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