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

Abstract

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 kappa opiate receptor (KOR), 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 EEG spectral power. 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 KOR 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.

The G Protein–Biased κ-Opioid Receptor Agonist RB-64 Is Analgesic with a Unique Spectrum of Activities In Vivo

“…The KOR agonists are well known to induce dysphoria and an anhedonic-like response in humans and mice (Potter et al, 2011;Ranganathan et al, 2012). For these studies, the anhedonia-like effects of sal A, RB-64, or U69593 were tested in C57BL/6J mice using the curve-shift method of ICSS (Carlezon and Chartoff, 2007).…”

“…Thus, for instance, 1) angiotensin II receptor arrestin-biased agonists are being investigated for treating acute heart failure; 2) m-opioid receptor G protein biased agonists have been proposed as novel analgesics; 3) d-opioid receptor G protein-biased agonists are being considered for Parkinson disease, pain, and depression; and 4) the dopamine D 2 arrestin-biased agonists are being evaluated for treating schizophrenia and related disorders Pradhan et al, 2011;Whalen et al, 2011;DeWire et al, 2013;Monasky et al, 2013). Significantly, a wealth of data implies that G protein-biased KOR ligands might represent novel analgesics with lower addiction liability and fewer side effects (Bruchas et al, 2007;Tao et al, 2008;Ranganathan et al, 2012).…”

“…Although k-opioid receptor (KOR) agonists have long been recognized to be analgesic with low abuse potential, their use can be associated with severe side effects, including dysphoria, anhedonia, and hallucinations (Pfeiffer et al, 1986;Ranganathan et al, 2012;Tejeda et al, 2013). KOR activation induces p38 mitogen-activated protein kinase (MAPK) activation in vivo, thereby mediating KOR-induced aversion in mice, but not analgesia (Bruchas et al, 2007).…”

Novel Orally Available Salvinorin A Analog PR-38 Inhibits Gastrointestinal Motility and Reduces Abdominal Pain in Mouse Models Mimicking Irritable Bowel Syndrome

“…SA, the active component of S. divinorum, has recently been demonstrated to exhibit significant effects on smooth muscle relaxation, neuroprotection, and analgesia (Fichna et al, 2009a) and, similar to other KOR agonists, has a great potential to become a drug used in the clinical treatment of GI disorders dominated by diarrhea and abdominal pain, such as diarrhea-predominant IBS. However, in the case of SA, this potential is strongly hampered by its adverse effects, since it rapidly crosses the blood-brain barrier and causes short-lived hallucinations (Ranganathan et al, 2012). Therefore, attempts to develop new analogs with similar activity are undertaken.…”

“…It is widely known that SA is a strong, short-acting psychoactive compound, and its actions in humans range from impaired motor activity, visual effects, memory impairment, and unresponsiveness to feelings of anxiety/fear, distance from usual daily reality, and paranoia (Ranganathan et al, 2012;Maclean et al, 2013). To determine the potential side effects of PR-38, we focused our attention on behavioral parameters that undergo changes after administration of SA in rodents and mimic the effects of the compound in humans (Braida et al, 2009;Walentiny et al, 2010).…”