Pharmacokinetics of the potent hallucinogen, salvinorin A in primates parallels the rapid onset and short duration of effects in humans

doi:10.1016/j.neuroimage.2008.03.003

NeuroImage

Volume 41, Issue 3, 1 July 2008, Pages 1044-1050

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Abstract

Salvia divinorum, a mint plant originally used by the Mazatecs of Oaxaca, Mexico in spiritual rituals has gained popularity, in smoked form, as a legal hallucinogen in the United States and Europe. Abuse results in rapid onset and short-lasting effects that include visual hallucinations and motor-function impairment. Salvinorin A, the psychoactive component of S. divinorum, is a uniquely potent agonist at κ-opioid receptors, targets for new therapeutic drugs. We labeled salvinorin A with C-11 by acylation of salvinorin B with [¹¹C]-acetyl chloride to study whether its kinetic behavior in the brain parallels its uniquely fast, yet brief physiological effects. Positron emission tomography (PET) studies performed in 6 adult female baboons indicated extremely rapid brain uptake reaching a peak accounting for 3.3% of the total administered dose in 40 s and clearing with a half-life of 8 min. [¹¹C]-salvinorin A was distributed throughout the brain with the highest concentration in the cerebellum and a notable concentration in the visual cortex, perhaps accounting for its physiological effects when smoked. Naloxone administration did not reduce the overall concentration of [¹¹C]-salvinorin A significantly nor did it change its regional distribution. Peripheral organ kinetics suggested at least two modes of metabolism and excretion occur: through the renal and biliary systems. Our findings have revealed that the exceptionally rapid uptake and brief duration of salvinorin A in the brain match the time-course of visual hallucinations for S. divinorum when smoked. The effects of salvinorin A may occur at < 10 μg in the human brain, emphasizing its remarkable potency.

Introduction

Salvia divinorum has become increasingly popular as a recreational drug (Vortherms and Roth, 2006). Although demographic data are lacking, adolescent abuse has clearly been facilitated by the internet where dried salvia leaves and extracts are inexpensive and easily obtained, ‘how to’ guides are abundant, and thousands of videos on YouTube document its hallucinogenic effects (Gonzalez et al., 2006). When smoked, S. divinorum causes visual hallucinations and behavioral impairment within seconds that last only minutes.

In parallel to the rise in recreational use over the past decade, research using S. divinorum has advanced our understanding of the opioid receptor system. Salvinorin A, the active component of S. divinorum, is a neoclerodane diterpene structurally distinct from all other psychoactive drugs and acts as a potent and selective κ-opioid agonist (Roth et al., 2002). The κ-opioid receptor may be an important therapeutic target for analgesia (Millan, 1990) and neuroprotection (Zeynalov et al., 2006), among others. The dichotomy of S. divinorum as a target for abuse and therapy has both challenged and preserved its legal status in the United States where it is currently not listed under the Controlled Substances Act.¹

As a result of both S. divinorum's abuse liability and its therapeutic potential, there is a growing interest in understanding the in vivo behavior and effects of salvinorin A, other naturally occurring salvinorin compounds, and semi-synthetic derivatives of the salvinorin diterpene core (Vortherms and Roth, 2006; recently reviewed by Grundmann et al. (2007)). Herein, we synthesized carbon-11 (t_1/2 =20.4 min) labeled salvinorin A and used positron emission tomography (PET) to measure its pharmacokinetics and distribution in the brains and peripheral organs of female baboons. Our results are consistent with the rapid onset and short-lasting pharmacological effect of salvinorin A, which we conclude is directly linked to its kinetics in the brain.

Section snippets

General

[¹¹C]-Carbon dioxide was generated by an EBCO (Advanced Cyclotron Systems Inc) cyclotron by the nuclear reaction, ¹⁴N(p,α)¹¹C, using a nitrogen/oxygen (1000 ppm) target. Semipreparative high-performance liquid chromatography (HPLC) was performed using a Knauer HPLC system (Sonntek Inc., Woodcliff Lake, NJ, USA) with a model K-5000 pump, a model 87 variable wavelength monitor and NaI radioactivity detector. Specific activity was determined by measuring the radioactivity and the mass; the latter

Results and discussion

Salvinorin A was labeled with carbon-11, a positron emitting isotope, and studied using PET, a powerful noninvasive technique to image drug pharmacokinetics in the living brain at concentrations far below pharmacologically active doses (Fowler and Wolf, 1997). Salvinorin A was isolated from dried S. divinorum by a procedure similar to those previously described (Munro and Rizzacasa, 2003). Precursors for radiolabeling were synthesized by known chemical degradation pathways. Two positions for

Conclusion

By labeling salvinorin A with carbon-11, we were able to assess its pharmacokinetics using PET. Our main findings from PET studies in baboons were that (a) [¹¹C]-salvinorin A rapidly crosses the BBB reaching 3.3% of the injected dose within 40 s and clearing to half of peak by 8 min; (b) [¹¹C]-salvinorin A is distributed throughout the brain with a high concentration in the cerebellum and cortex; (c) [¹¹C]-salvinorin is metabolized through at least two pathways. Our studies reveal an

Acknowledgments

This work was carried out at Brookhaven National Laboratory under contract DE-AC02-98CH10886 with the U.S. Department of Energy and supported by its Office of Biological and Environmental Research. J.M.H. was supported by an NIH Postdoctoral Fellowship (1F32EB008320-01) and through the Goldhaber Distinguished Fellowship program at BNL. The authors are grateful to David Alexoff, Dr. Michael Schueller, Dr. Stephen Dewey, and Dr. Jean Logan for their helpful discussions and advice. We are grateful

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Citation Excerpt :
The dried leaves of the salvia divinorum plant can be smoked and produce a rapid onset of visual hallucinations, behavioral and motor function impairment which last only a few minutes (Hooker et al., 2008). PET studies after intravenous administration, to baboons (N = 6) of C11 radiolabeled salvinorin A, reached peak brain concentrations within 40 s and the compound was eliminated with a half-life of 8 min (Hooker et al., 2008). This extraordinarily rapid rate of brain entry and removal suggests active transport systems are playing a role in crossing the blood brain barrier.
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While the varied psychedelic agents described in this chapter share some properties, they have a range of pharmacologic effects that are reflected in the gradation in intensity of hallucinogenic effects from the classical agents to DMT, MDMA, ketamine, dextromethorphan and new drugs with activity in the serotonergic system. The common link seems to be serotonergic effects modulated by NMDA and other neurotransmitter effects. The range of hallucinogens suggest that they are distinct pharmacologic agents and will not be equally safe or effective in therapeutic targets. Newly synthesized specific and selective agents modeled on the legacy agents may be worth considering.
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The plant metabolite salvinorin A potently and selectively agonizes the human kappa-opioid receptor, an emerging target for next-generation analgesics. Here we review analogs of the salvinorin chemotype and their effects on selectivity, affinity and potency. Extensive peripheral modifications using isolated salvinorin A have delivered a trove of SAR information. More deep-seated changes are now possible by advances in chemical synthesis.
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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.
Pharmacology and Structure-Activity Relationship of Natural Products With Psychoactive Effects From Salvia divinorum, Mitragyna speciosa, and Ayahuasca
2017, Studies in Natural Products Chemistry
A rising awareness of natural products with hallucinogenic properties and their potential for abuse in recent years has led to the wider introduction of traditionally used medicines to the Western world. Among them are three plant extracts that present various medicinal properties. Extracts from Salvia divinorum (Diviner's sage), Mitragyna speciosa (Kratom), and Banisteriopsis caapi and Psychotria viridis (Ayahuasca) have gained interest both among public health and legal officials due to increased reports of their use for recreational purposes. There are confirmed active ingredients in each of these extracts that have been investigated further in vitro and in vivo as well as in human trials for both their potential medicinal benefits and their abuse potential. Salvinorin A from S. divinorum presents as a nonnitrogenous kappa opioid receptor agonist with potential applications for inflammation, pain, and depressive disorders. Mitragynine from M. speciosa has shown both opioid receptor and sympathomimetic activities and may provide applications in the treatment of pain and a variety of CNS disorders. N,N-Dimethyltryptamine from P. viridis, in combination with monoamine oxidase inhibitors from B. caapi, has long been useful in treating substance use disorders as well as depressive and anxiety afflictions. This chapter provides an overview of the mechanisms of action, structure-activity relationship, and current knowledge of the potential clinical applications of each extract and their respective active constituents and derivatives.
22-azidosalvinorin A exhibits antidepressant-like effect in mice
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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-HT_1A 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.

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Pharmacokinetics of the potent hallucinogen, salvinorin A in primates parallels the rapid onset and short duration of effects in humans

Abstract

Introduction

Section snippets

General

Results and discussion

Conclusion

Acknowledgments

Bioorg. Med. Chem. Lett.

NeuroImage

Drug Alcohol Depend.

Int. J. Radiat. Appl. Instrum., A Appl. Radiat. Isot.

Trends Pharmacol. Sci.

J. Chromatogr., B Analyt. Technol. Biomed. Life Sci.

J. Ethnopharmacol.

Bioorg. Med. Chem. Lett.

Opioid receptors and legal highs: Salvia divinorum and Kratom

Clin. Toxicol.

Use of Salvia divinorum, an unscheduled hallucinogenic plant: a web-based survey of 500 users