Our series of posts about the scientific research of Salvia divinorum is now six months old, and we’ve looked at a whole spectrum of research into this unique hallucinogen: from human studies of the subjective psychedelic effects of the drug, to the nuts and bolts of how Salvia’s pharmacology effects our brain, and even how Salvia’s main psychedelic component could be an important tool in the treatment of pain or addiction.

Since these topics are wide ranging and often confusing, we thought now would be a good time to summarise everything we’ve covered so far and bring them together, to give a bigger picture of the research taking place on Salvia. This should provide a good foundation on which to continue our exploration of the scientific research of psychedelics.

The Human Touch

Although much of the scientific research into psychedelics is performed with animals, unfortunately we can’t ask a mouse how it’s feeling or what it’s seeing. As such, currently the easiest way to understand the subjective effects of a psychedelic is to administer the drug to humans and ask what they’re experiencing! Many researchers have taken this approach with Salvia. Although this kind of study gives us a good idea of the typical psychedelic effects of Salvia, it can be hard to put the findings into hard data that’s useful to scientists. In this first blog post (Part 1, Part 2), I looked at two different research papers that examined the psychedelic effects of Salvia, but in slightly different ways.

The first study took a bunch of people who had previously used Salvia and got them to fill out a questionnaire. This is certainly the easiest way to gather information about the Salvia experience, but also takes control out of the hands of the experimenters; the authors can’t control how much Salvia these people are taking, or in what setting, or by what means. They also can’t screen them for psychological problems. So the findings must be taken with a pinch of salt. The authors find that Salvia is quite comparable to classic psychedelics like LSD or psilocybin, however Salvia does seem to possess some unique qualities too; often the subjects talk about feeling heavily sedated, and feeling like they are no longer in control of their experiences.

The second study had a different approach; they would have fewer participants (only four), but would completely control the actual administration of Salvia. Patients received very controlled doses in a comfortable environment, and were given different doses during separate sessions over the course of several weeks. The authors could measure things such as heart rate and blood pressure, and also observe the participants to check for any sign of distress. They could ask the participants about their experience before, during and after the drug, meaning they produced a much more detailed set of results than a simple questionnaire. These authors showed us that the participants almost always rated their experience as positive, and never felt a loss of control.

Controlled study: in the second study, more precise measurements could be taken, such as the typical dose-dependent time-course of a Salvia trip, approximated here.

These two studies differed in their approach to measuring the psychedelic experience, and they ended up with different results. The questionnaire study determined that the Salvia experience was often negative, and users felt they lost control. The controlled administration study showed us that if Salvia is taken carefully and in a comfortable setting, participants are likely to have a positive experience. We can conclude that Salvia is indeed a unique psychedelic, in that it produces a short trip that is often unpleasant, but that it also has potential to create positive experiences if handled in a certain way.

Molecular Mystery

The obvious next step in our blog was to look understand what made Salvia unique. Clearly, Salvia’s unusual effects compared to other psychedelics must be due to the molecular makeup of the plant. The chemical in the Salvia plant that causes psychedelic effects is called Salvinorin A, and is the world’s most potent naturally occurring hallucinogen. Whereas the classic psychedelics mainly activate serotonin receptors in the brain, causing vivid hallucinations, Salvinorin A barely activates these receptors at all. In fact, Salvinorin A binds strongly to only one receptor in the brain: the kappa-opioid receptor (KOR). It’s thought that the activation this receptor causes most of the psychedelic effects associated with Salvia. But it’s probably not that simple; Salvinorin A also activates other receptors, although nowhere near as strongly as the KOR. Understanding the exact mechanisms by which Salvia changes our perception will help scientists piece together how our consciousness works.

Salvinorin A has a unique structure compared to the classical psychedelics like LSD and Psilocybin, meaning it binds to completely different receptors.

Animal Assistance

Animals are a crucial part of modern scientific research, and animal models of diseases have led to many breakthroughs in fighting devastating illnesses like Alzheimer’s and Schizophrenia. Now animals are helping scientists understand our brains with studies into psychedelic substances. Animals can tell us things about how psychedelics change our brains that wouldn’t be possible in humans; for example, it would be difficult to get ethical approval to put a wire into the middle of a human’s brain! We decided to look at two papers that examined the effects of Salvia in animals, and similar to the human studies, they both produced different results due to different approaches to research methods.

Mice and zebrafish are two common research animals, and were used in these Salvia studies.

The first group looked at Salvia’s effects in mice. The authors tried to determine whether Salvia had abuse potential by seeing if mice would want to return to the place they were given the drug. Unlike most drugs of abuse, Salvia actually had an aversive effect on these mice, meaning that the mice tried to stay away from the place they were given the drug. However, the doses of Salvinorin A used in this study were extremely high; many times higher than the doses that humans use recreationally. Therefore the second group decided to look at the effects of lower doses of Salvia, this time in zebrafish. The fish in this study actually seemed to enjoy the Salvia experience at low doses, and were likely to return to the place they were given the drug. This, say the authors, is not only evidence that dose is extremely important when examining the Salvia experience, but is also an indication that Salvia may have the potential to be abused.

Fighting Addiction

If, as the above authors suggest, Salvia has the potential to be addictive at low concentrations, you wouldn’t think it would be a useful tool in the fight against addiction. However, let’s look back at the molecular effects of Salvia; Salvinorin A activates the KOR very strongly. The KOR is part of a family of receptors, including one called the mu-opioid receptor (MOR). Certain drugs of abuse such as Heroin activate the MOR quite strongly, leading to a strong ‘reward’ signal in the brain. But in this family of receptors, everyone doesn’t get along. The KOR actually strongly dislikes the MOR, and activating KORs reduces this ‘reward’ signal, opposing the actions of the MOR. It’s thought that this is a mechanism employed by the brain to try and regulate addiction; if you’re being rewarded too much, the KORs step in and try to keep the situation under control.

Salvinorin A reduces the addictive potential of cocaine.

This presents the KOR as a unique target to combat addiction. If the KOR is the body’s natural defense against addiction, we can manipulate the system to treat people who are addicted to harmful drugs such as cocaine. Of course, Salvinorin A is a very strong KOR activator, and is the focus of much research into developing a drug that can fight or treat addiction. It’s already been shown that giving Salvia to rats that are also taking cocaine makes them less likely to become addicted. If a form of Salvinorin A that does not produce intense psychedelic visions could be developed, it would have a lot of potential to prevent addiction.

Dose, Dose, Dose!

We have already seen that dose is very important when we consider the effects of Salvia; and in this blog post we looked at a couple more papers that enforced this point even further (See the full blog post here). In two more studies, we see that rats can enjoy the experience of low doses of Salvinorin A, and actively seek out the experience again. We also find out that Salvinorin A may have some mild anti-depressant or anti-anxiety effects in rats, again at low doses. Previously only pro-depressive effects of Salvia had been found, but at high doses. These interesting studies again demonstrate how dose drastically changes the effects of Salvia, and once more suggests that Salvia has abuse potential at low doses.

Salvinorin A has mild anti-anxiety and anti-depressive effects in rats.

Salvation From Pain

Not only does the KOR control addiction, it may also alleviate pain! Various KOR activating drugs are well known for their pain-killing properties, most notably the sedative Ketamine. Drugs that activate the KOR are mostly thought to be non-addictive; which is in stark contrast to traditional painkillers, which activate the MOR and are highly addictive. Therefore Salvinorin A is being investigated as a potential pain-killing drug without addictive properties.

In our most recent blog post, we look at a study that shows Salvia has various pain-killing properties in mice, significantly reducing the ability of animals to feel pain under mildly painful conditions. Scientists are already working on developing a form of Salvinorin A that would retain this pain-killing property, but that wouldn’t produce intense hallucinations and, importantly, would last much longer in the body than it naturally would. If these conditions are met, Salvinorin A may be the key to a potent, non-addictive painkiller that could revolutionise our treatment of pain!

Unique, Natural and Promising

We’ve barely scratched the surface of the research that’s being done on Salvia divinorum, yet we’ve discovered so much promise for our understanding of consciousness and our treatment of addiction and pain. Research into the plant is ongoing, and hopefully we will continue to bring you the latest advances and achievements in understanding its properties and effects.