Salvia divinorum (Salvia, Magic Mint) is a plant used for entheogenic purposes by the Mazatec people of Mexico. A relative of the common garden plant "scarlet sage" (Salvia splendens), S. divinorum contains several hallucinogens that include salvinorin A, the first non-nitrogenous agonist known for kappa opioid receptors (KOR).
I had known of salvinorin A since a highly-cited 2002 Proceedings of the National Academy of Sciences paper by Bryan Roth, Richard Rothman and colleagues (full text here). At that time, I had read several anecdotal reports (that I cannot locate now) that the hallucinations rendered by Salvia ingestion or smoking were so bizarre and disturbing that 8 of 10 first-time users declared they would not use it again. Hence, I never really thought that Salvia would become much of a public health problem or be embraced by recreational hallucinogen enthusiasts.
However, just Google "Salvia" and take a gander at the ads on the right sidebar.
I'm still not certain if Salvia is enough of a public health problem to warrant legislation but we just learned this week that North Carolina will join 13 other US states in criminalizing possession and use of the plant or extracts made thereof:
A bill that would outlaw the psychoactive herb Salvia divinorum has passed the state Senate, prompting consumers to rush to buy it legally.Senate Bill 138, sponsored by Sen. Bill Purcell, D-Laurinburg, would prohibit the "manufacture, sale, delivery, or possession" of Salvia divinorum. The law calls for a fine for the first two offenses and misdemeanor charges for subsequent offenses. Purcell stressed that North Carolina's law would not be as strict as those of 13 states, which made Salvia divinorum a drug on par with heroin.
Just two things I'd like to add about Salvia and salvinorin A:
The compound itself is remarkable - it is the first, naturally-occurring non-nitrogenous ligand ever identified for an opioid receptor (unlike morphine and codeine, for example.). It also begins in the plant as a rather simple structure: a diterpene. Without causing you convulsions from having to remember biochemistry, the major building block of many compounds is an isoprene unit, a branched 5-carbon unit that comprises all sorts of biochemicals such as cholesterol. Salvinorin A is a C-20 compound created by the action of geranylgeranyl synthetase.
Perhaps most striking is the tremendous selectivity of salvinorin A for KOR. When at Case Western Reserve University, Bryan Roth's group was supported by the National Institute for Mental Health to create a screening panel of neurochemical transporters and G-protein-coupled receptors for identifying the mechanism(s) of action of novel compounds. Now continuing at the University of North Carolina at Chapel Hill, Roth's panel now includes over 50 receptors and transporters.
Take a look at the binding of salvinorin A relative to another hallucinogen, LSD (lysergic acid diethylamide) from this paper:
Figure 2 [From PNAS 2002;99:11934] Large-scale screening of human cloned GPCRs reveals Salvinorin A is selective for KOR. Shown is the mean percent inhibition of radioligand binding or functional activity (metabotropic glutamate receptors only) to 50 receptors and transporters for LSD (yellow bars) and Salvinorin A (red bars) tested at 10 µM. With the exception of the rat β1 and β2 adrenergic and bovine dopamine transporter (DAT) all of the assays were performed with cloned human receptors heterologously expressed (see Materials and Methods and supporting information on the PNAS web site for details). As can be seen (arrow), Salvinorin A inhibited only KOR binding at 10 µM. See Table 5 for details. SERT, serotonin transporter; NET, norepinephrine transporter; DAT, dopamine transporter; rGABAA, rat GABA-A receptor.
One doesn't need a neuroscience degree or even knowledge of the axes of the graph to recognize that salvinorin A is amazingly selective for the KOR and far "cleaner" than LSD.
The encouraging aspect of this drug of abuse is that since it causes bizarre hallucinations, antagonists may prove useful in the treatment of schizophrenia or other forms of psychosis. Roth's group also reports that salvinorin A has significant antinociceptive (pain-killing) activity, although therapeutic realization of this activity will require that restricted distribution analogs might be required that don't cause hallucinations.
My second and final point is to give the reader some feel for just how disturbing are the hallucinations associated with salvinorin A. I have long been a fan of the anonymously-moderated recreational drug website, Erowid. While controversial for providing education on using illicit drugs, Erowid is an incredibly rich resource for science-based review information and detailed accounts of drug use. Not wanting to glorify or otherwise advocate for illicit drug use, the site is incredibly enlightening for those who don't use these agents, as evidenced by this account of salvinorin A-induced hallucinations; the Erowid site prefers that one not reproduce exact content but here is the author's description of the account provided:
This report provides an excellent description of how frighteningly shocking
and unpredictable a salvinorin journey can be. It also shows another variation of the bizarre physical dimensions encountered on this substance, and hints at some of the possible dangers that can arise through its use.
You can read this account and others here.
In closing, I can say that salvinorin A is yet another example of a natural product that has provided us with unique insights on human physiology and provides the basis for tools to not only investigate diseases but also to devise therapeutic agents that can act by mechanisms not currently represented in our pharmacopeia. I only hope that the progressive outlawing of this compound and the plant from which it is derived does not detract from the rate of research progress in this field.
Note added in proof: I was just reminded that my dear colleague DrugMonkey spoke of these Salvia legal issues when taken up by the California Assembly back in May 2008 - yes, 13 months ago - sorry, Drug.
Roth, B. (2002). Salvinorin A: A potent naturally occurring nonnitrogenous kappa opioid selective agonist Proceedings of the National Academy of Sciences, 99 (18), 11934-11939 DOI: 10.1073/pnas.182234399
Brain & Behavior
Comments
Wow! That graph is impressive! Really drives the point home.
Posted by: Coturnix | June 14, 2009 12:00 PM
One of the best articles on Salvia I've read. Good job. For more in depth info on the medicinal potential of salvia i recommend further readings: http://www.salviasociety.org/salvia-medicinal-uses.htm
As well as http://www.GoogleScholar.com another excellent place to locate lots of scientific research papers on Salvia Divinorum.
Posted by: Skona | June 14, 2009 1:25 PM
Posted by: cm | June 14, 2009 2:20 PM
Actually, I think it is 3D that really brought the message home. I am trying to imagine a 2D graph that could do the same and I am failing (it could be a failure of my imagination - perhaps someone can replot it and show me).
Posted by: Coturnix | June 14, 2009 2:25 PM
Gad zukes! If it's effects are so disturbing that almost nobody wants to use it again, what's the problem? Oh..the others that do want to use it again...what if they stop going to church as their sole source of visions and hallucinations. Why not a law to prohibit eating each others boogers, which I'm pretty sure 80% find disturbing too and it might get in the way of going to church, some how, this is my body and all that.... Come to think of it Tent Revivals make 80% of some populations disturbed also.
The laws, if there are to be any, should require truthful disclosure as to the effects and enforce one's self responsibility in its use.
Posted by: doug l | June 14, 2009 6:01 PM
Really great post! As someone who has spent their post-doc actively investigating the Kappa opioid receptor I find the ban in 13 states on Salvinorin A to be another example of political leaders who know nothing about science making senseless policy. Anything that is fun, introspective, or novel must therefore be dangerous. A "Public Health Concern" is just plain silly, if you ask me. How many examples of accident or death have resulted from Sal A use? How many from alcohol? How many from cigarettes? The Pacific NW has yet to ban "Sal A", and I'm doubting it is the first priority for many of the legislators up here considering we have bigger and more important things to deal with...
A few things that are worth mentioning.
1) Kappa opioid receptor (KOR) agonists are dysphoric. (See Land et al, 2008; Pfeiffer et al., 1986) I've listened to some politician's claim that people will get hooked on, or addicted to Sal A. The very idea that people will become addicted to a dysphoric substance seems paradoxical. Many users describe feeling great only after the Sal A wears off because the dysphoria is now gone and some even become nauseated and most never try it a second time.
2) The drug has an incredibly short duration of action, in vivo. Most users have only 10 minute "trips". It isn't a party drug like LSD for this very reason, and for the fact that the "trip" can easily be disrupted by too much noise, activity, motion in the surrounding environment. In our experiments, we are lucky if we can see more than a 15-20 minute effect on the increase in analgesic response since the drug wears off so quickly.
3) KORs are critical mediators of the stress response and they potentially mediate depression and anxiety-like behaviors. Sal A's remarkably high affinity is now being used by Bryan Roth and others (at Research Triangle Institute, actually) in structure-activity studies to make potent antagonists for the potential treatment of mood disorders. Several large pharmaceutical companies have Kappa-opioid receptor projects ongoing for using KOR as a target for the above mentioned diseases.
We are only starting to understand how the KOR works in the brain to mediate complex behaviors including its role in the stress response, anxiety, and depression behaviors. Salvinorin A, and its derivatives will likely bring us to using a potentially novel target. The very fact that Sal A can induce such "out of body", "alterations of space/time" seems to tell us that the Kappa receptor is pretty darn important in making us who we are...
Again, great post...
-mrb
Posted by: Mike | June 15, 2009 1:48 AM
Cool stuff. I read somewhere that "they" were working on several structural analogues to get that kind of selectivity at other opioid receptors.
Also, for my pharmacology class, I got to do a presentation on a topic of my choice, so I chose S. divinorum. If you get the chance, I'd love to hear input from someone that actually knows what they're talking about. Here's the link: http://www.synchronium.net/2008/10/25/salvia-divinorum-presentation-part-ii/ There's also some other good references at the end, including Roth, et al 2002. I'd recommend Roth & Vortherms (2006) (link: http://www.ncbi.nlm.nih.gov/pubmed/17035666 )
Posted by: Synchronium | June 15, 2009 5:54 AM
The ease with which politicians decide to infringe upon the fundamental human right to control ones own body is disturbing. I wish I could go back in time and slap around the idiots who allowed laws to be passed reintroducing prohibition without requiring an amendment to the Constitution.
Posted by: otakucode | June 15, 2009 8:22 AM
Wow. Great post & discussion. I knew nothing about this topic!
Of course, my parents' first question when I was chatting about this was where to get hallucinogenic sage for the Thanksgiving stuffing. They thought it might make the familyl get together more "interesting." Like the alcohol doesn't do that already...
Posted by: Pascale | June 15, 2009 11:00 AM
Wow, that figure has some rocking visuo-cognitive impact!
Can you imagine what it would have looked like had the authors used a bunch of conventional bar graphs, maybe with some annoying brackets and ********** symbols to denote significant differences? GAH! I'd have used this P20 to do my best Oedipus impersonation.
Thanks for this post Abel! I'll admit I had never heard of any of this until now.
Posted by: Nat | June 15, 2009 11:26 AM
Pascale and Nat, really, you have no excuse....
http://scienceblogs.com/drugmonkey/2008/05/salvia_divinorum_kappa_opioid_1.php
Posted by: DrugMonkey | June 15, 2009 3:31 PM
*looks around nervously* Heh, yeah, I remember that Brother Drug.
I was just....testing you, that's all.
Posted by: Nat | June 16, 2009 10:08 AM
No one can tell what each user's experience will be. No way should this stuff be legal. Kudos to legislators for realizing this.
Posted by: Fred F. | June 16, 2009 8:40 PM
As someone who has tried smoking salvia myself I think the ban is not warranted without further research. I had a really mind altering experience of feeling disconnected from my body, like feeling that my hands are not my own but a totally robotic extension of myself combined with an unstoppable urge to hysterically laugh. After the trip, I thought a bit about it and my hands actually are robotic-like extensions that I (my brain) controls using nerves to stimulate muscle contraction.
I certainly didn't experience anything bad. I just cannot understand why an adult should not be allowed to try something like it. I would do it again, but not in order to get "high" or something but to see what kind of weird experinence I get I out of it the second time. Salvia is definitely not addictive and I don't see where the evidence is that its dangerous. Have any salvia related deaths been reported? Any other anti-social behavior associated with it?
I think it should be regulated (concentration of preparation, purity standards, no driving, only adults etc) but an outright ban would in no way be rational.
Posted by: bb | June 18, 2009 9:42 AM
The Salvinorin A "scaffolding" has served to create a number of analogues which have differing affinitity to mu, kappa, and sigma receptors. One in particular, dubbed "herkinorin", has show very strong selective affinity for the mu opioid receptor, yet does not induce receptor regulation. Thus, it or something like it may end up being a potent analgesic without the problems of tolerance and addiction.
Scheduling Salvinorin A will bring to a halt this type of research.
Posted by: John | June 19, 2009 8:57 PM
I've used Salvia more than 200 times. It is completely benign and this is just another example of bureaucrats trying to maintain job security.. "let's see...what else can we do to put on our record..oh, I know! Stir up fear over an exotic plant and convince parent's their kids are dying from its use and that we saved them through heroic legislation." yadda yadda..
It does induce impressive hallucinations and while they can be quite mind blowing during the trip, their is no sense of "I" to relate to, therefore lessening the impact of the experience once you come down. 30 minutes later you can be making a sandwich, reflecting on what it was like to live the life of a shopping cart for eternity.
Another odd thing that we have experienced in group settings is a collective hallucination where we were all seeing the same thing, despite only 1 person smoking salvia. For instance, we all began to see leaves falling from the ceiling, or beings with red eyes and shapeshifting features moving on the perimeter. It made me wonder if the person on the substance was somehow bending consensus reality and we were witnessing what they saw.
But alas that may sound too far fetched for the rigorous materialist. Scoff, but you don't have the right unless you were to attempt it yourself.
Posted by: JohnE 5 | June 23, 2009 4:44 PM
Such a drug is only considered for abuse and used recreationally by uneducated fools who have no respect for the plant, its history nor the experience. There are enough kids on youtube devoid of attention in daily life that have to give this plant a bad name. Personally I think its an innate human right to alter our own conciousness, in the right context of course.
Posted by: SmithX7 | June 23, 2009 7:44 PM
JohnE 5,
That's pretty awesome, man. I have ocasionally experienced this group-high phenomenon with marijuana, believe it or not. Materialists need to get high more often, IMO.
As an aside, I predict that this herb will be yet one more big target for the war on drugs. Obviously, the drug merchants must be well connected with state legislatures.
Posted by: Mapou | June 24, 2009 10:00 PM
This is a really informative article. I wish that Salvia wasnt their focus of attention and instead they worried about alcohol. For more great information on Salvia check out: http://www.freshsalvia.com/blog
Posted by: Sally dee | June 26, 2009 1:16 PM
So what, you can buy thousands of chemicals that get you way higher and are made by good, clean white people. This stuff comes from mexico, and mexicans are dirty swine. When the white people learned that dirty mexicans and negros puffed marijuana, they knew that stuff had to be banned. Can't be having dirty mexicans and negros enjoying themselves in a good white christian nation like America.
Posted by: Meh | June 26, 2009 10:32 PM
This is a very nice site really well put together i like it. I also found this other site it has some great info as well http://www.salviadivinorumblog.com/
Posted by: Ayahuasca-Seeds | July 3, 2009 8:53 PM
The graph showing percentage inhibition of salvia is really outstanding.
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Posted by: Michael Lee | July 8, 2009 6:34 AM
Gee, salvia spammers!
Posted by: Tsu Dho Nimh | August 30, 2009 8:45 PM
It comes down to this...do you want some 16 year old kid taking hits of this while driving his car on the highway next to you and your children in car seats in the back seat? WAKE UP!!!!!!
Posted by: DM | October 13, 2009 1:16 PM
This stuff comes from mexico, and mexicans are dirty swine. When the white people learned that dirty mexicans and negros puffed marijuana, they knew that stuff had to be banned.
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Posted by: hosting | October 18, 2009 4:13 AM
It is also important for people to realise that Salvia Divinorum is not a party drug. If you're taking this form of substance when trying to have a good time or party with mates,
Posted by: Salvia divinorum | November 2, 2009 2:40 PM