Search

Background: Diviner's sage (Salvia divinorum; Lamiaceae) is the source of the powerful hallucinogen salvinorin A (SalA). This neoclerodane diterpenoid is an agonist of the human Κ-opioid receptor with potential medical applications in the treatment of chronic pain, addiction, and post-traumatic stress disorder. Only two steps of the approximately twelve step biosynthetic sequence leading to SalA have been resolved to date. Results: To facilitate pathway elucidation in this ethnomedicinal plant species, here we report a chromosome level genome assembly. A high-quality genome sequence was assembled with an N50 value of 41.4 Mb and a BUSCO completeness score of 98.4%. The diploid (2n = 22) genome of ~ 541 Mb is comparable in size and ploidy to most other members of this genus. Two diterpene biosynthetic gene clusters were identified and are highly enriched in previously unidentified cytochrome P450s as well as crotonolide G synthase, which forms the dihydrofuran ring early in the SalA pathway. Coding sequences for other enzyme classes with likely involvement in downstream steps of the SalA pathway (BAHD acyl transferases, alcohol dehydrogenases, and O-methyl transferases) were scattered throughout the genome with no clear indication of clustering. Differential gene expression analysis suggests that most of these genes are not inducible by methyl jasmonate treatment. Conclusions: This genome sequence and associated gene annotation are among the highest resolution in Salvia, a genus well known for the medicinal properties of its members. Here we have identified the cohort of genes responsible for the remaining steps in the SalA pathway. This genome sequence and associated candidate genes will facilitate the elucidation of SalA biosynthesis and enable an exploration of its full clinical potential. [ABSTRACT FROM AUTHOR]

Abstract Background Diviner’s sage (Salvia divinorum; Lamiaceae) is the source of the powerful hallucinogen salvinorin A (SalA). This neoclerodane diterpenoid is an agonist of the human Κ-opioid receptor with potential medical applications in the treatment of chronic pain, addiction, and post-traumatic stress disorder. Only two steps of the approximately twelve step biosynthetic sequence leading to SalA have been resolved to date. Results To facilitate pathway elucidation in this ethnomedicinal plant species, here we report a chromosome level genome assembly. A high-quality genome sequence was assembled with an N50 value of 41.4 Mb and a BUSCO completeness score of 98.4%. The diploid (2n = 22) genome of ~ 541 Mb is comparable in size and ploidy to most other members of this genus. Two diterpene biosynthetic gene clusters were identified and are highly enriched in previously unidentified cytochrome P450s as well as crotonolide G synthase, which forms the dihydrofuran ring early in the SalA pathway. Coding sequences for other enzyme classes with likely involvement in downstream steps of the SalA pathway (BAHD acyl transferases, alcohol dehydrogenases, and O-methyl transferases) were scattered throughout the genome with no clear indication of clustering. Differential gene expression analysis suggests that most of these genes are not inducible by methyl jasmonate treatment. Conclusions This genome sequence and associated gene annotation are among the highest resolution in Salvia, a genus well known for the medicinal properties of its members. Here we have identified the cohort of genes responsible for the remaining steps in the SalA pathway. This genome sequence and associated candidate genes will facilitate the elucidation of SalA biosynthesis and enable an exploration of its full clinical potential.

Schizophrenia is a complex mental health disorder with positive, negative and cognitive symptom domains. Approximately one third of patients are resistant to currently available medication. New therapeutic targets and a better understanding of the basic biological processes that drive pathogenesis are needed in order to develop therapies that will improve quality of life for these patients. Several drugs that act on neurotransmitter systems in the brain have been suggested to model aspects of schizophrenia in animals and in man. In this paper, we selectively review findings from dopaminergic, glutamatergic, serotonergic, cannabinoid, GABA, cholinergic and kappa opioid pharmacological drug models to evaluate their similarity to schizophrenia. Understanding the interactions between these different neurotransmitter systems and their relationship with symptoms will be an important step towards building a coherent hypothesis for the pathogenesis of schizophrenia.

Ulises Coffeen, Francisco Pellicer Research in Neurosciences, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Mexico City, México Abstract: Salvia divinorum is a herbal plant native to the southwest region of Mexico. Traditional preparations of this plant have been used in illness treatments that converge with inflammatory conditions and pain. Currently, S. divinorum extracts have become popular in several countries as a recreational drug due to its hallucinogenic effects. Its main active component is a diterpene named salvinorin A (SA), a potent naturally occurring hallucinogen with a great affinity to the κ opioid receptors and with allosteric modulation of cannabinoid type 1 receptors. Recent biochemical research has revealed the mechanism of action of the anti-inflammatory and analgesic effect of SA at the cellular and molecular level. Nevertheless, because of their short-lasting and hallucinogenic effect, the research has focused on discovering a new analogue of SA that is able to induce analgesia and reduce inflammation with a long-lasting effect but without the hallucinatory component. In this review, we explore the role of S. divinorum, SA and its analogues. We focus mainly on their analgesic and anti-inflammatory roles but also mention their psychoactive properties. Keywords: Salvia divinorum, salvinorin A, pain, inflammation, psychoactivity

The psychoactive plant Salvia divinorum has long been used medicinally by Indigenous people from southern Mexico, the only place where it is endemic, and is now studied by pharmaceutical researchers. I analyze competing ways the two groups "make medicine" with salvia, attending simultaneously to material/embodied and semiotic/linguistic dimensions of those practices. I introduce two concepts – stripping and enrobing – to show that differences in how the groups interact with salvia have ethical and political consequences. Those repercussions matter because salvia is but one of many plants important to marginalized groups whose ties to them are threatened by international medical interests. [ABSTRACT FROM AUTHOR]

Betaflexiviridae is a family of plant-infecting RNA viruses with 11 recognized genera, of which genomes have diverse organization with three to six open reading frames (ORFs). A genome sequence of a novel Betaflexiviridae species, named Salvia divinorum RNA virus 1 (SdRV1), was identified in Salvia divinorum, herbal mint plant with hallucinogenic properties. The SdRV1 genome was predicted to have four ORFs encoding a replicase polyprotein (REP), a movement protein (MP), a coat protein (CP), and a putative nucleic acid-binding protein (NBP). Phylogenetic analyses based on the REP, MP, and CP sequences indicated that SdRV1 is most closely related to members of the genus Citrivirus. However, the genome organization of SdRV1 is the same as that of the genus Prunevirus. Moreover, the SdRV1 NBP had greatest sequence similarity with members of the genus Carlavirus. A complex evolutionary history involving ancestors of these three genera might have resulted in the unique phylogenetic position of SdRV1, which could be considered the founding member of a new genus in the family Betaflexiviridae. The genome sequence of SdRV1 might be useful for studies on the evolution of Betaflexiviridae. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Salvia divinorum is a medicinal plant traditionally used in hallucinogenic ethnopharmacological practices and for its analgesic and antinflammatory properties. Its active compounds include diterpenes known as salvinorins which act as potent κ opioid receptor agonists. Aim of the study Given its effects in acute animal models of pain, as well as its antinflammatory attributes, we decided to investigate the analgesic effects of an SD extract in neuropathic (sciatic loose nerve ligature) and inflammatory (intra plantar carrageenan) pain models in rats. We also determined in this study the electrocorticographic changes to correlate similar hallucinogenic state and behavior as those produced in humans. Material and methods Mechanical and thermonociceptive responses, plantar test and von Frey assay, respectively, were measured in adult Wistar rats 30 min, 3 h and 24 h after the intraperitoneal administration of saline or an hydroponic SD extract. We also evaluated carbamazepine and celecoxib, as gold reference drugs, to compare its antinociceptive effects. Results Our results showed that administration of SD extract induced antialgesic effects in both neuropathic and inflammatory pain models. All those effects were blocked by nor-binaltorphimine (a Kappa opioid receptor antagonist). Moreover, it was observed an increase of the anterior power spectral density and a decrease in the posterior region as electrocorticographic changes. Conclusion The present investigation give evidence that SD is capable to reduce algesic response associated to neuropathic and inflammatory nociception. This study support therapeutic alternatives for a disabling health problem due to the long term pain with high impact on population and personal and social implications. [ABSTRACT FROM AUTHOR]

We developed an immunochromatographic assay (ICA) that enables rapid analysis of salvinorin A (Sal A) in Salvia divinorum within 10 min. The result shows that no Sal A in other samples of Lamiaceae plants was detected, but it could recognize Sal A among other substances in complex samples. The main advantage of the ICA is its high performance in combination with low cost, simplicity, and speed. Our newly developed combined ICA/indirect competitive ELISA(icELISA) system enables analysis of large numbers of samples over short periods of time without cumbersome pretreatments in complex mixtures. This method can complement other instrumental analyses for salvinorins, and could be used to deter S. divinorum abuse. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Salvia divinorum commonly known as diviner's sage, is an ethnomedicinal plant of the mint family (Lamiaceae). Salvia 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. divinorum diterpene synthases (di TPSs), the ent-copalyl diphosphate ( ent- CPP) synthase Sd CPS1, and the clerodienyl diphosphate ( CLPP) synthase Sd CPS2. Mining of leaf- and trichome-specific transcriptomes revealed five di TPSs, two of which are class II di TPSs (Sd CPS1-2) and three are class I enzymes (Sd KSL1-3). Of the class II di TPSs, transient expression in Nicotiana benthamiana identified Sd CPS1 as an ent- CPP synthase, which is prevalent in roots and, together with Sd KSL1, exhibits a possible dual role in general and specialized metabolism. In vivo co-expression and in vitro assays combined with nuclear magnetic resonance ( NMR) analysis identified Sd CPS2 as a CLPP synthase. A role of Sd CPS2 in catalyzing the committed step in salvinorin A biosynthesis is supported by its biochemical function, trichome-specific expression and absence of additional class II di TPSs in S. divinorum. Structure-guided mutagenesis revealed four catalytic residues that enabled the re-programming of Sd CPS2 activity to afford four distinct products, thus advancing our understanding of how neo-functionalization events have shaped the array of different class II di TPS functions in plants, and may promote synthetic biology platforms for a broader spectrum of diterpenoid bioproducts. [ABSTRACT FROM AUTHOR]

Salvia divinorum (Lamiaceae) is an annual herb used by indigenous cultures of Mexico for medicinal and ritual purposes. The biosynthesis of salvinorin A, its major bioactive neo-clerodane diterpenoid, remains virtually unknown. This investigation aimed to identify the enzyme that catalyzes the first reaction of salvinorin A biosynthesis, the formation of (-)-kolavenyl diphosphate [(-)-KPP], which is subsequently dephosphorylated to afford (-)-kolavenol. Peltate glandular trichomes were identified as the major and perhaps exclusive site of salvinorin accumulation in S. divinorum. The trichome-specific transcriptome was used to identify candidate diterpene synthases (diTPSs). In vitro and in planta characterization of a class II diTPS designated as SdKPS confirmed its activity as (-)-KPP synthase and its involvement in salvinorin A biosynthesis. Mutation of a phenylalanine into histidine in the active site of SdKPS completely converts the product from (-)-KPP into ent-copalyl diphosphate. Structural elements were identified that mediate the natural formation of the neo-clerodane backbone by this enzyme and suggest how SdKPS and other diTPSs may have evolved from ent-copalyl diphosphate synthase. [ABSTRACT FROM AUTHOR]

A planta Salvia divinorum Epling & Játiva (SDI), da família Lamiaceae, tem sido usada por séculos pela cultura mazateca e vem ganhando popularidade como droga recreacional nos últimos anos. Seu princípio ativo - Salvinorina A (SA) - é agonista dos receptores opióides kappa, com potencial psicotrópico. A utilização da planta vem crescendo na Europa e na América do Norte, apesar de ainda não existirem provas concretas sobre abuso. A presente revisão da literatura contemporânea aborda as evidências sobre o potencial de abuso de SDI, bem como o crescente uso recreacional, ainda que seja alucinógeno permitido legalmente e de fácil compra em muitos países.The plant Salvia divinorum Epling & Játiva (SDI), of the Lamiaceae family, has been used for centuries by the Mazateca culture and has gained popularity as a recreational drug in the last years. Its active principle, Salvinorin A (SA), is a potentially psychotropic agonist of the kappa opioid receptors. The use of SDI has increased in Europe and North America, although there are no concrete proofs about abuse. The present review discusses current evidence on potential SDI abuse, as well as its increasing recreational use, although it is considered a legalized hallucinogen easily acquired in many countries.

Salvinorin A is a potent hallucinogen, isolated from the ethnomedical plant Salvia divinorum. Salvinorin A is a selective high efficacy kappa-opioid receptor (KOPr) agonist, and thus implicates the KOPr system and its endogenous agonist ligands (the dynorphins) in higher functions, including cognition, and perceptual effects. Salvinorin A is the only selective KOPr ligand to be widely available outside research or medical settings, and salvinorin A- containing products have undergone frequent non-medical use. KOPr/dynorphin systems in the brain are known to be powerful counter-modulatory mechanisms to dopaminergic function, which is important in mood and reward engendered by natural and drug reinforcers (including drugs of abuse). KOPr activation (including by salvinorin A) can thus cause aversion and anhedonia in preclinical models. Salvinorin A is also a completely new scaffold for medicinal chemistry approaches, since it is a non-nitrogenous neoclerodane, unlike all other known opioid ligands. Ongoing efforts have the goal of discovering novel semi-synthetic salvinorin analogs with potential KOPr-mediated pharmacotherapeutic effects (including partial agonist or biased agonist effects), with a reduced burden of undesirable effects associated with salvinorin A.

Opioids are widely used to treat millions suffering from pain, but their analgesic utility is limited due to associated side effects. Herein we report the development and evaluation of a chemical probe exhibiting analgesia and reduced opioid-induced side effects. This compound, kurkinorin (5), is a potent and selective μ-opioid receptor (MOR) agonist (EC50 = 1.2 nM, >8000 μ/κ selectivity). 5 is a biased activator of MOR-induced G-protein signaling over β-arrestin-2 recruitment. Metadynamics simulations of 5's binding to a MOR crystal structure suggest energetically preferred binding modes that differ from crystallographic ligands. In vivo studies with 5 demonstrate centrally mediated antinociception, significantly reduced rewarding effects, tolerance, and sedation. We propose that this novel MOR agonist may represent a valuable tool in distinguishing the pathways involved in MOR-induced analgesia from its side effects. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Covering: 1990 to 2015 The clerodane diterpenoids are a widespread class of secondary metabolites and have been found in several hundreds of plant species from various families and in organisms from other taxonomic groups. These substances have attracted interest in recent years due to their notable biological activities, particularly insect antifeedant properties. In addition, the major active clerodanes of Salvia divinorum can be used as novel opioid receptor probes, allowing greater insight into opioid receptor-mediated phenomena, as well as opening additional areas for chemical investigation. This article provides extensive coverage of naturally occurring clerodane diterpenes discovered from 1990 until 2015, and follows up on the 1992 review by Merritt and Ley in this same journal. The distribution, chemotaxonomic significance, chemical structures, and biological activities of clerodane diterpenes are summarized. In the cases where sufficient information is available, structure activity relationship (SAR) correlations and mode of action of active clerodanes have been presented. [ABSTRACT FROM AUTHOR]

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 surroundingSalvia divinorumand its effects in a New Zealand context. To explore the experiences ofSalvia divinorumusers, 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. [ABSTRACT FROM PUBLISHER]

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. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Salvinorin A is a kappa opioid agonist and the principal psychoactive constituent of the Salvia divinorum plant, which has been used for hallucinogenic effects. Previous research on salvinorin A pharmacokinetics likely underestimated plasma levels typically resulting from the doses administered due to inefficient vaporization and not collecting samples during peak drug effects. Six healthy adults inhaled a single high dose of vaporized salvinorin A (n = 4, 21 mcg/kg; n = 2, 18 mcg/kg). Participant- and monitor-rated effects were assessed every 2 min for 60 min post-inhalation. Blood samples were collected at 13 time points up to 90 min post-inhalation. Drug levels peaked at 2 min and then rapidly decreased. Drug levels were significantly, positively correlated with participant and monitor drug effect ratings. Significant elevations in prolactin were observed beginning 5 min post-inhalation and peaking at 15 min post-inhalation. Cortisol showed inconsistent increases across participants. Hormonal responses were not well correlated with drug levels. This is the first study to demonstrate a direct relationship between changes in plasma levels of salvinorin A and drug effects in humans. The results confirm the efficacy of an inhalation technique for salvinorin A. [ABSTRACT FROM AUTHOR]

S alvia divinorum, a sage plant with leaves that can produce a psychoactive high, has been used for hundreds of years for its psycho-mimetic effects in religious rituals in South America. Salvia has now become popular mainly with adolescents and young adults for the short-lived relatively pleasant experiences many consider a 'legal high' and its ready availability through Internet purchases. The main (psycho)active compound in salvia is S alvinorin A, a potent κ-opioid agonist and although the short and long-term effects have not been examined in sufficient detail, it is widely believed to have low addictive potential and low toxicity. Recent findings, however, seem to suggest that S alvinorin A can precipitate psychiatric symptoms and negatively affect cognition. Its ready availability and increasingly widespread use requires clinicians to have knowledge and awareness of its effects. [ABSTRACT FROM AUTHOR]

The association of substance abuse and psychotic disorders is of interest to clinicians, academics, and lawmakers. Commonly abused substances, such as cannabis, cocaine, amphetamines, and alcohol, have all been associated with substance-induced psychosis. Hallucinogens can induce desired psychedelic effects and undesirable psychomimetic reactions. These are usually transient and resolve once the duration of action is over. Sometimes, these effects persist, causing distress and requiring intervention. This article focuses on the hallucinogenic substance Salvia divinorum, the use of which has been observed, particularly among youth worldwide. We present background information based on a review of the literature and on our own clinical encounters, as highlighted by two original case reports. We hypothesize that consumption of Salvia divinorum could be associated with the development of psychotic disorders. We propose that clinicians routinely inquire about the use of Salvia in patients with substance use disorders or psychotic illnesses. More research is required to assess any relationship between Salvia divinorum and psychosis. Additionally, we advocate increased public and medical awareness of this substance and other emerging drugs of abuse. [ABSTRACT FROM AUTHOR]

Salvinorin A is a potent hallucinogen, isolated from the ethnomedical plant Salvia divinorum. Salvinorin A is a selective high efficacy kappa-opioid receptor (KOPr) agonist, and thus implicates the KOPr system and its endogenous agonist ligands (the dynorphins) in higher functions, including cognition and perceptual effects. Salvinorin A is the only selective KOPr ligand to be widely available outside research or medical settings, and salvinorin A-containing products have undergone frequent nonmedical use. KOPr/dynorphin systems in the brain are known to be powerful countermodulatory mechanisms to dopaminergic function, which is important in mood and reward engendered by natural and chemical reinforcers (including drugs of abuse). KOPr activation (including by salvinorin A) can thus cause aversion and anhedonia in preclinical models. Salvinorin A is also a completely new scaffold for medicinal chemistry approaches, since it is a non-nitrogenous neoclerodane, unlike other known opioid ligands. Ongoing efforts have the goal of discovering novel semi-synthetic salvinorin analogs with potential KOPr-mediated pharmacotherapeutic effects (including partial agonist or biased agonist effects), with a reduced burden of undesirable effects associated with salvinorin A. [ABSTRACT FROM AUTHOR]

Recent social and legal responses to novel psychoactive drugs (NPDs) have been attributed to media panics rather than these substance's actual harms. NPDs, including botanical substances new to Western markets such as Salvia divinorum, newly synthesized analogues such as synthetic cannabinoids and 'bath salts,' and new ways of administering drugs, such as combining prescription cough syrup with soda ('purple drank') have been the target of various forms of legislation at the state and/or federal level. We systematically examine print media coverage of NPDs in the U. S. between 2005 and 2013 to determine whether media attention was temporally associated with legislative change. Results indicate that each drug had a brief window during which it was the focus of sensationalistic reporting. In addition, federal legislation banning synthetic cannabinoids and 'bath salts' appear to be closely linked to media reporting as spikes in coverage both preceded and followed the bans. [ABSTRACT FROM AUTHOR]

Introduction Novel psychoactive substances (NPS) are new psychotropic drugs, not scheduled under the International Conventions on Psychotropic Substances, but which may pose a relevant public health threat. In this study, we investigated knowledge and use of NPS in a sample of Italian youth in urban and rural areas. Methods Between December 2012 and October 2013, we administered a questionnaire to a sample of 3011 healthy subjects (44.7% men; 55.3% women), aged between 16 and 24 years and recruited in urban, intermediate and rural areas of Italy. Results Of the global sample, 53.3% declared to have some knowledge on NPS, with a higher knowledge in urban areas. Mephedrone (26%), desomorphine (22.6%) and methamphetamine (21.7%) were the most commonly known drugs. NPS use was reported by 4.7% of the sample, without significant differences between urban and rural areas; mephedrone (3.3%), synthetic cannabinoids (1.2%) and Salvia divinorum (0.3%) consumption has been identified. NPS use was also predictive of binge-drinking behaviours ( χ2(4) = 929.58, p < .001). Discussion Urban areas may represent a focal point for preventive strategies, given the presence of higher levels of NPS knowledge. Moreover, the association between binge-drinking habits and NPS use was really strong. This issue should not be underestimated because of its medical, psychopathological and social consequences. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

This study examined the overall psychological effects of inebriation facilitated by the naturally-occurring plant hallucinogen Salvia divinorum using a double-blind, randomized, placebo-controlled trial. Thirty healthy individuals self-administered Salvia divinorum via combustion and inhalation in a quiet, comfortable research setting. Experimental sessions, post-session interviews, and 8-week follow-up meetings were audio recorded and transcribed to provide the primary qualitative material analyzed here. Additionally, post-session responses to the Hallucinogen Rating Scale provided a quantitative groundwork for mixed-methods discussion. Qualitative data underwent thematic content analysis, being coded independently by three researchers before being collaboratively integrated to provide the final results. Three main themes and 10 subthemes of acute intoxication emerged, encompassing the qualities of the experience, perceptual alterations, and cognitive-affective shifts. The experience was described as having rapid onset and being intense and unique. Participants reported marked changes in auditory, visual, and interoceptive sensory input; losing normal awareness of themselves and their surroundings; and an assortment of delusional phenomena. Additionally, the abuse potential of Salvia divinorum was examined post hoc. These findings are discussed in light of previous research, and provide an initial framework for greater understanding of the subjective effects of Salvia divinorum, an emerging drug of abuse. [ABSTRACT FROM AUTHOR]

Salvia divinorum (Lamiaceae) is a herb native to Mexico where it is used by Mazatec shamans for spiritual and divination purposes. S. divinorum products are easily available to consumers and are used worldwide as legal highs because of the hallucinogenic effects caused mainly by salvinorin A. Highly popular videos and websites on the internet depicting the use of S. divinorum products have contributed to an increase in their consumption. Recent reports have highlighted the potential of these products to induce psychosis in consumers. In Mexico, dried leaf extracts of S. divinorum are sold in different strengths, claiming to correlate with increasing amounts of salvinorin A. In order to determine the variability of salvinorin A content between brands and to investigate possible correlation between brand strengths, this study sought to quantify salvinorin A in commercial products available in Mexico using an HPLC method. The HPLC analytical method showed a correlation coefficient R² > 0.99, with LOD of 0.44 µg/mL and LOQ of 1.34 µg/mL. The retention time for salvinorin A was 23.09 ± 0.95 min and the measured concentrations ranged between 8.32 ± 0.65 and 56.52 ± 3.77 mg/g dried leaf. The results for brand c did not show an agreement between the declared and the calculated amount of salvinorin A. Additionally, the emergence in Mexico of high strength salvia products (100×), the lack of regulation and the observed variability of salvinorin A content between brands of commercial legal highs products of S. divinorum could result in a health problem for consumers. [ABSTRACT FROM AUTHOR]

Background and Purpose: Acute activation of κ opioid (KOP) receptors results in anticocaine-like effects, but adverse effects, such as dysphoria, aversion, sedation and depression, limit their clinical development. Salvinorin A, isolated from the plant Salvia divinorum, and its semi-synthetic analogues have been shown to have potent KOP receptor agonist activity and may induce a unique response with similar anticocaine addiction effects as the classic KOP receptor agonists, but with a different side effect profile.Experimental Approach: We evaluated the duration of effects of Mesyl Sal B in vivo utilizing antinociception assays and screened for cocaine-prime induced cocaine-seeking behaviour in self-administering rats to predict anti-addiction effects. Cellular transporter uptake assays and in vitro voltammetry were used to assess modulation of dopamine transporter (DAT) function and to investigate transporter trafficking and kinase signalling pathways modulated by KOP receptor agonists.Key Results: Mesyl Sal B had a longer duration of action than SalA, had anti-addiction properties and increased DAT function in vitro in a KOP receptor-dependent and Pertussis toxin-sensitive manner. These effects on DAT function required ERK1/2 activation. We identified differences between Mesyl Sal B and SalA, with Mesyl Sal B increasing the Vmax of dopamine uptake without altering cell-surface expression of DAT.Conclusions and Implications: SalA analogues, such as Mesyl Sal B, have potential for development as anticocaine agents. Further tests are warranted to elucidate the mechanisms by which the novel salvinorin-based neoclerodane diterpene KOP receptor ligands produce both anti-addiction and adverse side effects.Linked Articles: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2. [ABSTRACT FROM AUTHOR]

Rationale: Salvinorin A is a recreational drug derived from Salvia divinorum, a sage species long used as an entheogen. While salvinorin A has potent hallucinogenic properties, its abuse potential has not been assessed consistently in controlled behavioural and neurochemical studies in rodents. Objective: This study aimed to assess salvinorin A abuse potential by measuring its capacity to establish and maintain self-administration behaviour and to modify dopamine (DA) levels in the nucleus accumbens (NAcc) of rats. Results: Male Lister Hooded (LH) and Sprague-Dawley (SD) rats were allowed to self-administer salvinorin A (0.5 or 1.0 μg/kg/infusion) intravenously 2 h/day for 20 days under a continuous schedule of reinforcement and lever pressing as operandum. LH rats discriminated between the active and inactive levers but did not reach the acquisition criterion for stable self-administration (≥12 active responses vs ≤5 inactive responses for at least 5 consecutive days). SD rats discriminated between the two levers at the lower dose only but, like LH rats, never acquired stable self-administration behaviour. Systemic salvinorin A increased extracellular DA in the NAcc shell of both LH (at ≥40 μg/kg) and SD rats (at ≥5 μg/kg), but injection into the ventral tegmental area (VTA) induced no significant change in NAcc DA concentration in LH rats and only brief elevations in SD rats. Conclusions: Salvinorin A differs from other commonly abused compounds since although it affects accumbal dopamine transmission, yet it is unable, at least at the tested doses, to sustain stable intravenous self-administration behaviour. [ABSTRACT FROM AUTHOR]

In recent years, recreational use of Salvia divinorum (Lamiaceae), a herbal drug that contains a hallucinogenic ingredient, salvinorin A, has become a new phenomenon among young drug users. In Taiwan, as in many other countries, dry leaves of S. divinorum and its related concentrated extract products are available via the Internet. Besides S. divinorum, there are many endemic Salvia species whose salvinorin A content is yet unknown. To understand the abuse liability of these products, the aim of this study was to assess the concentration of salvinorin A in endemic Salvia species and Internet-available salvinorin A-related products. Samples of S. divinorum were purchased via the Internet and samples of eight endemic species of Salvia were collected in Taiwan, including S. arisanensis Hayata, S. coccinea Juss. ex Murr, S. hayatana Makino ex Hayata, S. japonica Thumb. ex Murr, S. nipponica Miq. Var. formosana (Hayata) Kudo, S. scapiformis Hance, S. tashiroi Hayata. Icon. PI. Formosan, and S. keitaoensis Hayata. The content of salvinorin A was determined by high performance liquid chromatography (HPLC). Salvinorin A was extracted from the dry leaves of S. divinorum and endemic species of Salvia with methanol and analyzed on a C-18 column by isocratic elution with a mobile phase of acetonitrile--water. Salvinorin A was detected in S. divinorum, but not in the endemic Salvia species of Taiwan. Therefore, endemic species of Salvia in Taiwan may not possess hallucinogenic potential. However, the potential harm from S. divinorum available via the Internet should be thoroughly assessed in Taiwan, and control measures similar to those implemented in many other countries should be considered. [ABSTRACT FROM AUTHOR]

Salvia divinorum is a hallucinogen sold over the internet in several forms. Perhaps the most common method of use is smoking the dried leaf material. The sole presumed active constituent, salvinorin A, is a selective kappa-opioid receptor agonist. Upon smoking of the dried leaf material, some of the salvinorin A is destroyed or converted to other materials, leaving in question the actual amount of salvinorin A delivered that leads to the psychotomimetic effect. On average, 133 μg of salvinorin A was delivered in the smoke from an 830 mg per cigarette, which contained ∼2.7 mg of salvinorin A. Hence, only ∼5% of the salvinorin A available in the dried plant material was delivered in the smoke. Upon smoking, hydrolysis of salvinorin A to salvinorin B, an inactive and minor component of the leaf material, also occurs as evidenced by a higher delivered amount of salvinorin B vs salvinorin A (217 vs 133 μg per cigarette). Since smoking is an effective means of achieving the hallucinogenic effect and salvinorin A is the presumed sole active ingredient in the plant, the estimated effective dose of salvinorin A by inhalation is <133 μg per person. Considering the reported rapid metabolism of salvinorin A in vivo, the dose reaching the brain would be substantially less. [ABSTRACT FROM AUTHOR]