This review (2019) examines the analgesic, anti-inflammatory, and psychoactive properties of the hallucinogenic plant Salvia Divinorum and its bioactive (analog) constituents.
Salvia divinorum is a herbal plant native to the southwest region of Mexico. Traditional preparations of this plant have been used in illness treatments that converge with inflammatory conditions and pain. Currently, S. divinorum extracts have become popular in several countries as a recreational drug due to its hallucinogenic effects. Its main active component is a diterpene named salvinorin A (SA), a potent naturally occurring hallucinogen with a great affinity to the κ opioid receptors and with allosteric modulation of cannabinoid type 1 receptors. Recent biochemical research has revealed the mechanism of action of the anti-inflammatory and analgesic effect of SA at the cellular and molecular level. Nevertheless, because of their short-lasting and hallucinogenic effect, the research has focused on discovering a new analogue of SA that is able to induce analgesia and reduce inflammation with a long-lasting effect but without the hallucinatory component. In this review, we explore the role of S. divinorum, SA and its analogues. We focus mainly on their analgesic and anti-inflammatory roles but also mention their psychoactive properties.
Salvia divinorum is a herbal plant from southwestern Mexico long used in Mazatecan medical and religious practice. Traditional preparations have been applied to ailments that overlap with inflammatory conditions and pain such as headaches, gastrointestinal complaints and rheumatism, while modern extracts with elevated salvinorin A concentrations are widely used recreationally for their potent, short-lived hallucinogenic effects. Phytochemical work has identified a series of neo-clerodane diterpenes (salvinorins A–F), with salvinorin A (SA) the dominant active component; pharmacological screening shows SA is a high-affinity agonist at κ opioid receptors (KORs) and modulates cannabinoid type 1 (CB1) receptors, but lacks action at the classical 5-HT2A serotonin receptor targeted by psilocybin and LSD. This review aims to synthesise available evidence on S. divinorum, SA and semi-synthetic analogues with emphasis on analgesic and anti-inflammatory effects, while also describing psychoactive properties and safety signals. Coffeen and Pellicer focus mainly on preclinical pharmacology, mechanistic biochemical data, animal models of inflammation and pain, and early reports in humans and poison-control data to consider therapeutic potential and remaining translational challenges.
Papers cited by this study that are also in Blossom
Maqueda, A. E. · Plant Medicines Healing and Psychedelic Science (2018)
Johnson, M. W., Maclean, K. A., Reissig, C. J. et al. · Drug and Alcohol Dependence (2011)
Maqueda, A. E., Valle, M., Addy, P. H. et al. · International Journal of Neuropsychopharmacology (2015)
The extracted text presents a narrative review rather than a methods-driven systematic review: no explicit search strategy, databases, date ranges, or formal inclusion/exclusion criteria are reported in the provided sections. The investigators draw on ethnobotanical reports, biochemical receptor screening, in vitro experiments, animal models (rodent and zebrafish), selected human experimental and observational reports, and studies of semi-synthetic analogues to assemble the account. Because primary study designs vary across the sources cited, the review integrates receptor binding and signalling data, pharmacokinetic and imaging findings (for example PET in rodents and baboons), behavioural assays of reward and nociception (conditioned place preference, self-administration, tail-flick, hot-plate and formalin tests), models of intestinal inflammation and colitis, and toxicology results from in vivo and in vitro studies. The extracted text does not describe a formal risk-of-bias assessment or quantitative meta-analysis approach.
Psychoactivity: Salvinorin A produces a distinct profile of brief, intense subjective effects. Field reports of traditional aqueous leaf preparations described lightheadedness, altered proprioception and amplified imagery without frank hallucinations, but modern concentrated extracts give potent hallucinatory experiences in humans. The reported hallucinogenic dose of SA in humans is 250–500 µg and its potency is slightly lower than LSD. Experimental human reports and animal work indicate rapid onset and short duration of action: intravenous SA in baboons reached 3.3% of the injected dose in brain within 40 seconds and cleared to half the peak by 8 minutes, consistent with rapid smoked effects in humans. Neuroimaging and electrophysiology studies implicate KOR-rich regions (periaqueductal grey, bed nucleus of the stria terminalis, cerebellar vermis, hypothalamus, auditory and sensory cortices) and changes in anterior versus posterior cortical spectral power. Behavioural models of reward show strain- and species-dependent results: SA induced conditioned place preference in zebrafish and Wistar rats (with increased nucleus accumbens dopamine), but failed to support self-administration in some rat strains; the rewarding effects in zebrafish and some rodent models were blocked by the KOR antagonist nor-BNI and by the CB1 antagonist rimonabant. Chronic human use can produce withdrawal-like symptoms (anxiety, irritability, malaise) and functional impairment consistent with substance use disorder criteria in some cases. Inflammation: Ethnobotanical use for gastrointestinal disorders prompted preclinical studies showing anti-inflammatory actions of SA and extracts. In mouse models of intestinal inflammation, SA inhibited motility and hypermotility during inflammation via mechanisms involving KOR and CB1 receptors and in some assays CB2, suggesting cross-talk between opioid and endocannabinoid systems in the gut. In vitro, SA reduced inducible nitric oxide synthase (iNOS) expression following LPS challenge in macrophages, lowered pro-inflammatory TNF-α and restored anti-inflammatory IL-10 production, and prevented epithelial barrier dysfunction via NOS-2–related pathways. SA inhibited leukotriene B4 (LTB4) biosynthesis in a concentration-dependent manner in isolated macrophages and reduced LT levels in zymosan-induced peritonitis and carrageenan pleurisy, indicating potential utility against LT-mediated inflammatory states. Intraperitoneal, oral and intracolonic SA showed anti-inflammatory effects in two experimental colitis models and produced analgesia in mice with ongoing intestinal inflammation; these effects were mediated by KOR and CB1 receptors. Analgesia: A body of preclinical evidence indicates SA and S. divinorum extracts have antinociceptive properties. Peripheral administration produced dose-dependent effects in thermal (tail-flick) and chemical (acetic-acid abdominal constriction) nociception assays as well as in the hot-plate test; analgesia was reversed by nor-BNI, implicating KOR. Co-administration of a hydroponic S. divinorum extract with anandamide (a cannabinoid agonist) produced synergistic analgesia in the hot-plate test at low doses. Central administration studies showed intrathecal SA increased tail-flick latencies at 13.9–23.1 nmol, and intracerebroventricular SA or a derived ester produced analgesia in wild-type but not KOR knockout mice. Ligand-binding assays report high affinity of SA for the κ1 receptor (K i 18.7 ± 3.4 nM) and very low affinity for a κ2 subtype (K i >10,000 nM), indicating receptor subclass selectivity. Repeated SA administration over about 7 days reduced formalin-induced mechanical allodynia, decreased neuronal hyperexcitability and glial activation in models of chronic pain via spinal KOR and CB1 mechanisms. Local microinjection of SA into the insular cortex produced marked antinociception in a rat neuropathic pain model, a finding the investigators attribute to KOR affinity and CB1 modulation. Analogues: Because SA has limitations for therapeutic use—poor oral viability, very short duration of action, rapid metabolism to inactive salvinorin B and P-glycoprotein efflux—considerable medicinal chemistry work has produced roughly 600 semi-synthetic analogues, principally modifying the C2 acetate or the furan ring to extend duration and alter receptor profiles. Examples include herkinorin, a µ-opioid receptor (MOR)–selective agonist that produced antinociception in formalin tests with apparent minimal tolerance and which activated MOR and KOR without recruiting β-arrestin pathways; PR-38 (2-O-cinnamoylsalvinorin B) with K i 9.6 nM at KOR and K i 52 nM at MOR, which modulates intestinal motility via MOR and KOR, retains CB1 interaction and is orally bioavailable; and β-THP SalB, a C2-substituted derivative with preserved binding affinity (full characterisation not provided in the extracted text). Several analogues show efficacy in acute, inflammatory and neuropathic pain models, and some have improved pharmacokinetic or receptor-signalling properties. Side effects and toxicity: Human poison-control data over a 10-year period report neurologic, cardiovascular and gastrointestinal effects following intentional S. divinorum exposures, with worse outcomes when combined with other substances; the study cited is limited by small sample size and lack of laboratory confirmation. Rodent studies reported no major changes in cardiac conduction, temperature or galvanic skin response after acute or chronic SA administration, and no significant histological changes in spleen, blood, brain, liver, kidney or bone marrow at examined doses, suggesting relatively low in vivo toxicity in those assays. By contrast, in vitro studies across multiple cell lines (neuronal, hepatic, pulmonary, renal, intestinal) indicated dose- and time-dependent cytotoxicity, with concentrations such as 50 µM and, after prolonged exposure, 10 µM reducing cell viability in hepatic lines. The investigators note that extensive in vivo and clinical toxicology studies are still needed. Other findings: The investigators' own laboratory work reported that intraperitoneal S. divinorum ethyl acetate extract did not increase nucleus accumbens dopamine in Wistar rats, supporting the view that salvinorins may have lower addiction potential relative to classical drugs of abuse.
Coffeen and Pellicer interpret the assembled evidence as indicating that S. divinorum, salvinorin A and selected analogues possess credible anti-inflammatory and analgesic effects in preclinical models, mediated primarily via high-affinity KOR agonism and modulation of endocannabinoid receptors (CB1 and in some assays CB2). They highlight multiple mechanistic actions—reduction of iNOS, suppression of TNF-α, restoration of IL-10, inhibition of leukotriene biosynthesis and suppression of motility and nociceptive signalling in inflamed tissues—as supportive of potential utility in conditions such as inflammatory bowel disease, neuropathic pain and other LT-related inflammatory states. Positioning these findings against earlier research, the investigators note the pharmacological distinctness of SA from classical serotonergic hallucinogens because it lacks 5-HT2A activity, and they underscore the rapid pharmacokinetics that explain short-lived subjective effects. The discussion emphasises medicinal chemistry efforts to overcome limitations of SA—poor oral bioavailability, brief receptor binding and rapid metabolism to inactive salvinorin B—and presents several analogue strategies that have shown promise in prolonging activity or shifting receptor selectivity. Key limitations acknowledged include the predominance of preclinical data, variability across species and strains in behavioural responses, sparse and limited human safety data, and mixed signals from in vitro cytotoxicity studies. The extracted text also highlights pharmacokinetic barriers (enzymatic degradation, P-glycoprotein efflux) and the need to separate analgesic/anti-inflammatory efficacy from undesired hallucinogenic effects. As implications, the investigators propose that further development of non-hallucinogenic, longer-acting salvinorin analogues could provide alternative therapies for inflammatory and neuropathic pain and help address gaps in analgesic drug development; they also suggest that the apparent lack of increased nucleus accumbens dopamine in some models points to potentially lower addiction risk. Ultimately, Coffeen and Pellicer call for more extensive in vivo toxicology and clinical studies to define safety, dosing, efficacy and translational potential.
Salvia divinorum (Lamiaceae) is a herbal plant native to the southwest region of Mexico. It was used for medical and religious purposes for centuries in the Mazatecan culture and has a hallucinatory component. Recently, S. divinorum extracts have been used in several countries as a recreational drug due to its hallucinogenic effects; 1 its expanded use has been facilitated by its accessibility on the Internet.However, traditional preparations with smaller quantities have been used in illness treatments that converge with inflammatory conditions and pain, such as headaches, gastrointestinal (GI) problems, or rheumatism.Mazatecan people also use S. divinorum for healing multiples conditions, including insect bites, eczema, candidiasis, cystitis, and menstrual cramps, and even depression or alcohol addiction.These multiple therapeutic targets implicate a complex pharmacology and mechanism of action for this mystical plant. In 1982, Ortega et al isolated a new neo-clerodane diterpene named salvinorin, which is the main active compound of S. divinorum.Two years later, Valdés et al isolated the components named divinorin A (a psychotropic terpenoid) and divinorin B, but later it was confirmed that both structures correspond to salvinorin A (SA) and B (SB), respectively, proposed by Ortega et al.Currently, phytochemical research has led to the isolation of several diterpenes, from SA to salvinorin F. As mention earlier, the main active diterpene of the plant is the SA, and it has been reported to be the most powerful naturally occurring hallucinogen.Pharmacological screening of a battery of 50 receptors, transporters, and ion channels showed that SA shows significant activity only with the κ opioid receptors (KORs), and importantly, SA shows no action at the 5-HT2A serotonin receptor, which is the main molecular target for the classical hallucinogens such as psilocybin and lysergic acid diethylamide (LSD).Also, it has been described that the role of SA in the cannabinoid system, through the modulation of the cannabinoid type 1 (CB1) receptors, maybe due to the crossinteraction between KOR and CB1 receptors.Moreover, the peripheral action of SA includes inhibition of leukotrienes and cytokines related with inflammatory processes.In this article, we review the role of S. divinorum, SA, and its analogues, focusing mainly on their analgesic and antiinflammatory roles, as well as their psychoactive properties.
In a field research project performed between 1973 and 1983, Díaz described that the intake of an aqueous preparation of crushed leaves of S. divinorum produced short-lasting lightheadedness, dysphoria, tactile and proprioceptive sensations, a sense of depersonalization, amplified sound perception, and increased visual and auditory imagery, with no actual hallucinations.However, currently, the consumption of leaf extracts of S. divinorum with increased SA concentrations, which are sold on Internet sites, produces a potent hallucinatory effect. The reported hallucinogenic dosage of salvinorin A in humans is 250-500 µg, and its potency is slightly inferior to the well-known synthetic hallucinogen, LSD.Experimental consumption of SA in healthy volunteers indicated experiences related to disruptions in vestibular and interoceptive signals (eg, change in spatial orientation), and also recurring experiences like revisiting childhood memories, cartoon-like imagery, and contact with entities.Chronic consumption produces subjective symptoms of withdrawal, mainly anxiety, irritability, and malaise; also, this pattern of use results in failure to fulfill major role obligations leading to exacerbation of social and interpersonal problems, which are criteria used to diagnose substance use disorder.Animal research reveals that even in less evolved species, SA exhibits rewarding effects. In a model of conditioned place preference (CPP) in zebrafish, SA induced a "trancelike" effect which was blocked by pretreatment with the KOR antagonist Nor-binaltorphimine and with the CB1 antagonist rimonabant.In rats, SA action depends on the strain, dosage, and administration route. In Wistar rats, SA has shown rewarding effects in CPP model and induces an increase of extracellular dopamine in nucleus accumbens (Nacc);however, in two different strains (Male Lister Hooded and Sprague Dawley), SA could not establish a self-administration behavior and was only capable of slightly modifying extracellular levels of dopamine in Nacc.In this regard, in our laboratory, we found that intraperitoneal administration of S. divinorum ethyl acetate extract in Wistar rats does not modify dopamine levels in Nacc, suggesting that S. divinorum extract does not induce addictive behavior.As mentioned earlier, studies in humans, non-human primates, and rodents have shown that the hallucinogenic effects produced by SA are associated with the activation of the KOR but not 5-HT2A receptor.Also, the minutes-long hallucinogenic and dissociative effects of recreational S. divinorum in humans have been described in detail.Recently, our group analyzed these effects in rats, by recording the changes in electrocorticogram (ECoG) activity in the anterior and posterior regions of the brain (associated with motor activity and somatosensory perception, respectively) following the administration of S. divinorum extract. We found that S. divinorum extract increased absolute power gradually in the anterior cortex, whereas it decreased absolute power in the posterior cortex at all frequency bands, from 10 minutes after the administration of S. divinorum,in a similar way to the decrease in spectral activity in the posterior region caused by inhalation of SA in humans.Hooker et al, through a small positron emission tomography (PET) system that measures brain metabolic changes using a radiotracer (18 FDG), revealed evidence that intraperitoneal administration of SA in rodents may activate brain circuits that mediate the effects of the drug on cognition, mood, fear and anxiety, and motor output, regions associated with the distribution of KOR, for example, the periaqueductal gray, bed nucleus of the stria terminalis, the cerebellar vermis, and the hypothalamus. Also, this effect was observed in the auditory, sensory, and frontal cortices.The same group showed that intravenous administration of SA in baboons crosses the blood-brain barrier reaching 3.3% of the injected dose within 40 seconds and clearing to half of the peak by 8 minutes, consistent with the distinctly rapid onset and recovery of hallucinations from smoked S. divinorum in humans. SA was mainly concentrated in the cerebellum and visual cortex, which may explain its behavioral and hallucinogenic effects when inhaled.Interestingly, Stiefel et al proposed that the consciousness-altering effects produce by SA are processed in part by the claustrum, a site with a high density of KOR.
In Mazatec culture, S. divinorum is normally ingested by chewing fresh leaves or drinking an infusion for treating GI disorders like abdominal swelling, diarrhea, and intestinal spasms, illnesses that course with chronic inflammation. During the last decade, different studies have focused on proving the effect of S. divinorum and SA in inflammatory models. For instance, using croton oil as an irritant that produces experimental chronic inflammation in the mouse small intestine, Capasso et al demonstrated that under physiological state SA exerts a weak effect on motility (independent effect from activation of KOR), but during the inflammatory state, SA inhibits motility at doses that were inactive in control animals through a KOR-dependent mechanism.The same group has shown an inhibitory effect of SA on ileitis-induced hypermotility, involving not only KOR but also CB1 receptors. KOR ligands play a role in the treatment of GI disorders, such as postoperative ileus, irritable bowel syndrome, and intestinal inflammation.Moreover, activation of CB receptors inhibits excitatory cholinergic neurotransmission in mouse gastric preparations.In this sense, SA inhibited contractions of the mouse colon, stomach, and ileum in vitro; prolonged colonic propulsion; and slowed upper GI transit in vivo by activating KOR, CB1, and interestingly by activating cannabinoid type 2 receptors (CB2).These findings suggest a cross-interaction between KOR and CB receptors in the regulation of GI tract under inflammatory conditions. In vitro studies have shown that SA reduces the inducible nitric oxide synthase (iNOS, the enzyme which synthesizes NO in pathophysiological states) expression in lipopolysaccharide (LPS) insult in macrophages, but not cyclooxygenase (COX-2).SA also reduces the levels of pro-inflammatory cytokine TNF-α and restores the cytokine IL-10 production, which acts by limiting the inflammatory response in macrophages.Furthermore, SA reduces endotoxemia-induced GI hyper-motility through opioid and endocannabinoid pathways and also prevents epithelial barrier dysfunction via NOS-2 related pathway but not COX2.KOR and CB1 receptors are localized and overexpressed in the enteric nervous system and immune cells after peripheral inflammation, for example, in clinical disorders like IBD. In this regard, Fichna et al found that intraperitoneal, oral, and intracolonic administration of SA displayed anti-inflammatory activity in two models of experimental colitis as well as analgesia in mice with ongoing acute intestinal inflammation, effects mediated by KOR and CB1 receptors, showing the role of SA as a possible therapeutic agent in the treatment of IBD.Recently, new target of SA action has been identified, that is, by inhibiting leukotriene (LT) biosynthesis. LTs are potent inflammatory lipids mediators, synthesized from arachidonic acid. SA inhibits LTB4, which has been associated with increased chemotaxis, in a concentration-dependent manner . SA reduces LT production in isolated macrophages and in zymosan-induced peritonitis and carrageenan-induced pleurisy. These features open the possibility to use this naturally occurring compound for the treatment of LT-related diseases.Moreover, SA displays a significant control over the allergic inflammation, and its beneficial effect is also correlated with LTs inhibition.
Pain is one of the most common causes of the medical and dental consultations. People suffering from long-lasting pain have their social and working activities affected. The development of adverse effects and the substantial costs that carry the current pain treatments are problems that drive to find new therapeutic alternatives. The biomedical research on S. divinorum, their metabolites, and semi-synthetic analogs in the last decade has shown their potential as an analgesic agent. Peripheral administration of SA in mice induces antinociceptive effect in thermal (tail-flick) and chemonociceptive (acetic acid abdominal constriction) assays in a dose-dependent manner. Moreover, in the hot plate test, SA shows a dose-response effect diminishing nociceptive behavior. Also, similar to inflammation process, pretreatment with nor-BNI (KOR antagonist) reverses the analgesic effect.Further, following the same experimental line, using the hot plate test, in our laboratory, we coadministrated S. divinorum hydroponic extract (containing both salvinorin A and B) and anandamide (cannabinoid agonist), and we found a synergic effect at low doses of both compounds (10 and 30 µg/kg, respectively). This coadministration induced an analgesic effect in two of the main behavioral responses of this test, licking and escape, involved in the spinal and supraspinal nociceptive process (Figure). Despite the evidence for the analgesic effect of S. divinorum in traditional use or in experimental models, their role in the central processing of pain has not been totally studied. On this subject, intrathecal administration of SA in mice increases the tail-flick latencies in a dose-dependent manner (13.9-23.1 nmol); 39 furthermore, intracerebroventricular injection of different doses (1-30 µg) of SA and salvinorinyl-2-propionate (SA derived) produces analgesia only in wildtype mice but not in KOR knockout mice. The same group determined, by means of ligand binding experiments, that salvinorin A has a high affinity for κ1 receptor (K i 18,7±3.4) but not for κ2 opioid receptor (low-affinity KOR, result from δ-κ heterodimerization, K i >10,000), demonstrating selectivity for this receptor subclass.The relief from chronic and neuropathic pain is a challenge for medical science. Current treatments produce tolerance and addiction and are also associated with a high financial cost. SA could be an alternative to traditional treatments, but has the limitation due to its low potency and a very short half-life.However, Guida et al showed evidence that the repeat administration of SA for almost 7 days was capable of reducing mechanical allodynia induced by formalin, reducing neuronal hyperexcitability and glial activation and subsequently contributing to the establishment of a series of dysfunctions associated with chronic pain, a mechanism involving KOR and CB1 receptors at spinal cord level.The development of neuropathic pain is associated with cortical nuclei belonging to the neuropathic pain matrix. One of these structures is the insular cortex (IC), which is related to cognitive processes such as memory or subjective responses such as suffering, a fundamental part of the human consciousness.The IC shows a moderate expression of KOR (although the IC is anatomically surrounded by the claustrum, it does not have the high KOR density that the claustrum has). However, we found in a recent experiment that the direct microinjection of SA in this nucleus in deep cortical layers (V and VI) is capable of inducing a powerful antinociceptive effect in a model of neuropathic pain in rats. This effect may be explained by the high affinity of this compound to KOR and also because of the allosteric modulation of the CB1 receptors.
The therapeutic use of SA has different issues including the administration route (eg, oral route is not viable because of its susceptibility to enzymatic degradation), the short-term effect due to the short binding duration (only minutes) and its high metabolic rate (salvinorin B, the major metabolite is inactive), and also because it is a substrate for P-glycoprotein efflux transporter.Therefore, the development of new derivates of S. divinorum that are capable of producing analgesic and anti-inflammatory effects but with a long-lasting duration is a current challenge. Currently, there are about 600 semisynthetic SA analogues that involve the substitution at the C2 acetate group, only a change at C2, or a change to the furan ring. These structural modifications of SA increase its efficacy and duration of action (for a complete review, see Roach and Shenvi).Some of these analogues have been proved in acute, inflammatory, and neuropathic pain models (Table, Figure). One of the first analogues of SA is herkinorin, a µ opioid selective agonist that possesses antinociceptive properties. Herkinorin was tested in a model of acute and inflammatory pain in rats (formalin test). The drug was able to reduce the nociceptive behavior even after repeated administrations, suggesting minimal tolerance. Herkinorin activated µ opioid receptor (MOR) and KOR in vitro, without recruiting β arrestins or internalizing the receptor (β arrestin interactions is associated with receptor desensitization and morphine FigureThe figure shows the analgesic effect of intraperitoneal injection of different doses of anandamide (AN, 3 and 30 mg/kg), Salvia divinorum extract (SD, 10 and 100 mg/kg), and its coadministration (SD + AN, 10 and 3 mg/kg, respectively) in the hot plate test in rats. Notes: (A) Licking behavior: this behavior is presented between 2 and 4 seconds after the animal is put in the hot plate and is related to supraspinal nuclei activation. (B) Escape behavior: this behavior also involves supraspinal nuclei and is related to cognitive processes. Note that in both behavioral responses, the SD + AN administration induces a significant analgesic effect with respect to vehicle administration (VEH), similar to the high dose of SD, suggesting a synergistic effect (*ANOVA, P=0.05).
antinociceptive tolerance), so Herkinorin is useful for producing anti-nociception without inducing desensitization and resulting in drug tolerance.Another novel analogue 2-O-cinnamoylsalvinorin B (PR-38), which has been synthesized from SA in a simple two-stage process, displayed a good affinity for KOR and MOR with Ki values of 9.6 and 52 nM, respectively. Recently, in a complete research, Salaga et al showed that PR-38 is a strong regulator of intestinal motility, a mechanism mediated by MOR and KOR, and also PR-38 preserved the ability of SA to interact with CB1 receptor. Furthermore, it is able to regulate pain signaling in physiological and pathophysiological conditions via MOR but not KOR or CB1. Moreover, they showed that PR-38 is available orally, which implies a great potential for clinical use.β-Tetrahydropyran salvinorin B (β-THP SalB) has a large protecting group with the substitution of the tetrahydropyran at the C-2 position and has similar binding affinity and
The prominent use of S. divinorum, SA, and its analogues in the chronic diseases that occur with inflammation and pain urge to consider the possible cytotoxicity after the prolonged use of these substances. However, currently there are only a few studies related to this issue. A retrospective review of exposures to S. divinorum reported to the California Poison Control System for 10 years points out that intentional Salvia exposures resulted in a variety of neurologic, cardiovascular, and GI effects. Besides, the use of concomitant substances of abuse was associated with a high rate of complications and psychomotor disturbances. Nonetheless, this study has some limitations like the small sample size; the lack of laboratory tests or biological markers or specific physiological effects; therefore, the exposure to S. divinorum was confirmed only by history.In this sense, a study in rodents showed that acute administration of SA in rats and chronic administration in the mouse has no effects on cardiac conduction, temperature, or galvanic skin response. Also, a nonsignificant rise was seen in pulse pressure. Moreover, histological studies of spleen, blood, brain, liver, kidney, and bone marrow did not show any significant histological changes at any of the doses examined. This suggests that SA has relatively low toxicity.In vitro studies in different cell lines, including dopaminergic neurons, lung, kidney, liver, and intestine, showed that the administration of both S. divinorum and SA is associated with cytotoxic effects, in a dose-and time-dependent manner.Similarly, the same group showed that administration of 50 µM of SA is cytotoxic in different hepatic cell lines; besides, 10 µM of the compound also induced a significant decrease in the cellular viability of cells, in particular, after longer periods of incubation, suggesting that SA shows a low toxicological profile.Nevertheless, extensive in vivo and clinical studies are needed to clearly evaluate their toxicological effects.
Today, we are facing a crisis in relation to the use and abuse of opiates and related molecules. In fact, new molecules are not being developed as analgesics, fundamentally because of the long time taken by the processes to position these new agents until they are properly marketed. One solution in this regard is to look back at the ancestral ethnobotany and the repositioning of existing molecules for new clinical applications. In this sense, S. divinorum can be used as an alternative therapy for inflammatory and neuropathic pain, due in part to the presence of salvinorin A, a powerful KOR agonist and an allosteric modulator of CB1 receptors. The experimental evidence supports the fact that S. divinorum, SA, and their analogues decrease the pain induced by neuropathy and inflammation. Moreover, the fact that S divinorum administration does not increase the release of dopamine in the Nacc suggests that salvinorins and their analogues can be a suitable therapeutic alternative without the risk of producing addiction. Long-lasting pain has been among the major therapeutic challenges of the 21st century due to its disabling effects, especially with the growing population of the elderly. In this regard, finding new molecules or associations to decrease or alleviate pain is of utmost importance.
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