We’re living in an era that will be known as a psychedelic renaissance. Cannabis has been rehabilitated, while psilocybe mushrooms are explored as an option for treatment resistant depression. Not a lot of research has been done on Salvia Divinorum so far, because Salvia Divinorum differs strongly from every other natural psychoactive substance we know. Salvia Divinorum causes very strong dissociative effects, but this takes place through the Kappa opioid receptor, a receptor that’s uniquely affected by Salvia Divinorum.

In contrast to the classical psychedelics, that target serotonin receptors in your brain, Salvia Divinorum’s effect on the Kappa opioid receptor lead to a generally uncomfortable trip. People who expose themselves to Salvia often claim to experience being other objects, like fence posts. This is typical of Salvia’s dissociative nature. Whereas psychedelics like LSD lead people to experience reality in an enhanced manner, dissociatives like Salvia transport people’s consciousness away from this reality. People generally consider the experience frightening, but nonetheless a subset of people tend to seek it out. They often speak of “confronting the terror”.

So what leads some people to seek out Salvia Divinorum? My suggestion is that Salvia Divinorum appeals to people who have suffered severe social stress at an early age. In mice, there’s a way of inducing social defeat stress. Breed a group of mice to be large, then put one of these large mice in a cage with a normal sized mouse and incite a conflict between them. Do this a few times and the other mouse becomes socially averse and depressed. This is what we refer to as social defeat stress, scientists use this as a model for the stress suffered by human beings throughout life.

One thing that has been noted is that mice who are exposed to such stress experience chances in their Kappa opioid receptor system. Our mammal bodies produce a substance known as Dynorphin, which interacts with the Kappa opioid receptor. Expose a mouse to social stress once and dynorphin is released into the brain. Do it all the time and the brain stops producing dynorphin.

Most interestingly, you can take a mouse and give the mouse a synthetic kappa opioid agonist, a substance triggering activity at the receptor. What tends to be found is that mice exposed to social defeat are alright with receiving the treatment, but mice who have not been exposed to social defeat avoid the place where they receive the synthetic kappa opioid agonist.

Since it became clear that the kappa opioid receptor is involved in the depression caused by social stress, people began looking for treatments that function through the kappa opioid receptor. The first strategy focused on preventing effects at this receptor. It was thought that the suffering unfolds as a consequence of the activity triggered at the receptor. Instead, the effect is likely opposite: Just as normal opioids function as painkillers for physical pain, we can think of the kappa opioid receptor as a place where painkillers for social pain carry out their function.

More recent studies suggest that in people who have been exposed to long term psychosocial stress, Kappa opioid agonists will have stronger antidepressant properties than Kappa opioid antagonists. The strongest natural kappa opioid agonist you’ll encounter, is Salvia Divinorum. So, when we consider all of this, a lot of things begin to make sense. To start with, consider how many people who experience traumatic events tend to dissociate from the experience. Many people don’t remember the traumatic experience. Those who were present often claim the victim seemed mentally absent. It seems to me that an acute dose of dynorphin leads to these dissociative effects, that are meant to protect the mind from severe suffering.

Another thing worth noting, is that despite being so frightening (or perhaps because), Salvia Divinorum apparently gives its users increased happiness and self-confidence. This makes sense, when we consider that Salvia Divinorum, as a strong Kappa opioid agonist, reverses the cognitive adaptation that takes place to chronic social defeat stress. It thereby disrupts internalized social hierarchies. There have been case studies, of people who treated themselves with Salvia Divinorum.

Perhaps most importantly, studies show that rats exposed to chronic mild stress end up suffering anhedonia. They don’t consider normal experiences pleasurable anymore and stop seeking out sugary flavors. Human beings exposed to chronic mild stress often display the same problem. It’s an aspect of depression, the fact that normal activities are no longer pleasurable. When these rats are given Salvinorin A, the active substance of Salvia Divinorum, the anhedonia is reversed. On the other hand, normal rats, not exposed to chronic stress, show no change in behavior.

The conventional pharmaceutical arsenal, operates on the basis of the serotonin hypothesis of depression. This works in some cases, but doesn’t work in others. That doesn’t necessarily mean that it addresses the correct originating cause when it does work however. If your sourdough bread has fermented too long you can add baking powder and you won’t taste the excessive sour flavor. Similarly, if something goes wrong in the brain, you can artificially raise serotonin levels and perhaps mask another problem.

What I expect is that there exists an entire demographic of people in society, who have gone through repeated social defeat stress and as a result end up displaying a form of depression akin to that seen in lab animals. In many cases this may be related to human dominance hierarchies. Cubicle concubines working for bosses, people born into poverty, sex slaves in Syria, teenagers in school and people in abusive relationships, may all end up with a similar behavioral profile, that features signs of learned helplessness, shyness and anhedonia.

I’m a strong believer in the idea that natural medicine is better than synthetic medicine. There are a number of reasons for this. One reason is that natural medicine tends to feature chemical bonds our metabolism can properly cope with. On the other hand, fluoxetine (Prozac) to name an example, features strong carbon-fluoride bonds, in a substance that ends up circulating through your brain. So why do patients, even mildly depressed patients, receive Prozac and other synthetic SSRI’s, rather than natural SSRI’s like St John’s wort? The main reason is that patentable drugs are profitable and patents create an incentive to market them towards doctors. Nobody can earn a lot of money from St John’s wort.

So, my expectation is that in a sane society, a society unlike ours where the financial incentive structures function properly, Salvia Divinorum will be a plant that will be researched and used to treat patients suffering from symptoms of chronic social defeat stress. Its dysphoric properties are noteworthy, but don’t seem to prohibit successful treatment. The dysphoric aspects of Salvia Divinorum may be addressed too however, by coadministering natural substances that reduce anxiety. As an example, a combination of cannabidiol and Salvia Divinorum may help certain patients. Alternatively, we know that other plants in the Salvia genus besides Salvia Divinorum contain significant amounts of Salvinorin A. A few generations of selective breeding may then result in plants that have an effect similar to Salvia Divinorum, but more suitable for some patients.