As I mentioned before, I got to give a 10 minute presentation on Salvia divinorum to my pharmacology class. It went down pretty well, so I thought I’d write it up for you guys! Clicking on any slide will open it full size in a new window/tab.
The first thing you should know about Salvia Divinorum is that it’s a very potent hallucinogen. I mean, realllly potent. It’s name directly translates to “Sage of the Seers” or “Diviner’s Sage”, so already we know it’s gonna be cool. Salvia Divinorum is a member of the mint family, along with other common herbs, such as basil, rosemary and garden sage. In fact, Salvia is the Sage genus, which includes the common sage as well as S. Divinorum. This plant is native to one region only — the Oaxaca [“wahaka”] province of Mexico, where it grows best in a moist, shady environment.
Salvia Divinorum found extensive use among the Mazatec, the indigenous people of this region. Their religion is a blend of traditional superstition and a flavour of Christianity (also superstition!) brought over by the Spanish conquistadors. They make extensive use of the natural psychoactive plants and fungi in their rituals, including Salvia Divinorum, Morning Glory seeds and psilocybin mushrooms. Salvia in particular was used very much as a learning tool to facilitate visions, particularly in the context of healing or divination (hence the name).
Salvia was also a common medicine, prescribed for such ailments as diarrhoea, headaches and rheumatism. It was also the number one cure for a semi-magical disease known as “panzón de borrego”, or swollen belly.It’s no surprise to see a difference in use between the Mazatec and the “west”. The majority of use in the USA, UK and other developed nations is for recreation, while the Mazatec adopt a somewhat more “respectful” approach. Traditionally, salvia leaves were chewed, or an extract was prepared by crushing the leaves and consuming the liquid. There is no indication the plant was ever smoked by these people, which makes sense — the active compound has a very high vaporisation temperature. It is only the western world who smoke high powered extracts though a bong with a turboflame lighter!
The effects are many and varied, depending greatly on the amount consumed. Uncontrollable laughter is perhaps the most obvious effect, but it doesn’t happen to everyone. Other effects include remembering past memories, dissociation of the body and mind, a sensation of a force or pressure pushing or pulling on the body, usually in a particular direction, perceiving membranes or films or multiple small tiles covering surfaces and merging with, or becoming other objects. This is in no way comparable to any of the classic hallucinogens, such as LSD or Mescalin in effect or duration, as the Salvia experience usually lasts 15 to 60 minutes.
The active compound of Salvia Divinorum is Salvinorin-A, a diterpine compound. I know what you’re thinking — “why should I care?” — well, you should! Salvinorin-a is the only known psychoactive diterpene AND the first non-alkaloidal (or non-nitrogenous) hallucinogen to be discovered. It acts as an agonist at the kappa opioid receptor, which is also unusual. The other, classical hallucinogens work at the 5-HT2a receptor, and the other opioid receptor ligands tend to be alkaloids.
Shown here is a receptor selectivity profile, comparing the LSD in red with salvinorin-a in green. As you can see, the salvinorin-a is very selective for the kappa opioid receptor and not a lot else, while LSD shows activity across multiple receptors.
Shown here is the proposed kappa receptor:salvinorin-a binding complex, produced from various mutagenesis studies.An active dose of salvinorin-a can be as low as 200 micrograms, around the same as LSD, making it one of the most potent hallucinogens. But, as I’ve already mentioned, the experience usually lasts under an hour. Salvinorin-A does not remain in the body for long, with a half life of between 20 to 80 minutes in nonhuman primates.
So, an interesting drug, but is it also interesting clinically? Definitely! First off, salvinorin-a has shown promise in analgesia (pain relieving) studies in mice. Salvinorin-a, when injected intraperitoneally, produced an increased tail flick latency in these mice. The tail flick test is designed to measure the pain threshold — the mouses tail is laid out flat on a plate, and at one point along the plate, a beam of light is focused on the plate from underneath, creating a hot spot underneath the end of the mouses tail. As soon as the mouse begins to notice any pain, it flicks its tail to the side, so an increase in this amount of time shows an increased pain threshold. This antinociceptive effect is abolished if the mice are first pre-treated with a kappa antagonist, or are genetically engineered to lack kappa receptors, which proves salvinorin-a acts on these receptors in vivo as well as in vitro, shown by the previous graph. To make sure this effect was consistent and really did show an increased resistance to pain, other assays, such as the hotplate and chemo-nociceptive acetic acid abdominal constriction assays were done and produced results concordant with analgesia.
As I mentioned before, Salvia was administered by the Mazatec for diarrhoea, but it has now been shown to prevent myenteric cholinergic transmission in the small intestines of a guinea pig, effectively stopping muscle contraction.
Salvia may also shed some light on depression. Other kappa selective agonists typically produce depressive like behaviour in animal models, and salvinorin-a seems to produce a similar response. This supports the hypothesis that kappa opioid receptor signalling plays a role in depressive behaviours, but there has been at least one case report where salvia divinorum was used to treat refractory depression — depression that responds to nothing else. Before we can conclude anything from this, further work, including clinical trials must be undertaken. Either way, interesting stuff!
As we’ve seen, salvinorin-a is a bit strange, offering us an exciting new molecule to play around with. Already, chemical tweaking of the molecular structure has given us a selective agonist for the mu receptor and further research might lead to many novel, receptor-specific compounds.
Salvia has also shed some light on kappa receptors and their role in hallucinatory diseases. If the kappa agonist, salvinorin-a is able to produce such intense hallucinations (proving the involvement of kappa receptors in modulating our perception), could a kappa antagonist help reduce hallucinations in diseases with prominent perceptual disturbances, such as Alzheimer’s or Schizophrenia? There are many avenues Salvia Divinorum could lead us down, but if one thing’s for certain, more research is needed!
There are some great papers here, all of which I’d recommend, but if you can’t be bothered, there’s a brilliant TV documentary on there, Sacred Weeds. Definitely worth a watch. Thanks!