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Salvia Divinorum Presentation Part II

By John Clarke

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!

The slides are avail­able as a PDF here: Salvia Divinorum Present­a­tion [836kB].

2 Responses to Salvia Divinorum Presentation Part II

  1. BlackHat Botanicals says:

    There is also some spec­u­la­tion that salvia may yield com­pounds in the treat­ment of AIDS and cancer. I was sur­prised you only focused on Salvinorin-A in your present­a­tion. Other Salvinor­ins, -B, -C, etc. Have been dis­covered as well. Also, several Divinor­ums. It appears some of these other com­pounds may mit­ig­ate or mod­u­late the effects of Salvinorin- A.

  2. Paul Jones says:

    All this stuff seems to be 45 years old, does everything on here still apply? what dif­fer­ences are there now in 2013, has the research moved on? watch­ing TV the other day (the Wright show) they were dis­cuss­ing an article which said that brain dis­eases such as Parkinson’s etc could be cured by 2017, is this true and has it got any­thing to do with the topics dis­cussed above?

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