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Salvinorin a and Related Compounds As Therapeutic Drugs for Psychostimulant-Related Disorders

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Salvinorin a and Related Compounds As Therapeutic Drugs for Psychostimulant-Related Disorders See discussions, stats, and author profiles for this publication at: http://www.researchgate.net/publication/270217015 Salvinorin A and related compounds as therapeutic drugs for psychostimulant-related disorders ARTICLE in CURRENT DRUG ABUSE REVIEWS · OCTOBER 2014 DOWNLOADS VIEWS 53 322 4 AUTHORS, INCLUDING: Rafael Guimarães dos Santos João Paulo Machado-de-Sousa Ribeirão Preto Medical School, University of … University of São Paulo 35 PUBLICATIONS 114 CITATIONS 41 PUBLICATIONS 394 CITATIONS SEE PROFILE SEE PROFILE Available from: Rafael Guimarães dos Santos Retrieved on: 16 August 2015 Send Orders for Reprints to [email protected] 128 Current Drug Abuse Reviews, 2014, 7, 128-132 Salvinorin A and Related Compounds as Therapeutic Drugs for Psychostimulant-Related Disorders R.G. dos Santos*,1, J.A.S. Crippa1,2, J.P. Machado-de-Sousa1,2 and J.E.C. Hallak1,2 1Department of Neuroscience and Behavior, Ribeirão Preto Medical School, University of São Paulo, SP, Brazil 2National Institute for Translational Medicine (INCT-TM), CNPq, Brazil Abstract: Pharmacological treatments are available for alcohol, nicotine, and opioid dependence, and several drugs for cannabis-related disorders are currently under investigation. On the other hand, psychostimulant abuse and dependence lacks pharmacological treatment. Mesolimbic dopaminergic neurons mediate the motivation to use drugs and drug-induced euphoria, and psychostimulants (cocaine, amphetamine, and methamphetamine) produce their effects in these neurons, which may be modulated by the opioid system. Salvinorin A is a κ-opioid receptor agonist extracted from Salvia divinorum, a hallucinogenic plant used in magico-ritual contexts by Mazateca Indians in México. Salvinorin A and its analogues have demonstrated anti-addiction effects in animal models using psychostimulants by attenuating dopamine release, sensitization, and other neurochemical and behavioral alterations associated with acute and prolonged administration of these drugs. The objective of the present article is to present an overview of the preclinical evidence suggesting anti-addictive effects of salvinorin A and its analogues. Keywords: Hallucinogens, psychedelics, psychostimulants, Salvia divinorum, salvinorin A. INTRODUCTION only non-nitrogenous natural κ-opioid receptor agonist currently known, and does not present affinity for other receptors After cannabis, stimulants (cocaine and amphetamine) are associated with perceptual alterations produced by certain the most consumed illegal recreational drugs worldwide [1, 2]. drugs, such as dopamine, serotonin, or glutamate [10-12]. Among those seeking treatment for drug-related disorders in the Importantly, in contrast with classical hallucinogens (mescaline, Americans, cocaine remain the most prevalent primary drug of LSD, psilocybin, DMT), salvinorin A does not behave as an abuse [1]. Stimulant abuse causes considerable health problems agonist at the 5-HT2A receptor [10-12]. in several countries [2-6]. Pharmacologists have been searching for drugs with therapeutic effects in psychostimulant-related Salvinorin A produces mental effects at only 4.5 µg/kg, disorders for decades, without success [5-6]. Thus, novel making this compound the most active natural psychoactive approaches are necessary to help those with problematic product, almost in the same range as LSD [9, 10, 13-18]. This stimulant use who are seeking treatment. compound produces alterations on perceptions, mood, and on somatic sensations that are powerful but short-lived, lasting The leaves of the hallucinogenic plant Salvia divinorum (“of around 15 min [9, 10, 14-18]. the diviners”) are eaten or drunk in a water infusion by the Mazatec Indians of Oaxaca, Mexico, for medicinal and ritual Preclinical [19-50] and clinical [51-54] studies suggest that purposes [7-11]. Although S. divinorum is illegal in some compounds that act as agonists of the κ-opioid receptor produce countries, the plant is not regulated in many others, and several effects that are potentially beneficial for patients suffering products derived from it (plants, dried leaves, extracts for psychostimulant-related disorders. Thus, the objective of the smoking and tinctures for oral administration) are sold for present text is to review data from preclinical and clinical young adults that use these products to induce powerful studies suggesting that κ-opioid receptor agonists, including hallucinations [10-14]. salvinorin A, may produce therapeutic effects in patients with psychostimulant-related disorders. In vitro and in vivo studies demonstrated that the only known and likely major active constituent of S. divinorum is the κ-opioid receptor agonist salvinorin A [10-12]. Other related METHODS chemicals are present in S. divinorum, such as salvinorins B-I, The present review focused on studies conducted in the last salvidivins A-D, salvinicins A-B, and divinatorins A-E, but little 15 years evaluating the modulatory action of κ agonists on the is known about their pharmacology [10-12]. Salvinorin A is the effects of psychostimulants (i.e., cocaine, amphetamine and methamphetamine). Preclinical and clinical studies published in English up to September 2014 were reviewed. Electronic *Address correspondence to this author at the Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de searches were performed using PubMed. Ribeirão Preto, Universidade de São Paulo, Hospital das Clínicas, Terceiro Andar, Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo, Brazil. Tel/Fax: + 55 16 3602 2703, E-mail: [email protected] 1874-4737/14 $58.00+.00 © 2014 Bentham Science Publishers Salvinorin A and Psychostimulant Abuse Current Drug Abuse Reviews, 2014, Vol. 7, No. 2 129 κ-Opioid Receptor Agonists Modulate Dopaminergic although its perceptual and cognitive side-effects present an Neurotransmission and the Effects of Psychostimulants important limitation. However, these psychological effects are probably more prominent or maximized in standard Studies in Rodents abuse liability studies in which individuals who participate Several studies in rodents showed that the effects have drug-related problems and are poorly prepared for produced by κ agonists are contrary to those produced by strong hallucinogenic effects. The salvinorin A studies drugs such as cocaine, amphetamine and methamphetamine, conducted in healthy volunteers could have likely resulted in which are all dopamine agonists [20, 21, 24-26, 28-33, 36- distressing psychedelic effects were it not for the fact that 38, 40, 43-46, 49, 50]. For instance, these compounds do not these participants were expecting and prepared for strong modify basal dopamine levels, a hallmark of the stimulants hallucinogenic effects (see below the Section Human [21, 25, 30]. κ-Opioid receptor agonists attenuate stimulant- Psychopharmacology of Salvinorin A). induced increases in locomotor activity in rats [21, 29, 46]. Acute i.m. doses of enadoline (20-80 µg/kg) modestly κ-Opioid agonists also decrease responding maintained by reduce the reinforcing effects of intravenous (i.v.) cocaine in cocaine and reduce the reinstatement of abolished cocaine volunteers with poly-substance (opiates and cocaine) abuse and amphetamine use in rats [24, 28, 31, 32, 38, 46]. In histories [52]. Acute i.v. doses of the κ-receptor agonist/µ- mice, these compounds reduce the enhancement of dopamine receptor antagonist nalbuphine (5 mg/70 kg) slightly reduce release produced by non-neurotoxic doses of the reinforcing effects of cocaine and significantly decrease methamphetamine, and also inhibit the reduction of diastolic blood pressure in current cocaine abusers [53]. The dopamine levels produced by neurotoxic doses of this neuroendocrine alterations produced by cocaine stimulant [25]. administration to current cocaine abusers on luteinizing hormone, cortisol, and adrenocorticotropic hormone are Studies in Nonhuman Primates attenuated by acute i.v. administration of nalbuphine (5 Several studies investigated the pharmacology of κ mg/70 kg), while effects on testosterone are not observed agonists in monkeys [19, 22, 23, 26, 27, 33-35, 39-40, 48]. [54]. κ-Opioid agonists dose-dependently decrease self- administration of cocaine in monkeys [19, 22, 34, 35]. κ- Human Psychopharmacology of Salvinorin A Opioid agonists often induce vomiting and sedative effects, which typically occur only for a few days, since tolerance The human pharmacology of inhaled (0.375-21 µg/kg quickly develops [19, 22, 34, 35]. These undesirable [14, 18], 12 mg [17]), sublingual (up to 4 mg), and smoked behavioral effects could reduce the potential clinical uses of (1,017 μg) [16] salvinorin A was investigated in healthy these drugs. Clinical trials with a large number of patients volunteers. Sublingual salvinorin A did not produce should be performed to elucidate the impact of these side- significant effects [15], while inhaled and smoked effects in clinical populations. administration produced intense subjective effects that start in less than a minute, peak within 10 min, and return to Administration of gradually increasing doses of κ-opioid baseline within 15-30 min [9, 10, 13-18]. These effects agonists for 28 days do not produce alterations on include hallucinatory and dissociative experiences, such as biochemical parameters (hematocrit, white blood cells, urea alterations in visual perception, time and spatial orientation, nitrogen, creatinine, alanine aminotransferase and glucose) cognition, emotions and self-awareness, which are generally
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