Clinical Toxicology
January 1, 2008
Kavita M. Babu, Christopher R Mccurdy, Edward W Boyer
221 citations
Salvia divinorum and Kratom are unscheduled dietary supplements that activate opioid receptors and produce distinct psychoactive effects. Salvinorin A, from Salvia divinorum, is a highly selective kappa-opioid receptor agonist that causes visual hallucinations and synesthesia. Kratom's main alkaloid, mitragynine, acts as a partial opioid agonist with morphine-like effects, while its minor alkaloid 7-hydroxymitragynine is more potent than morphine. Both Kratom alkaloids activate supraspinal mu- and delta-opioid receptors, which explains their use by chronic narcotics users to ease opioid withdrawal. Despite widespread Internet availability, these substances elude traditional toxicologic monitoring, and the article aims to inform toxicologists and poison control specialists about them.
Neuropharmacology
September 1, 2007
Catherine B Willmore-Fordham, Daniel M Krall, Christopher R Mccurdy et al.
49 citations
Salvinorin A, a plant-derived hallucinogen, acts through the kappa-opioid receptor system, producing effects such as pain relief, sedation, dysphoria, and distorted perceptions. In experiments with male rats trained to recognize a known kappa-opioid agonist, salvinorin A fully substituted for that agonist at three different doses without altering response rates. A kappa-selective antagonist blocked this substitution, confirming the receptor mechanism. These findings support salvinorin A's potential for therapeutic developments, including pain relief, while also raising public concern about its misuse.
Behavioural Pharmacology
October 1, 2012
Mitchell T Harden, Staci E Smith, Jennifer A Niehoff et al.
37 citations
Salvinorin A (SalvA), a compound from the plant Salvia divinorum that activates κ-opioid receptors, may have antidepressant effects. In a study using male and female Long-Evans rats, chronic mild stress (CMS) for three weeks reduced their preference for sucrose water, indicating anhedonia, a key symptom of depression. After three more weeks of CMS, rats given daily injections of 1 mg SalvA per kilogram of body weight showed a reversal of this anhedonia, while control rats did not. Nonstressed rats given the same dose showed no change in sucrose preference. The findings suggest that chronic SalvA treatment acts as an effective antidepressant in this animal model.
Brain Sciences
August 28, 2025
Seif Abouheif, Ahmed Awad, Christopher R Mccurdy
1 citation
Indolethylamine N-methyltransferase (INMT) is an enzyme that adds a methyl group to compounds such as tryptamine, serotonin, and dopamine. Dysregulation of INMT activity is linked to neuropsychiatric disorders, neurodegeneration, and several cancers. This review describes the enzyme's structure, its role in disease, and methods to measure its activity, including both radiolabeled and non-radiolabeled assays. It also surveys natural and synthetic inhibitors of INMT that may have therapeutic value. The authors argue that INMT is an underexplored target for drug development and that integrating structural biology, disease pathology, and inhibitor profiling could advance therapeutic applications.
Journal of Clinical Psychopharmacology
Chad J Reissig, Ling Chen, Srikanth C Nallani et al.
1 citation
A single dose of kratom, a plant from Southeast Asia, produced some opioid-like effects in recreational polydrug users with opioid experience. In a double-blind, placebo-controlled study with 40 participants, kratom at doses of 3 grams or more caused pupil constriction, and the 12 gram dose increased ratings of drug liking, good effects, and high. No deaths or serious adverse events occurred; the most common side effects were somnolence, vomiting, and nausea. The findings suggest kratom can produce effects associated with drugs of abuse, but results may not apply to other kratom products.
bioRxiv (Cold Spring Harbor Laboratory)
September 29, 2024
Sabrina Zequeira, Emely A. Gazarov, Alara A. Güvenli et al.
preprint
Acute cannabis smoke enhanced working memory accuracy in aged male rats but impaired it in aged females, with no effects in young adults of either sex. The same smoke had minimal effects on a hippocampus-dependent memory task regardless of age or sex. Chronic oral Δ9-tetrahydrocannabinol (Δ9THC) enhanced working memory in aged rats of both sexes while not affecting young adults, and did not affect spatial learning or memory in either age group. Minimal age differences in Δ9THC pharmacokinetics were observed. Cannabis and Δ9THC can attenuate working memory impairments that emerge in aging without exacerbating age-associated hippocampus-dependent cognitive decline.
Journal of Analytical Toxicology
April 30, 2026
Alexandria S. Senetra, Sushobhan Mukhopadhyay, Yi-Hua Chiang et al.
Delta-8-THC, a cannabinoid growing in popularity for its reported therapeutic effects, was studied in male rats to understand its pharmacokinetics. After a single oral dose of 7.5 mg/kg, the compound showed very low oral bioavailability of 3.0%, with a peak plasma concentration of 13.4 ng/mL reached in 0.5 hours. Intravenous dosing at 1.25 mg/kg revealed a clearance rate higher than rat liver blood flow, suggesting elimination occurs partly outside the liver, and a large volume of distribution, indicating extensive movement into tissues. The elimination half-life was 13.9 hours. These findings suggest that oral Delta-8-THC is poorly absorbed, while its distribution and clearance patterns resemble those of other cannabinoids.
Pharmacological reports : PR
April 1, 2026
Elmira Zolali, Mallory Burns, Sebastiano Intagliata et al.
Combining the sigma1 receptor antagonist CM304 with delta9-tetrahydrocannabinol (THC) enhances pain relief without worsening THC's side effects. In mice, CM304 increased the pain-blocking effect of THC and caused greater body temperature drops when combined. A high dose of CM304 alone reduced movement. In rats, CM304 made THC's pain relief more potent. CM304 did not produce THC-like effects in rats trained to recognize THC, nor did it amplify THC's subjective effects. The findings suggest sigma1 receptor antagonists could be safer adjuncts to cannabinoid-based pain treatments, offering pain relief without increasing adverse effects like sedation or abuse potential.
The FEBS Journal
May 1, 2006
Brian E. Kane, Marcelo J. Nieto, Christopher R Mccurdy et al.
Salvinorin A, a potent kappa opioid receptor agonist, binds to a specific cluster of residues in transmembrane helices II and VII, including Q115, Y119, Y312, Y313, and Y320, rather than to traditional opioid binding sites. A model is proposed where the ligand aligns vertically between these helices, spanning residues one to two turns down the helix faces. The extracellular loop 2 (EL-2) plays an indirect role in binding and selectivity. These findings clarify the structural basis for salvinorin A's unique binding and selectivity.