The Journal of pharmacology and experimental therapeutics
March 1, 2004
Charles Chavkin, Sumit Sud, Wenzhen Jin et al.
212 citations
Salvinorin A, a diterpene from Salvia divinorum, is a high-affinity and selective full agonist at human kappa-opioid receptors. In human embryonic kidney-293 cells, salvinorin A fully inhibited forskolin-stimulated cAMP production, while derivatives like 2-propionate and 2-heptanoate were partial agonists. Further tests using chimeric G proteins confirmed its potency and efficacy. In Xenopus oocytes with minimal receptor reserve, salvinorin A acted as a full agonist, more efficacious than standard agonists U50488 and U69593, and similar to dynorphin A. The 2-position substituent is critical for receptor binding and activation. Salvinorin A is the first known naturally occurring non-nitrogenous full agonist at kappa-opioid receptors.
The Journal of pharmacology and experimental therapeutics
August 1, 2006
Michael A Ansonoff, Jiwen Zhang, Traci Czyzyk et al.
101 citations
Salvinorin A, the active component of the hallucinogenic plant Salvia divinorum, produces pain relief (antinociception) and lowers body temperature in mice by activating the kappa-opioid receptor. These effects were observed after injection of salvinorin A or a similar compound, salvinorinyl-2-propionate, into the brain of normal mice, but not in mice genetically lacking the kappa-opioid receptor. Salvinorin A showed high affinity specifically for the kappa-1 subclass of opioid receptors. In contrast, salvinorin B, an inactive derivative, had no effect on pain or body temperature. The findings confirm that salvinorin A acts through the kappa-opioid receptor to produce its behavioral effects.
The Journal of pharmacology and experimental therapeutics
February 1, 2007
Richard B Rothman, Daniel L Murphy, Heng Xu et al.
75 citations
Salvinorin A, a hallucinogenic compound that activates kappa-opioid receptors, also partially inhibits mu-opioid receptor binding through an allosteric mechanism. In cells expressing human mu-opioid receptors, salvinorin A reduced binding of two different radioligands (DAMGO and diprenorphine) in a dose-dependent, nonlinear way, altering both the number of binding sites and their affinity. It also slowed the dissociation of these ligands from the receptor and acted as an uncompetitive inhibitor of receptor signaling. Similar effects were observed in rat brain tissue. Together, these findings indicate that salvinorin A modulates the mu-opioid receptor allosterically, not by binding at the same site as typical opioids.
The Journal of pharmacology and experimental therapeutics
February 1, 2009
Eduardo R Butelman, Thomas E Prisinzano, Haiteng Deng et al.
67 citations
Salvinorin A, the main active component of the hallucinogenic plant Salvia divinorum, produces rapid behavioral effects in nonhuman primates, including sedation and postural relaxation, similar to synthetic kappa-agonists. These effects occur within 1 to 2 minutes of intravenous injection and can be blocked by the opioid antagonist nalmefene. The drug enters the central nervous system within 1 minute at concentrations matching its affinity for brain kappa-receptors. This is the first systematic documentation of such rapid unconditioned effects in a primate species, consistent with human reports of the drug's fast and powerful effects.
The Journal of pharmacology and experimental therapeutics
January 1, 2007
Eduardo R Butelman, Marek Mandau, Kevin Tidgewell et al.
64 citations
The hallucinogen salvinorin A, derived from the plant Salvia divinorum, acts as a high-efficacy kappa-opioid agonist in nonhuman primates. In a neuroendocrine biomarker assay measuring the anterior pituitary hormone prolactin, salvinorin A produced dose- and time-dependent effects in adult male and female rhesus monkeys (n = 4 each). It was approximately equipotent to the synthetic kappa-agonist U69,593 (ED50 0.015 mg/kg vs. 0.0098 mg/kg) but had a shorter duration. The effects were blocked by a high dose of the opioid antagonist nalmefene (0.1 mg/kg) but not by a low dose (0.01 mg/kg) or by the 5HT2 receptor antagonist ketanserin. Effects were more robust in females. Cloning of the rhesus monkey kappa-opioid receptor gene showed high homology with the human gene.
The Journal of pharmacology and experimental therapeutics
February 1, 2008
Jun-Xu Li, Kenner C Rice, Charles P France
51 citations
In rhesus monkeys trained to distinguish the hallucinogen DOM from a placebo, the drug's effects lasted up to two hours and were blocked by serotonin 5-HT2A receptor antagonists but not by the dopamine antagonist haloperidol. Other hallucinogens such as LSD and 2C-T-7 produced DOM-like effects, but the kappa-opioid hallucinogen salvinorin A did not, nor did several other psychoactive drugs. These results confirm that 5-HT2A receptors play a key role in the discriminative stimulus effects of certain hallucinogens in nonhuman primates, and they reveal that different classes of hallucinogens produce qualitatively distinct effects.
The Journal of pharmacology and experimental therapeutics
February 1, 2014
Patrick Thurner, Anna Stary-Weinzinger, Hend Gafar et al.
41 citations
Ibogaine, a psychoactive alkaloid used to treat addiction, can cause dangerous heart rhythm problems by blocking hERG potassium channels. Experiments on mammalian kidney cells expressing hERG channels showed that block occurred from either side of the cell membrane and depended on pH. Block happened only when channels were activated, not when resting. Stronger depolarizations increased block speed and extent. The drug shifted channel activation and inactivation to more negative voltages, slowed deactivation, and accelerated inactivation. Mutations Y652A and F656A reduced ibogaine's potency, but an inactivation-deficient mutant remained sensitive. Molecular docking suggested binding inside the channel cavity regardless of ibogaine's protonation state. Kinetic modeling indicated preferential binding to open and inactivated states.
The Journal of pharmacology and experimental therapeutics
November 1, 2009
K S Murnane, N Murai, L L Howell et al.
34 citations
MDMA (ecstasy) has two mirror-image forms, or enantiomers, that produce different effects: one acts more like a stimulant, the other more like a hallucinogen. In mice trained to recognize one or the other enantiomer, a stimulant drug fully substituted only for the stimulant-like enantiomer, and a hallucinogen-like drug fully substituted only for the hallucinogen-like enantiomer. Cocaine and a tryptamine hallucinogen substituted for both, but each was more potent for one enantiomer than the other. These results indicate that the two enantiomers of MDMA produce qualitatively distinct internal sensations in mice, helping explain the drug's complex psychoactive profile.
The Journal of pharmacology and experimental therapeutics
December 1, 2014
Douglas A Smith, Jessica M Bailey, Diarria Williams et al.
31 citations
Tolerance developed to the head twitch response (HTR) elicited by daily administration of the phenethylamine-derived hallucinogens DOI and 2C-T-7 in mice, but not to the tryptamine-derived drugs DPT and DIPT. Tolerance to DOI was insurmountable by increasing dose, and cross-tolerance to 2C-T-7 and DPT was also insurmountable in DOI-tolerant mice. These results suggest that phenethylamine-derived 5-HT2A agonists may be limited for chronic therapeutic use by rapid tolerance development that persists even when switching to a different structural class. Tryptamine-derived hallucinogens may have a reduced tolerance potential and could be more suitable for long-term administration.
The Journal of pharmacology and experimental therapeutics
June 1, 2012
Eduardo R Butelman, Michael Caspers, Kimberly M Lovell et al.
27 citations
The major efflux transporter P-glycoprotein at the blood-brain barrier modulates the central nervous system effects of the hallucinogen salvinorin A. Pretreatment with either the competing substrate loperamide (0.032-0.32 mg/kg) or the selective blocker tariquidar (0.32-3.2 mg/kg) dose-dependently enhanced salvinorin A-induced ptosis, but not facial relaxation, in nonhuman primates. Neither agent affected the effects of U69,593, a κ-agonist that is a poor P-glycoprotein substrate. Tariquidar (3.2 mg/kg) also increased peak levels of salvinorin A in cerebrospinal fluid after intravenous administration. These findings demonstrate that P-glycoprotein activity can influence salvinorin A's behavioral effects and CNS entry.
The Journal of pharmacology and experimental therapeutics
April 1, 2010
Jun-Xu Li, Wouter Koek, Kenner C Rice et al.
17 citations
Serotonin (5-HT)1A receptor agonists attenuated the effects of the 5-HT2A receptor agonist DOM in rhesus monkeys but not in rats, indicating a species difference in how these receptor systems interact. DOM and other 5-HT2A agonists produced similar discriminative stimulus effects in both species, and these effects were blocked by a 5-HT2A antagonist. The 5-HT1A agonists 8-OH-DPAT and F13714 reduced DOM's effects only in monkeys, an effect prevented by a 5-HT1A antagonist. The findings suggest that while the DOM stimulus is mediated by 5-HT2A receptors in both species, the modulatory role of 5-HT1A receptors differs markedly between rats and monkeys, which has implications for studying drugs with multiple mechanisms.
The Journal of pharmacology and experimental therapeutics
March 1, 2009
Jun-Xu Li, Kenner C Rice, Charles P France
16 citations
In rhesus monkeys trained to distinguish the hallucinogen DOM from a placebo, three related compounds—DOM, 2C-T-7, and DPT—all produced dose-dependent increases in drug-appropriate responding. Three antagonists (MDL100907, ketanserin, and ritanserin) each shifted the dose-response curves of all three agonists rightward in a parallel, competitive manner. The calculated apparent affinities (pA₂ values) for each antagonist were similar across agonists and correlated with their binding affinities at 5-HT₂A receptors, not at 5-HT₂C or alpha₁ adrenergic receptors. These results provide quantitative evidence that the 5-HT₂A receptor subtype predominantly, if not exclusively, mediates the discriminative stimulus effects of these hallucinogenic drugs in rhesus monkeys.
The Journal of pharmacology and experimental therapeutics
January 1, 2025
Claire E Miller, Phillip R Zoladz
10 citations
Post-traumatic stress disorder (PTSD) is a debilitating condition with symptoms including intrusive memories, avoidance, anxiety, and altered physiology. Current treatments are often insufficient, with nonresponse rates exceeding 50%. Psilocybin, a psychedelic from Psilocybe mushrooms, has shown antidepressant and anxiolytic effects in preclinical and clinical studies. This review summarizes evidence for psilocybin's behavioral effects and links them to potential efficacy in treating PTSD symptoms. It explores proposed mechanisms, benefits, drawbacks, and challenges for future research, aiming to highlight this promising area for novel PTSD therapies.
The Journal of pharmacology and experimental therapeutics
January 17, 2024
Ana Ribeiro-Davis, Dalia Y Al Saeedy, Fay M Jahr et al.
10 citations
In a rat model of Gulf War Illness (GWI), a single antidepressant dose of ketamine reversed epigenetic changes in the hippocampus. Ketamine inhibited the upregulation of histone deacetylase enzymes, restored acetylation at the Bdnf gene promoter, and increased brain-derived neurotrophic factor (BDNF) protein expression. It also increased dendritic spine density and altered spine types, shifting from S-type to T-type spines. These results suggest ketamine's antidepressant effect in GWI-related depression involves histone modifications that boost BDNF and reshape synaptic connections, supporting further clinical trials for GWI-related depression.
The Journal of pharmacology and experimental therapeutics
May 1, 2025
Amaya R Jenkins, Daniela B Radl, Thomas J Kornecook et al.
8 citations
Ketamine produces short-lived increases in reward responsiveness in rats under nonstressful conditions, but under ongoing chronic stress it rescues blunted reward responsiveness for nearly one week. These findings highlight the role of environmental context in ketamine's effects on reward processing and suggest its antianhedonic action may contribute to its antidepressant efficacy.
The Journal of pharmacology and experimental therapeutics
September 18, 2024
Candace B Johnson, Donna Walther, Matthew J Baggott et al.
5 citations
MDMA is effective as a treatment for PTSD but carries cardiovascular and neurological risks. Researchers tested two new compounds, 5-MABB and 6-MABB, in rat brain tissue and in live rats trained to recognize MDMA. The S isomers of both compounds released serotonin, norepinephrine, and dopamine, similar to MDMA. The R isomers released serotonin and partially released norepinephrine but not dopamine. All compounds caused rats to respond as if they had received MDMA, with effects increasing with dose. The R isomers were less potent behaviorally. The findings suggest the aminoalkyl benzofuran structure is a promising starting point for developing safer MDMA-like drugs.
The Journal of pharmacology and experimental therapeutics
October 18, 2024
Rachel Luba, Gabriela Madera, Rebecca Schusterman et al.
2 citations
Lenabasum, a selective CB2 receptor agonist, was tested for abuse potential in 56 people who use cannabis recreationally. At the target therapeutic dose of 20 mg, lenabasum did not increase ratings of drug liking compared with placebo. However, higher, supratherapeutic doses of 60 and 120 mg did produce dose-dependent increases in drug liking, though less than nabilone, an FDA-approved medication. Lenabasum was safe and well tolerated, but it does have abuse potential and should be used cautiously in clinical settings.
The Journal of pharmacology and experimental therapeutics
January 1, 2025
Megan Wells, Jan Hoffmann, Autumn Stage et al.
1 citation
Combining a single dose of ketamine with chronic fluoxetine (Prozac) reduces fear memory in mice two weeks after fear conditioning, though it does not reduce anxiety or fear generalization in an open field test. Fluoxetine alone was most effective at reducing fear generalization. Current PTSD medications lead to symptom remission in fewer than 30% of patients. This study offers preliminary support for a more effective therapeutic option for stress-related disorders.