Journal of psychopharmacology (Oxford, England)
April 1, 2016
Matthew W Johnson, Katherine A Maclean, Michael J Caspers et al.
11 citations
After inhaling a high dose of vaporized salvinorin A (18–21 mcg/kg), plasma levels of the compound peak at 2 minutes and then rapidly decline. Higher drug levels are strongly linked to stronger subjective and observer-rated drug effects. Prolactin rises significantly from 5 minutes onward, peaking at 15 minutes, while cortisol increases are inconsistent across participants. Hormonal changes do not closely track drug levels. This work demonstrates a direct relationship between salvinorin A plasma concentrations and drug effects in humans, validating an efficient inhalation method.
The International Journal of Neuropsychopharmacology
April 26, 2021
Alison Wakeford, Alexander M. Sherwood, Thomas E Prisinzano et al.
6 citations
Synthetic cathinones produce behavioral effects similar to either psychostimulants like methamphetamine or entactogens like MDMA, depending on their dopaminergic or serotonergic activity. In squirrel monkeys trained to distinguish methamphetamine or MDMA from a placebo, cathinones such as MDPV, α-PVP, and methcathinone fully substituted for methamphetamine but only partially for MDMA, indicating primarily dopamine-mediated effects. Conversely, mephedrone and methylone fully substituted for MDMA but not for methamphetamine, suggesting a primary role for serotonin. These differences in interoceptive effects in nonhuman primates may reflect the subjective effects these drugs produce in humans.
Analytical methods : advancing methods and applications
December 21, 2013
Michael J Caspers, Todd D Williams, Kimberly M Lovell et al.
6 citations
A method using liquid chromatography-tandem mass spectrometry (LC-MS/MS) measures the hallucinogen salvinorin A in non-human primate cerebrospinal fluid (CSF) and human plasma. For CSF, simple dilution with acetonitrile and formic acid replaces solid phase extraction. Human plasma requires centrifugation, then loading onto a C18 SPE column. A shallow acetonitrile/water gradient elutes the compound. Limits of quantification are 0.0125 ng/mL for CSF and 0.05 ng/mL for plasma. Interday precision and accuracy are below 1.7% and 9.42% for CSF and 3.47% and 12.37% for plasma. The method determined salvinorin A concentrations in a Rhesus monkey study and a human trial using behaviorally active doses.
Frontiers in Pharmacology
January 1, 2022
Kelly F Paton, Dan Luo, Anne C La Flamme et al.
Kappa opioid receptor (KOR) agonists, including analogues of Salvinorin A, reduced pain in a mouse model of chemotherapy-induced neuropathic pain. 16-Ethynyl SalA was more potent than morphine at reducing mechanical allodynia, and SalA, 16-Ethynyl SalA, and EOM SalB were more potent at reducing cold allodynia. Sex differences appeared in mechanical allodynia testing: U50,488 was more potent in males, SalA more potent in females, but no sex differences occurred in cold allodynia. Chronic U50,488 (10 mg/kg) restored mechanical and cold pain responses to healthy levels over 23 days. KOR agonists may be developed to treat this condition.
Psychopharmacology
May 1, 2020
C Austin Zamarripa, Jennifer E Naylor, Sally L Huskinson et al.
Combining the kappa opioid receptor (KOR) agonists salvinorin A or nalfurafine with oxycodone reduced self-administration of oxycodone in adult male rhesus monkeys under a progressive ratio schedule. Oxycodone alone was self-administered above saline levels at sufficient doses. Adding salvinorin A reduced mean injections per session to saline levels, and nalfurafine reduced them to levels significantly lower than oxycodone alone. Pretreatment with the KOR antagonist nor-BNI reversed nalfurafine's effect, indicating the effect is KOR-dependent. The authors propose that combinations of KOR agonists with prescription opioids may have reduced abuse liability.
The Journal of pharmacology and experimental therapeutics
July 1, 2019
Eduardo R Butelman, Bryan D McElroy, Thomas E Prisinzano et al.
Activating the kappa opioid receptor system with the agonist salvinorin A caused dose-dependent decreases in self-grooming behavior in male mice, indicating anhedonia. Two short-acting kappa antagonists, LY2444296 and LY2795050, dose- and time-dependently prevented these grooming deficits. At kappa-selective doses, both antagonists also reduced immobility in the forced swim test, suggesting anti-anhedonia effects. The findings implicate the kappa-receptor system in an ethologically relevant measure of anhedonia and show that these antagonists can produce effects consistent with rapid anti-anhedonia.
Neuroscience Letters
April 23, 2018
Yan Zhou, Rachel S Crowley, Thomas E Prisinzano et al.
A single injection of the kappa opioid receptor agonist Mesyl Salvinorin B (MSB) at 3 mg/kg prevented the alcohol deprivation effect—a model of relapse—in both male and female mice that had developed excessive alcohol intake. A lower dose combination of MSB (0.3 mg/kg) with naltrexone (1 mg/kg) also reduced the effect, suggesting synergy. MSB alone or combined with naltrexone shows potential for treating alcohol relapse.
Psychopharmacology
August 1, 2017
Amy W M Ewald, Peter J Bosch, Aimee Culverhouse et al.
Two novel analogues of salvinorin A, EOM Sal B and β-THP Sal B, were tested in rats for their ability to reduce cocaine-related behaviors and their side effects. EOM Sal B dose-dependently reduced drug-seeking behavior in a reinstatement model and, along with β-THP Sal B, attenuated cocaine-induced hyperactivity without affecting general locomotion. Neither compound produced anxiety-like or depressive-like effects in the elevated plus maze or forced swim tests. However, β-THP Sal B caused aversion in the conditioned place aversion test. EOM Sal B showed no effect on sucrose self-administration, indicating selectivity for cocaine-related behaviors. EOM Sal B was more potent than salvinorin A and β-THP Sal B with fewer side effects.
Journal of Natural Products
July 28, 2017
Anil Yilmaz, Rachel Saylor Crowley, Alexander M. Sherwood et al.
Columbin, a natural compound from plants used in traditional medicine, was modified to create derivatives that might activate the kappa-opioid receptor (KOR), a target for conditions like anxiety, depression, and addiction. The derivatives showed slightly improved activity at the KOR compared to the original columbin, but neither the parent compound nor its derivatives were potent KOR ligands. This study is the first to test columbin at the KOR and explores chemical modifications that can be made to the columbin molecule.
Neuropharmacology
November 1, 2014
Bronwyn M Kivell, Zeljko Uzelac, Santhanalakshmi Sundaramurthy et al.
Salvinorin A (SalA), a selective κ-opioid receptor (KOR) agonist, increases dopamine transporter (DAT) activity in cells and rat striatum, which reduces dopamine signaling. This effect is mediated by KOR activation and the ERK1/2 pathway, and involves physical interaction between KOR and DAT proteins. SalA also decreases serotonin transporter activity but does not affect norepinephrine transporter activity. The enhanced dopamine transport, combined with reduced dopamine release, may contribute to the dysphoric and pro-depressant effects of SalA and other KOR agonists.
Psychopharmacology
July 1, 2014
Kevin B Freeman, Jennifer E Naylor, Thomas E Prisinzano et al.
A kappa opioid agonist, salvinorin A, can punish self-administration of cocaine and remifentanil in monkeys. In a two-lever choice design, monkeys chose between equal doses of cocaine or remifentanil, with one option mixed with varying doses of salvinorin A. Choice for the drug combined with salvinorin A decreased as its dose increased, while operant response rates were unaffected. The findings suggest that kappa agonists may have potential to curtail drug abuse when delivered contingently, such as in combination formularies for prescription medications.
Advances in pharmacology (San Diego, Calif.)
January 1, 2014
Bronwyn M Kivell, Amy W M Ewald, Thomas E Prisinzano
Salvinorin A, a compound from the plant Salvia divinorum, activates kappa-opioid receptors and reduces drug-seeking behaviors by regulating dopamine levels, similar to traditional kappa-opioid agonists but with fewer side effects like sedation and depression. However, its rapid metabolism limits clinical use. Newer analogs based on Salvinorin A's structure show improved pharmacokinetics and retain anti-addictive effects, offering promise for developing addiction treatments.
European Journal of Pharmacology
November 15, 2013
Aashish S Morani, Amy W M Ewald, Katherine M Prevatt-Smith et al.
Activating the κ opioid receptor with the salvinorin A analogue 2-methoxy-methyl salvinorin B (MOM Sal B) at 0.3 mg/kg reduced cocaine-seeking behavior in rats, but also reduced sucrose reinforcement. No sedation was observed—locomotion in cocaine-induced hyperactivity and open field tests was unchanged—yet the forced swim test showed increased immobility and decreased swimming times, indicating pro-depressive effects. The compound thus modulates cocaine-seeking non-selectively without sedation, but depressive side effects may limit its therapeutic use.
Organic & biomolecular chemistry
September 21, 2009
Denise S Simpson, Kimberly M Lovell, Anthony Lozama et al.
Modifying the furan ring of salvinorin A, the active component of Salvia divinorum, produced new compounds with activity at opioid receptors. A computational study predicted salvinorin A to be a reproductive toxicant in mammals, suggesting its use may have adverse effects. Two new compounds, piperidine 21 and thiomorpholine 23, were identified as selective partial agonists at kappa opioid receptors. This suggests further structural changes could yield ligands with good opioid receptor selectivity but lower toxicity.
Bioorganic & Medicinal Chemistry Letters
November 15, 2007
Kenneth G Holden, Kevin Tidgewell, Alfred Marquam et al.
Removing the C-1 ketone from salvinorin A and its analogue herkinorin changes their activity at opioid receptors. A derivative called 1-deoxo-1,10-dehydrosalvinorin A acts as a moderately potent antagonist at all three opioid receptor subtypes. Herkinorin, a mu opioid agonist, becomes a weak antagonist when its C-1 ketone is removed. These results indicate the C-1 ketone is a key structural feature for mu agonist activity.