In the last blog post we looked at the unique psychedelic properties of Salvia divinorum. Along with the classical psychedelic effects such as visual distortions, Salvia also induces feelings of strange movement, shifting realities and a loss of control. Scientists often call Salvia’s effects ‘psychotomimetic’, meaning Salvia mimics the delusions experienced in disorders such as Schizophrenia. (Please note – this does NOT mean that salvia causes schizophrenia, only that some parts of the experience can be temporarily similar to some of the symptoms.)

The kappa-opioid receptor

What makes Salvia so unique? For one thing Salvia’s main psychotropic compound, Salvinorin A, has a unique structure that is quite different from the classical psychedelics (figure 1). More importantly, Salvinorin A activates an unusual receptor in the brain, the kappa-opioid receptor (KOR). Drugs that activate the KOR have been known to induce psychotomimetic effects like depersonalisation and a sense of unreality. That means it’s likely that the activation of this receptor is Salvia’s main mode of psychedelic action.

Figure 1: Salvinorin A has a unique structure compared to the classical psychedelics LSD and Psilocybin.

But how do we know that Salvia activates the KOR, and what is it about Salvia’s active psychedelic components that set it apart from classical psychedelics like LSD or psilocybin? This blog post is a brief summary of the first paper to demonstrate Salvinorin A’s strong preference for the KOR. This finding might tell us something about certain aspects of consciousness, and presents Salvinorin A as a new target for research into the treatment of psychiatric disorders.

Roth et al (2002)

Roth and his colleagues set out to investigate the receptor targets of Salvinorin A, including the three families of opioid receptors (mu, delta and kappa), and families of receptors activated by the classical psychedelics such as the 5-HT (serotonin) and dopamine receptors. They carry out ‘radioligand-binding assays’ to ‘see’ Salvinorin A binding to the KOR and also measure how strong that binding is. This is done by first modifying the Salvinorin A molecules by attaching something radioactive to them. Then, the radioactive Salvinorin-A (or “Radioligand”) is pipetted onto some cells with the KOR on their surface. Then the cells are washed clean. If the substance in question binds strongly to those receptors, then the radioligand remains bound to the receptor even after the washing stage, and by measuring the radioactivity of the cells at the end, you know just how strongly the substance binds to the receptors. Repeating the process with different receptors and different concentrations of a drug can tell us which receptors a drug targets and shed light on how it binds to the receptors.

The authors carry out this experiment in vitro (in a petri dish) with human cells expressing the receptor, and also in situ (in tissue from guinea pig and rat brains).

 

Figure 2: Binding strength of Salvinorin A and LSD to various neurotransmitter receptors. Binding strength roughly relative to maximum binding of Salvinorin A to KORs. 5-HTR = Serotonin receptors, DAR = Dopaminergic receptors, MOR = Mu-opioid receptors, DOR = Delta-opioid receptors, KOR = Kappa-opioid receptrs. Adapted from Roth et al (2002).

The authors found that Salvinorin A bound very strongly to KORs, but did not bind to the other opioid receptors: mu and delta. They also found that Salvinorin A did not bind at all to the 5-HT2A receptor, which is an important target of “classic hallucinogens” such as LSD and psilocybin. In fact, Salvinorin A had very little activity at any of the other receptors investigated. Figure 2 shows a simplified interpretation of the receptor binding of both Salvinorin A and LSD, showing how different these psychedelic compounds are.

The authors also performed some molecular modelling analysis to try and see how Salvinorin A ‘locks’ into position at the KOR. By comparing the structure of Salvinorin A to a synthetic KOR agonist (the catchily-named ‘U69593’), the authors could make educated guesses about how Salvinorin A is binding to KORs (figure 3). Understanding how Salvinorin A binds to KORs could be useful for developing drugs that activate or inhibit the KOR more effectively.

Figure 3: Molecular modelling of binding state of Salvinorin A to the KOR. The collection of grey and red spherical blobs in the middle represents a molecule of Salvinorin A. Everything else is the KOR; the red and blue spirals are called ‘trans-membrane domains’, and are held together by the yellow strings at the top. The green parts are the areas of the KOR that Salvinorin A is actually binding to, keeping it anchored in the receptor and activating the KOR. Image from Vortherns & Roth (2006).

Conclusions

So in addition to Salvia being the world’s most potent natural psychedelic, it’s also unique in the way it works in our brains. Salvinorin A belongs to a rare class of molecules that activate KORs very selectively, and it’s very likely this is the main mode of action through which Salvia achieves its ‘psychotomimetic’ effects. However, Salvinorin A has also been shown to activate certain dopaminergic receptors as well (Seeman et al, 2009), so KOR activation may not be the only mechanism of Salvia’s effects. It’s still possible that other compounds in Salvia (not just Salvinorin A) have psychedelic effects, but no evidence of this has been found so far.

The fact that KOR activation induces psychotomimetic effects such as disorientation, feelings of unreality and loss of self-awareness tells us something; KORs are probably involved in systems in the brain that regulate perception and cognition. Since hallucinations, depersonalisation and other perceptual distortions are often symptoms of disorders such as Schizophrenia, better understanding of the KOR and its effects could lead to the development of new treatments for psychiatric disorders. Perhaps we could even gain a better understanding of psychiatric disorders in general. The study of Salvinorin A and its effects is a promising avenue of investigation in neuroscience research.

 

References

Roth BL, Baner K, Westkaemper R, Siebert D, Rice KC, Steinberg S, Ernsberger P & Rothman RB (2002) Salvinorin A: a potent naturally occurring nonnitrogenous kappa-opioid selective agonist. PNAS 99(18):11934-11939

Seeman P, Guan H-C & Hirbec H (2009) Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A and modafinil. Synapse 63:698-704

Vortherns A & Roth BL (2006) Salvinorin A. Molecular Interventions 6(5):257-265