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Dose-Related Behavioral, Subjective, Endocrine, and Psychophysiological Effects of the κ Opioid Agonist Salvinorin A in Humans

  • Mohini Ranganathan
    Correspondence
    Address correspondence to Mohini Ranganathan, M.D., Psychiatry Service, 116A, VA Connecticut Healthcare System, 950 Campbell Avenue, West Haven, CT 06516
    Affiliations
    Psychiatry Service, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut

    Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, Connecticut

    Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
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  • Ashley Schnakenberg
    Affiliations
    Psychiatry Service, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut

    Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, Connecticut

    Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
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  • Patrick D. Skosnik
    Affiliations
    Psychiatry Service, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut

    Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, Connecticut

    Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
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  • Bruce M. Cohen
    Affiliations
    Harvard Medical School, Boston, Massachusetts

    McLean Hospital, Belmont, Massachusetts
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  • Brian Pittman
    Affiliations
    Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, Connecticut

    Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
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  • R. Andrew Sewell
    Affiliations
    Psychiatry Service, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut

    Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, Connecticut

    Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
    Search for articles by this author
  • Deepak Cyril D'Souza
    Affiliations
    Psychiatry Service, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut

    Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, Connecticut

    Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
    Search for articles by this author

      Background

      Salvia divinorum (Salvia) is an increasingly popular recreational drug amongst adolescents and young adults. Its primary active ingredient, Salvinorin A (SA)—a highly selective agonist at the κ opiate receptor—is believed to be one of the most potent naturally occurring hallucinogens. However, there is little experimental data on the effects of SA in humans.

      Methods

      In a 3-day, double-blind, randomized, crossover, counterbalanced study, the behavioral, subjective, cognitive, psychophysiological, and endocrine effects of 0 mg, 8 mg, and 12 mg of inhaled SA were characterized in 10 healthy individuals who had previously used Salvia.

      Results

      SA produced psychotomimetic effects and perceptual alterations, including dissociative and somaesthetic effects, increased plasma cortisol and prolactin, and reduced resting electroencephalogram spectral power. The SA administration was associated with a rapid increase of its levels in the blood. SA did not produce euphoria, cognitive deficits, or changes in vital signs. The effects were transient and not dose-related. SA administration was very well-tolerated without acute or delayed adverse effects.

      Conclusions

      SA produced a wide range of transient effects in healthy subjects. The perceptual altering effects and lack of euphoric effects would explain its intermittent use pattern. Such a profile would also suggest a low addictive potential similar to other hallucinogens and consistent with κ opiate receptor agonism. Further work is warranted to carefully characterize a full spectrum of its effects in humans, to elucidate the underlying mechanisms involved, and to explore the basis for individual variability in its effects.

      Key Words

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      References

        • Chavkin C.
        • Sud S.
        • Jin W.
        • Stewart J.
        • Zjawiony J.K.
        • Siebert D.J.
        • et al.
        Salvinorin A, an active component of the hallucinogenic sage salvia divinorum is a highly efficacious kappa-opioid receptor agonist: Structural and functional considerations.
        J Pharmacol Exp Ther. 2004; 308: 1197-1203
        • Gonzalez D.
        • Riba J.
        • Bouso J.C.
        • Gomez-Jarabo G.
        • Barbanoj M.J.
        Pattern of use and subjective effects of Salvia divinorum among recreational users.
        Drug Alcohol Depend. 2006; 85: 157-162
        • Roth B.L.
        • Baner K.
        • Westkaemper R.
        • Siebert D.
        • Rice K.C.
        • Steinberg S.
        • et al.
        Salvinorin A: A potent naturally occurring nonnitrogenous kappa opioid selective agonist.
        Proc Natl Acad Sci U S A. 2002; 99: 11934-11939
        • Ford J.A.
        • Watkins W.C.
        • Blumenstein L.
        Correlates of Salvia divinorum use in a national sample: findings from the 2009 National Survey on Drug Use and Health.
        Addict Behav. 2011; 36: 1032-1037
        • Baggott M.J.
        • Erowid E.
        • Erowid F.
        • Galloway G.P.
        • Mendelson J.
        Use patterns and self-reported effects of Salvia divinorum: An internet-based survey.
        Drug Alcohol Depend. 2010; 111: 250-256
        • Lange J.E.
        • Daniel J.
        • Homer K.
        • Reed M.B.
        • Clapp J.D.
        Salvia divinorum: Effects and use among YouTube users.
        Drug Alcohol Depend. 2010; 108: 138-140
        • Nyi P.P.
        • Lai E.P.
        • Lee D.Y.
        • Biglete S.A.
        • Torrecer G.I.
        • Anderson I.B.
        Influence of age on Salvia divinorum use: Results of an Internet survey.
        J Psychoactive Drugs. 2010; 42: 385-392
        • Sumnall H.R.
        • Measham F.
        • Brandt S.D.
        • Cole J.C.
        Salvia divinorum use and phenomenology: Results from an online survey.
        J Psychopharmacol. 2010; 25: 1496-1507
        • Paulzen M.
        • Grunder G.
        Toxic psychosis after intake of the hallucinogen salvinorin A.
        J Clin Psychiatry. 2008; 69: 1501-1502
        • Gonzalez D.
        • Riba J.
        • Bouso J.C.
        • Gomez-Jarabo G.
        • Barbanoj M.J.
        Pattern of use and subjective effects of Salvia divinorum among recreational users.
        Drug Alcohol Depend. 2006; 85: 157-162
        • Vortherms T.A.
        • Roth B.L.
        Salvinorin A: from natural product to human therapeutics.
        Mol Interv. 2006; 6: 257-265
        • Pichini S.
        • Abanades S.
        • Farre M.
        • Pellegrini M.
        • Marchei E.
        • Pacifici R.
        • et al.
        Quantification of the plant-derived hallucinogen Salvinorin A in conventional and non-conventional biological fluids by gas chromatography/mass spectrometry after Salvia divinorum smoking.
        Rapid Commun Mass Spectrom. 2005; 19: 1649-1656
        • Johnson M.W.
        • MacLean K.A.
        • Reissig C.J.
        • Prisinzano T.E.
        • Griffiths R.R.
        Human psychopharmacology and dose-effects of salvinorin A, a kappa opioid agonist hallucinogen present in the plant Salvia divinorum.
        Drug Alcohol Depend. 2011; 115: 150-155
        • Mendelson J.E.
        • Coyle J.R.
        • Lopez J.C.
        • Baggott M.J.
        • Flower K.
        • Everhart E.T.
        • et al.
        Lack of effect of sublingual salvinorin A, a naturally occurring kappa opioid, in humans: A placebo-controlled trial.
        Psychopharmacology (Berl). 2011; 214: 933-939
        • Siebert D.J.
        Salvia divinorum and salvinorin A: New pharmacologic findings.
        J Ethnopharmacol. 1994; 43: 53-56
        • Addy P.H.
        Acute and post-acute behavioral and psychological effects of salvinorin A in humans.
        Psychopharmacology (Berl). 2012; 220: 195-204
        • Pascoe J.E.
        • Williams K.L.
        • Mukhopadhyay P.
        • Rice K.C.
        • Woods J.H.
        • Ko M.C.
        Effects of mu, kappa, and delta opioid receptor agonists on the function of hypothalamic-pituitary-adrenal axis in monkeys.
        Psychoneuroendocrinology. 2008; 33: 478-486
        • Blackford S.P.
        • Little P.J.
        • Kuhn C.M.
        Mu- and kappa-opiate receptor control of prolactin secretion in rats: Ontogeny and interaction with serotonin.
        Endocrinology. 1992; 131: 2891-2897
        • Ur E.
        • Wright D.M.
        • Bouloux P.M.
        • Grossman A.
        The effects of spiradoline (U-62066E), a kappa-opioid receptor agonist, on neuroendocrine function in man.
        Br J Pharmacol. 1997; 120: 781-784
        • Coltro Campi C.
        • Clarke G.D.
        Effects of highly selective kappa-opioid agonists on EEG power spectra and behavioural correlates in conscious rats.
        Pharmacol Biochem Behav. 1995; 51: 611-616
        • Valenza G.
        • Carboncini M.C.
        • Virgillito A.
        • Creatini I.
        • Bonfiglio L.
        • Rossi B.
        • et al.
        EEG complexity drug-induced changes in disorders of consciousness: A preliminary report.
        Conf Proc IEEE Eng Med Biol Soc. 2011; 2011: 3724-3727
        • Greenwald M.K.
        • Roehrs T.A.
        Mu-opioid self-administration vs passive administration in heroin abusers produces differential EEG activation.
        Neuropsychopharmacology. 2005; 30: 212-221
        • Bocker K.B.
        • Hunault C.C.
        • Gerritsen J.
        • Kruidenier M.
        • Mensinga T.T.
        • Kenemans J.L.
        Cannabinoid modulations of resting state EEG theta power and working memory are correlated in humans.
        J Cogn Neurosci. 2010; 22: 1906-1916
        • Venables N.C.
        • Bernat E.M.
        • Sponheim S.R.
        Genetic and disorder-specific aspects of resting state EEG abnormalities in schizophrenia.
        Schizophr Bull. 2009; 35: 826-839
        • Sponheim S.R.
        • Clementz B.A.
        • Iacono W.G.
        • Beiser M.
        Clinical and biological concomitants of resting state EEG power abnormalities in schizophrenia.
        Biol Psychiatry. 2000; 48: 1088-1097
        • Hooker J.M.
        • Munro T.A.
        • Beguin C.
        • Alexoff D.
        • Shea C.
        • Xu Y.
        • et al.
        Salvinorin A and derivatives: Protection from metabolism does not prolong short-term, whole-brain residence.
        Neuropharmacology. 2009; 57: 386-391
        • Perron B.E.
        • Ahmedani B.K.
        • Vaughn M.G.
        • Glass J.E.
        • Abdon A.
        • Wu L.T.
        Use of Salvia divinorum in a Nationally Representative Sample.
        Am J Drug Alcohol Abuse. 2011; 38: 108-113
        • D'Souza D.C.
        • Perry E.
        • MacDougall L.
        • Ammerman Y.
        • Cooper T.
        • Wu Y.T.
        • et al.
        The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: Implications for psychosis.
        Neuropsychopharmacology. 2004; 29: 1558-1572
        • Kay S.R.
        • Fiszbein A.
        • Opler L.A.
        The positive and negative syndrome scale (PANSS) for schizophrenia.
        Schizophr Bull. 1987; 13: 261-276
        • Mason O.J.
        • Morgan C.J.
        • Stefanovic A.
        • Curran H.V.
        The psychotomimetic states inventory (PSI): Measuring psychotic-type experiences from ketamine and cannabis.
        Schizophr Res. 2008; 103: 138-142
        • Bremner J.D.
        • Krystal J.H.
        • Putnam F.W.
        • Southwick S.M.
        • Marmar C.
        • Charney D.S.
        • et al.
        Measurement of dissociative states with the Clinician-Administered Dissociative States Scale (CADSS).
        J Trauma Stress. 1998; 11: 125-136
        • Strassman R.J.
        • Qualls C.R.
        • Uhlenhuth E.H.
        • Kellner R.
        Dose-response study of N,N-dimethyltryptamine in humans.
        Arch Gen Psychiatry. 1994; 51: 98-108
        • Strassman R.J.
        Human psychopharmacology of N,N-dimethyltryptamine.
        Behav Brain Res. 1996; 73: 121-124
        • Wechsler D.
        Administration and Scoring Manual for the Wechsler Adult Intelligence Scale.
        3rd ed. The Psychological Corporation, San Antonio, TX1997
        • Brunner E.
        • Domhof S.
        • Langer F.
        Nonparametric Analysis of Longitudinal Data in Factorial Experiments.
        John Wiley and Sons, New York2002
        • Krystal J.H.
        • Perry E.
        • Gueorguieva R.
        • Belger A.
        • Madonick S.
        • A-D A.
        • et al.
        Comparative and interactive human psychopharmacologic effects of ketamine and amphetamine: Implications for glutamatergic and dopaminergic model psychoses and cognitive function.
        Arch Gen Psychiatry. 2005; 62: 985-994
        • Butelman E.R.
        • Mandau M.
        • Tidgewell K.
        • Prisinzano T.E.
        • Yuferov V.
        • Kreek M.J.
        Effects of salvinorin A, a kappa-opioid hallucinogen, on a neuroendocrine biomarker assay in nonhuman primates with high kappa-receptor homology to humans.
        J Pharmacol Exp Ther. 2007; 320: 300-306
        • Butelman E.R.
        • Harris T.J.
        • Kreek M.
        Apparent efficacy of kappa-opioid receptor ligands on serum prolactin levels in rhesus monkeys.
        Eur J Pharmacol. 1999; 383: 305-309
        • Butelman E.R.
        • Kreek M.J.
        kappa-Opioid receptor agonist-induced prolactin release in primates is blocked by dopamine D(2)-like receptor agonists.
        Eur J Pharmacol. 2001; 423: 243-249
        • Peckys D.
        • Landwehrmeyer G.B.
        Expression of mu, kappa, and delta opioid receptor messenger RNA in the human CNS: A 33P in situ hybridization study.
        Neuroscience. 1999; 88: 1093-1135
        • Sim-Selley L.J.
        • Daunais J.B.
        • Porrino L.J.
        • Childers S.R.
        Mu and kappa1 opioid-stimulated [35S]guanylyl-5'-O-(gamma-thio)-triphosphate binding in cynomolgus monkey brain.
        Neuroscience. 1999; 94: 651-662
        • Carlezon Jr, W.A.
        • Beguin C.
        • DiNieri J.A.
        • Baumann M.H.
        • Richards M.R.
        • Todtenkopf M.S.
        • et al.
        Depressive-like effects of the kappa-opioid receptor agonist salvinorin A on behavior and neurochemistry in rats.
        J Pharmacol Exp Ther. 2006; 316: 440-447
        • Zhang Y.
        • Butelman E.R.
        • Schlussman S.D.
        • Ho A.
        • Kreek M.J.
        Effects of the plant-derived hallucinogen salvinorin A on basal dopamine levels in the caudate putamen and in a conditioned place aversion assay in mice: Agonist actions at kappa opioid receptors.
        Psychopharmacology (Berl). 2005; 179: 551-558
        • Grilli M.
        • Neri E.
        • Zappettini S.
        • Massa F.
        • Bisio A.
        • Romussi G.
        • et al.
        Salvinorin A exerts opposite presynaptic controls on neurotransmitter exocytosis from mouse brain nerve terminals.
        Neuropharmacology. 2009; 57: 523-530
        • Bromm B.
        • Ganzel R.
        • Herrmann W.M.
        • Meier W.
        • Scharein E.
        Pentazocine and flupirtine effects on spontaneous and evoked EEG activity.
        Neuropsychobiology. 1986; 16: 152-156
        • Wikler A.
        Clinical and electroencephalographic studies on the effects of mescaline, N-allylnormorphine and morphine in man; a pharmacologic analysis of the functions of the spontaneous electrical activity of the cerebral cortex.
        J Nerv Ment Dis. 1954; 120: 157-175
        • Riba J.
        • Anderer P.
        • Morte A.
        • Urbano G.
        • Jane F.
        • Saletu B.
        • et al.
        Topographic pharmaco-EEG mapping of the effects of the South American psychoactive beverage ayahuasca in healthy volunteers.
        Br J Clin Pharmacol. 2002; 53: 613-628
        • Maksimow A.
        • Sarkela M.
        • Langsjo J.W.
        • Salmi E.
        • Kaisti K.K.
        • Yli-Hankala A.
        • et al.
        Increase in high frequency EEG activity explains the poor performance of EEG spectral entropy monitor during S-ketamine anesthesia.
        Clin Neurophysiol. 2006; 117: 1660-1668
        • Donzanti B.A.
        • Althaus J.S.
        • Payson M.M.
        • Von Voigtlander P.F.
        Kappa agonist-induced reduction in dopamine release: site of action and tolerance.
        Res Commun Chem Pathol Pharmacol. 1992; 78: 193-210
        • Spanagel R.
        • Herz A.
        • Shippenberg T.S.
        Opposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway.
        Proc Natl Acad Sci U S A. 1992; 89: 2046-2050
        • Di Chiara G.
        • Imperato A.
        Opposite effects of mu and kappa opiate agonists on dopamine release in the nucleus accumbens and in the dorsal caudate of freely moving rats.
        J Pharmacol Exp Ther. 1988; 244: 1067-1080
        • Zhang Y.
        • Butelman E.R.
        • Schlussman S.D.
        • Ho A.
        • Kreek M.J.
        Effect of the kappa opioid agonist R-84760 on cocaine-induced increases in striatal dopamine levels and cocaine-induced place preference in C57BL/6J mice.
        Psychopharmacology (Berl). 2004; 173: 146-152
        • Shippenberg T.S.
        • Herz A.
        Place preference conditioning reveals the involvement of D1-dopamine receptors in the motivational properties of mu- and kappa-opioid agonists.
        Brain Res. 1987; 436: 169-172
        • Bals-Kubik R.
        • Herz A.
        • Shippenberg T.S.
        Evidence that the aversive effects of opioid antagonists and kappa-agonists are centrally mediated.
        Psychopharmacology (Berl). 1989; 98: 203-206
        • Suzuki T.
        • Shiozaki Y.
        • Masukawa Y.
        • Misawa M.
        • Nagase H.
        The role of mu- and kappa-opioid receptors in cocaine-induced conditioned place preference.
        Jpn J Pharmacol. 1992; 58: 435-442
        • Mori T.
        • Nomura M.
        • Nagase H.
        • Narita M.
        • Suzuki T.
        Effects of a newly synthesized kappa-opioid receptor agonist, TRK-820, on the discriminative stimulus and rewarding effects of cocaine in rats.
        Psychopharmacology (Berl). 2002; 161: 17-22
        • Crawford C.A.
        • McDougall S.A.
        • Bolanos C.A.
        • Hall S.
        • Berger S.P.
        The effects of the kappa agonist U-50,488 on cocaine-induced conditioned and unconditioned behaviors and Fos immunoreactivity.
        Psychopharmacology (Berl). 1995; 120: 392-399
        • Glick S.D.
        • Maisonneuve I.M.
        • Raucci J.
        • Archer S.
        Kappa opioid inhibition of morphine and cocaine self-administration in rats.
        Brain Res. 1995; 681: 147-152
        • Glick S.D.
        • Visker K.E.
        • Maisonneuve I.M.
        Effects of cyclazocine on cocaine self-administration in rats.
        Eur J Pharmacol. 1998; 357: 9-14
        • Kuzmin A.V.
        • Semenova S.
        • Gerrits M.A.
        • Zvartau E.E.
        • Van Ree J.M.
        Kappa-opioid receptor agonist U50,488H modulates cocaine and morphine self-administration in drug-naive rats and mice.
        Eur J Pharmacol. 1997; 321: 265-271
        • Schenk S.
        • Partridge B.
        • Shippenberg T.S.
        U69593, a kappa-opioid agonist, decreases cocaine self-administration and decreases cocaine-produced drug-seeking.
        Psychopharmacology (Berl). 1999; 144: 339-346
        • Heidbreder C.A.
        • Goldberg S.R.
        • Shippenberg T.S.
        The kappa-opioid receptor agonist U-69593 attenuates cocaine-induced behavioral sensitization in the rat.
        Brain Res. 1993; 616: 335-338
        • Vanderschuren L.J.
        • Schoffelmeer A.N.
        • Wardeh G.
        • De Vries T.J.
        Dissociable effects of the kappa-opioid receptor agonists bremazocine, U69593, and U50488H on locomotor activity and long-term behavioral sensitization induced by amphetamine and cocaine.
        Psychopharmacology (Berl). 2000; 150: 35-44
        • Collins S.L.
        • Gerdes R.M.
        • D'Addario C.
        • Izenwasser S.
        Kappa opioid agonists alter dopamine markers and cocaine-stimulated locomotor activity.
        Behav Pharmacol. 2001; 12: 237-245
        • Schenk S.
        • Partridge B.
        • Shippenberg T.S.
        Reinstatement of extinguished drug-taking behavior in rats: Effect of the kappa-opioid receptor agonist, U69593.
        Psychopharmacology (Berl). 2000; 151: 85-90
        • Sun W.
        • Xue Y.
        • Huang Z.
        • Steketee J.D.
        Regulation of cocaine-reinstated drug-seeking behavior by kappa-opioid receptors in the ventral tegmental area of rats.
        Psychopharmacology (Berl). 2010; 210: 179-188
        • Morani A.S.
        • Kivell B.
        • Prisinzano T.E.
        • Schenk S.
        Effect of kappa-opioid receptor agonists U69593, U50488H, spiradoline and salvinorin A on cocaine-induced drug-seeking in rats.
        Pharmacol Biochem Behav. 2009; 94: 244-249
        • Shippenberg T.S.
        • LeFevour A.
        • Heidbreder C.
        kappa-Opioid receptor agonists prevent sensitization to the conditioned rewarding effects of cocaine.
        J Pharmacol Exp Ther. 1996; 276: 545-554
        • Morani A.S.
        • Schenk S.
        • Prisinzano T.E.
        • Kivell B.M.
        A single injection of a novel kappa opioid receptor agonist salvinorin A attenuates the expression of cocaine-induced behavioral sensitization in rats.
        Behav Pharmacol. 2012; 23: 162-170
        • Morani A.S.
        • Kivell B.
        • Prisinzano T.E.
        • Schenk S.
        Effect of kappa-opioid receptor agonists U69593, U50488H, spiradoline and salvinorin A on cocaine-induced drug-seeking in rats.
        Pharmacol Biochem Behav. 2009; 94: 244-249
        • Zhang Y.
        • Butelman E.R.
        • Schlussman S.D.
        • Ho A.
        • Kreek M.J.
        Effects of the plant-derived hallucinogen salvinorin A on basal dopamine levels in the caudate putamen and in a conditioned place aversion assay in mice: Agonist actions at kappa opioid receptors.
        Psychopharmacology (Berl). 2005; 179: 551-558
        • Braida D.
        • Limonta V.
        • Capurro V.
        • Fadda P.
        • Rubino T.
        • Mascia P.
        • et al.
        Involvement of kappa-opioid and endocannabinoid system on Salvinorin A-induced reward.
        Biol Psychiatry. 2008; 63: 286-292
        • Todtenkopf M.S.
        • Marcus J.F.
        • Portoghese P.S.
        • Carlezon Jr, W.A.
        Effects of kappa-opioid receptor ligands on intracranial self-stimulation in rats.
        Psychopharmacology (Berl). 2004; 172: 463-470
        • Neumeyer J.L.
        • Mello N.K.
        • Negus S.S.
        • Bidlack J.M.
        Kappa opioid agonists as targets for pharmacotherapies in cocaine abuse.
        Pharm Acta Helv. 2000; 74: 337-344
        • Prisinzano T.E.
        • Tidgewell K.
        • Harding W.W.
        Kappa opioids as potential treatments for stimulant dependence.
        AAPS J. 2005; 7: E592-E599
        • Tomasiewicz H.C.
        • Todtenkopf M.S.
        • Chartoff E.H.
        • Cohen B.M.
        • Carlezon Jr, W.A.
        The kappa-opioid agonist U69,593 blocks cocaine-induced enhancement of brain stimulation reward.
        Biol Psychiatry. 2008; 64: 982-988
        • Mello N.K.
        • Negus S.S.
        Interactions between kappa opioid agonists and cocaine.
        Ann N Y Acad Sci. 2000; 909: 104-132
        • Rothman R.B.
        • Gorelick D.A.
        • Heishman S.J.
        • Eichmiller P.R.
        • Hill B.H.
        • Norbeck J.
        • et al.
        An open-label study of a functional opioid kappa antagonist in the treatment of opioid dependence.
        J Subst Abuse Treat. 2000; 18: 277-281
        • Mague S.D.
        • Pliakas A.M.
        • Todtenkopf M.S.
        • Tomasiewicz H.C.
        • Zhang Y.
        • Stevens Jr, W.C.
        • et al.
        Antidepressant-like effects of kappa-opioid receptor antagonists in the forced swim test in rats.
        J Pharmacol Exp Ther. 2003; 305: 323-330
        • Mucha R.F.
        • Herz A.
        Motivational properties of kappa and mu opioid receptor agonists studied with place and taste preference conditioning.
        Psychopharmacology (Berl). 1985; 86: 274-280
        • Shippenberg T.S.
        • Herz A.
        Differential effects of mu and kappa opioid systems on motivational processes.
        NIDA Res Monogr. 1986; 75: 563-566
        • Walsh S.L.
        • Strain E.C.
        • Abreu M.E.
        • Bigelow G.E.
        Enadoline, a selective kappa opioid agonist: Comparison with butorphanol and hydromorphone in humans.
        Psychopharmacology (Berl). 2001; 157: 151-162
        • Walsh S.L.
        • Geter-Douglas B.
        • Strain E.C.
        • Bigelow G.E.
        Enadoline and butorphanol: Evaluation of kappa-agonists on cocaine pharmacodynamics and cocaine self-administration in humans.
        J Pharmacol Exp Ther. 2001; 299: 147-158
        • Wadenberg M.L.
        A review of the properties of spiradoline: A potent and selective kappa-opioid receptor agonist.
        CNS Drug Rev. 2003; 9: 187-198
        • Vohra R.
        • Seefeld A.
        • Cantrell F.L.
        • Clark R.F.
        Salvia divinorum: Exposures reported to a statewide poison control system over 10 years.
        J Emerg Med. 2011; 40: 643-650
        • Przekop P.
        • Lee T.
        Persistent psychosis associated with salvia divinorum use.
        Am J Psychiatry. 2009; 166: 832
        • Abi-Dargham A.
        Do we still believe in the dopamine hypothesis?.
        Int J Neuropsychopharmacol. 2004; 7: S1-S5
        • Bortolato M.
        • Aru G.N.
        • Frau R.
        • Orru M.
        • Fa M.
        • Manunta M.
        • et al.
        Kappa opioid receptor activation disrupts prepulse inhibition of the acoustic startle in rats.
        Biol Psychiatry. 2005; 57: 1550-1558

      Linked Article

      • Psychotomimetic Effects of Kappa Opioid Receptor Agonists
        Biological PsychiatryVol. 72Issue 10
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          The κ opioid receptor (KOR)-dynorphin system has been implicated in the pathogenesis and pathophysiology of affective disorders, drug addiction, and psychotic disorders (1). Within the brain, KOR expression is highest in regions implicated in the modulation of reward, mood, cognition, and perception (ventral tegmental area, nucleus accumbens, prefrontal cortex, hippocampus, striatum, amygdala, and hypothalamus). Accordingly, drugs directed at KOR as either antagonists or partial agonists have potential utility for a number of indications, especially as antidepressants and anxiolytics.
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