum is traditionally known as a ‘mind-altering’ or psychoactive herb used, among others things, as a tranquilizer, this property has not been validated with regard to its efficacy and safety. The objective of this study is to provide evidence for the sedative effects of S. divinorum and discriminate the nature of the responsible constituents by examining different experimental models. A battery of tests, including the open-field, hole-board, exploration cylinder, plus-maze and sodium pentobarbital-induced hypnosis potentiation, were used in mice after administration of non-polar, medium polar and/or polar extracts of the plant (10, 30 and 100 mg/kg). Polysomnographic analysis in rats receiving an active medium polar extract (10 and 100 mg/kg) containing salvinorins was also assessed to study the effects of this plant on sleep architecture. All tested extracts produced significant sedative-like responses, although those of the medium polar extract were more pronounced in mice. The sedative effect of this latter extract, which contains a mixture of salvinorins, caused fragmented sleep architecture in rats by diminishing rapid eye movement (REM) sleep and increased the quiet awake stage at 10 and 100 mg/kg. Our results provide evidence that S. divinorum exhibits sedative-like depressant properties that alter physiological sleep architecture.

González‐Trujano, M. E., Brindis, F., López‐Ruiz, E., Ramírez‐Salado, I., Martínez, A., & Pellicer, F. (2016). Depressant Effects of Salvia divinorum Involve Disruption of Physiological Sleep. Phytotherapy Research. http://dx.doi.org/10.1002/ptr.5617

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7 May - Psychedelics, Nature & Mental Health with Sam Gandy

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