Since the last blog post there have been dozens more research papers released regarding Salvia divinorum and its active compound Salvinorin A. Here I summarise some of the most interesting findings from these studies.

Cocaine sensitivity

Previous blog posts have examined the effects Salvinorin A have on cocaine addiction. I’ve discussed studies showing that giving Salvinorin A to rats before giving them access to cocaine reduces their potential to become addicted. However, these studies only look at an acute (single) administration of Salvinorin A, not chronic (long-term) administration. Chartoff et al. (2015) have just published a study investigating the acute and chronic effects of Salvinorin A administration on cocaine response. They find that, in accordance with previous findings, acute administration of Salvinorin A causes a reduction in the response to cocaine. However, long-term administration of Salvinorin A has complex effects that depend on the context; that is, when rats are given Salvinorin A in their home cages, the effects of cocaine are reduced, but when rats are given Salvinorin A in unfamiliar test cages, the effects of cocaine are enhanced. The authors suggest that Salvinorin A’s effects on the dopaminergic system (responsible for reward and drug dependence) are complex and depend on a number of factors, including the concept of location.

Salvinorin-A analogues and pain-killing

Many researchers are using Salvinorin A as a tool to produce non-addictive painkillers, as I’ve discussed previously. In the past few months, three groups have developed compounds based on Salvinorin A that have painkilling potential.

 

Figure 1: Salvinorin A analogues

Salaga et al. (2015) have been attempting to develop Salvinorin A analogues that have anti-itching effects. They have developed a Salvinorin A analogue, ‘5a’ (figure 1), that has no hallucinogenic or anxiety-inducing effects in mice. They then show that administering this compound to mice can reduce their response to an itch-inducing agent. These promising results put forward this analogue as a potential treatment of chronic itching.

White et al. (2015) are developing a Salvinorin A analogue with painkilling properties, RB-64 (figure 1). They show that, in mice, this compound does not induce the typical side effects of Salvinorin A (dysphoria, motor impairments) and had painkilling effects that lasted much longer than Salvinorin A. RB-64 is one of the frontrunners in the development of a non-addictive painkilling drug.

Lee et al. (2015) have been investigating Salvinorin A analogues and how they bind to the KOR. They found, using several Sal A analogues, that the size of the alkyl group at the C2 position of the analogues determined how well they bound to the KOR (shown in the diagram of ‘5a’, figure 1). Bit by bit, scientists are piecing together our understanding of KOR agonist dynamics.

Salvia’s receptor actions

When drugs bind to receptors, they cause a cascade of messages and signals that spread throughout the cell and affect the way the cell functions. As well as these fairly immediate effects on cell function, drugs can cause longer-term changes to cells. In particular, cells may change the types of receptors they have on their surfaces in response to a drug.

In the case of Salvinorin A, it has recently been discovered that in rat brains, the drug induces KOR internalisation (Placzek et al, 2015), which means the receptors are being brought back into the cell in response to their activation by Salvinorin A (figure 2). The receptors return to normal after a few hours, so this effect is unlikely to have any role in drug tolerance, but this study tells us more about how Salvinorin A and KOR interaction occurs.

Figure 2: Salvinorin A causes receptor internalisation of the KOR. This diagram shows how brain cells react to high concentrations of Salvinorin A; by internalising their Kappa-Opioid Receptors (KOR).

Psychotic risk?

Finally, a blog post on Salvia wouldn’t be complete without some biased scaremongering. El-Khoury & Sahakian (2015) report two of their case studies from Lebanon supposedly showing that Salvia divinorum can induce psychosis.

The first case concerns a 19-year old who suffered a psychotic episode several days after ingesting Salvia divinorum. The patient had previously suffered a psychotic episode a few years earlier, so this psychosis is almost certainly due to an underlying condition rather than due to an extremely delayed response to Salvia divinorum ingestion.

The second case concerns a 24-year old who had a family history of psychotic disorders. He had been smoking cannabis frequently for a year, along with weekly cocaine use, in addition to his moderate Salvia use. He had not been smoking Salvia immediately before his psychotic episode.

In both cases, Salvia could not be linked to the psychotic episodes. In both cases it seems that predisposition to mental disorders or concurrent drug use are more likely explanations. There is still no solid evidence that ingesting Salvinorin A alone has any toxic or psychotic effects on healthy individuals.

A final note

Unfortunately, due to the upcoming ban on psychoactive substances in the UK, this will be the last blog post discussing the use of Salvia divinorum in scientific research. I hope that over the course of the blog I have demonstrated the great potential of Salvia in developing an understanding of how our minds work and in treating pain and addiction. The studies I’ve discussed are excellent examples of why this ban will be a barrier to progress.

Hopefully it won’t be long until we can once again explore this unique and useful plant without risk of criminalisation. 

References

Chartoff, EH et al. (2015) Relative timing between kappa opioid receptor activation and cocaine determines the impact on reward and dopamine release. Neuropsychopharmacology, doi:10.1038/npp.2015.226

Salaga, M et al. (2015) Salvinorin A analogues PR-37 and PR-38 attenuate compound 48/80-induced itch responses in mice. British Journal of Pharmacology, doi:10.1111/bph.13212

White, KL et al. (2015) The G protein-biased kappa-opioid receptor agonist RB-64 is analgesic with a unique spectrum of activities in vivo. Journal of Pharmacology and Experimental Therapeutics, 352:98-109.

Lee, DYW et al. (2015) Synthesis and biological evaluation of 2-alkyl-2methoxymethyl-salvinorin ethers as selective kappa-opioid receptor agonists. Bioorganic & Medicinal Chemistry Letters, doi:10.1016/j.bmcl.2015.06.092

Placzek, MS et al. (2015) Immediate and persistent effects of Salvinorin A on the kappa opioid receptor in rodents, monitored in vivo with PET. Neuropsychopharmacology, 40:2865-2872

El-Khoury, J & Sahakian, N (2015) The association of Salvia divinorum and psychotic disorders: a review of the literature and case series. Journal of Psychoactive Drugs, 47:4, 286-292.