The main difference between Salvia divinorum and other types of sage is the presence of a substance called salvinorin. This diterpene compound (meaning that it only contains carbon, hydrogen and oxygen atoms) is present as salvinorin A (at 96%) and B (at 4%). Where salvinorin B is not known to have any psychoactive effects, salvinorin A is considered the most potent natural psychoactive substance.

Salvinorin can not be compared to any other drug. Where most natural occurring drugs contain alkaloids (containing nitrogen atoms), salvinorin is a diterpene. To a chemist this is a major difference. This chemical difference has an important practical consequence: salvinorin A does not give a positive reaction on urine tests for opiates or other alkaloid drugs.

Its potency is unique: when inhaled, effects can be felt from about 250 micrograms, while doses of 1 milligram can have extreme effects. Therefore it is extremely important to measure a dose very precisely, otherwise there is a risk of overdose.

Possibly Salvia contains other psychoactive substances, as reported by Valdés III. He discovered that a substance called divinorin C, chemically closely related to salvinorin A, might be active at an even lower dosage, but this has not been tested on humans. Other compounds in Salvia possibly contribute to the psychoactive effects, but only the psychoactivity of salvinorin A has been proven.

How it works in the brain

It is not known why salvinorin A is psychoactive, but there is some knowledge of its neurological action. Salvinorin A is a strong selective kappa opioid receptor agonist. This means that it “binds” and triggers activity in a particular class of proteins (the kappa opioid receptors) in the body.

Opiate drugs such as morphine are also opioid receptor agonists, but the main difference with salvinorin is that these activate both kappa and mu receptors. Activation of mu receptors is believed to cause opiate dependence. Because opiates have a strong effect on mu receptors and only weak effect on kappa receptors, they have mild visionary effects, but are strongly addictive. In contrast salvinorin A is a powerful selective kappa agonist. It strongly activates the vision-inducing kappa receptors but does not activate the addiction producing mu receptors. For this reason, salvinorin A causes strong visionary effects, but is not addictive.

For more information about this issue, see Erowid’s article on Salvinorin’s Kappa Opioid Activity and the article Salvinorin A: A potent naturally occurring nonnitrogenous kappa opioid selective agonist.