The hallucinogenic plant Salvia divinorum relieves facial pain, study finds

A compound extracted from a hallucinogenic mint plant reduces facial pain in mice by interacting with specific receptors in the nervous system. The research provides a biological basis for the plant’s historical use in indigenous medicine and suggests new avenues for treating persistent nerve pain. The study was published in the Journal of Ethnopharmacology.

Trigeminal pain, also known as orofacial pain, originates in the sensory nerves of the face and can be highly disruptive to daily life. For a large portion of the population, this type of discomfort persists despite standard medical treatments and pain relievers. In the Cañada region of Oaxaca, Mexico, traditional healers address this condition by preparing an infusion from the leaves of the *Salvia divinorum* plant.

The plant is a member of the mint family and is widely known for its fast-acting hallucinogenic effects. During spiritual ceremonies, healers use large quantities of the fresh leaves to induce visions. However, when treating physical ailments like headaches or rheumatism, they prepare a much weaker tea from only a few leaves. This ethnobotanical history inspired scientists to take a closer look at how the plant acts on the body’s pain pathways.

To understand how this plant alters pain perception without inducing heavy hallucinations, researchers Geovanna Nallely Quiñonez-Bastidas, Andrés Navarrete, and their colleagues investigated its primary active compound. The chemical, called salvinorin A, is known to produce mind-altering effects by binding to specific opioid receptors in the brain. The research team suspected the chemical might also interact with two other prominent sensory structures in the nervous system.

One target is the cannabinoid type 1 receptor, which is part of the system that responds to the active ingredients in cannabis. The other is the transient receptor potential vanilloid 1, a cellular channel involved in sensing heat and pain. Both of these receptors are heavily concentrated in the sensory nerves of the face. This makes them logical targets for investigating how a traditional plant medicine might soothe orofacial pain.

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To test the plant’s pain-relieving properties, the researchers conducted a small study using laboratory mice. They prepared a concentrated extract from dried *Salvia divinorum* leaves and also isolated the purified salvinorin A compound. They then injected a mild chemical irritant called formalin into the upper lip of the mice to simulate trigeminal pain. This minor irritation prompts the animals to repeatedly rub their faces, providing a measurable behavioral sign of discomfort.

The researchers observed the animals after administering varying doses of either the whole plant extract or the purified chemical. Both the plant extract and the purified salvinorin A reduced the amount of time the mice spent rubbing their faces. The purified chemical was highly potent, requiring only about one-tenth the dose of the full extract to achieve the exact same level of pain relief. This indicates that salvinorin A is the primary component driving the plant’s biological effects on pain.

The team wanted to isolate the specific biological pathways involved in this response. They injected a new group of mice with chemical blockers that temporarily disable specific nervous system receptors. Some mice received a blocker designed specifically for the cannabinoid receptor. Other mice received a blocker targeted at the vanilloid receptor. After disabling these specific cellular targets, the scientists administered the plant compound and exposed the mice to the lip irritant.

When either the cannabinoid or vanilloid receptors were chemically blocked, salvinorin A lost its ability to relieve the facial pain. The researchers also tested blockers for two other common nervous system pathways, but disabling those did not stop the compound from working. These outcomes demonstrate that the compound relies directly on the cannabinoid and vanilloid receptors to suppress pain signals in the face.

The researchers then performed a laboratory test using isolated tissue to biologically confirm these receptor interactions. They extracted the esophagus and its connected vagus nerve from rats. By applying mild electrical pulses, they prompted the nerve to trigger rhythmic muscle contractions in the esophagus tissue. The team then applied salvinorin A to the tissue bath to observe its effect on nerve transmission.

Applying the compound effectively stopped the nerve from triggering the muscle contractions. When the scientists added the same chemical blockers used in the live mouse experiment, the nerve impulses and muscle contractions returned to normal. This isolated tissue test provided direct physical evidence that salvinorin A alters nerve activity through the specified sensory receptors.

Finally, the researchers evaluated whether the pain-relieving doses of salvinorin A produced other behavioral side effects. They subjected the mice to a battery of tests designed to measure anxiety, motor coordination, sedation, and depression-like behavior. To measure anxiety, they observed how much time the mice spent exploring open areas versus hiding in enclosed spaces. For motor skills, they tracked the animals’ ability to walk on a rotating cylinder.

The compound did not alter the animals’ anxiety levels. Changes in the amount of time the mice spent in open areas were not statistically significant compared to untreated mice. The animals treated with the compound also performed just as well on the rotating cylinder, showing no signs of physical impairment. However, the animals did exhibit certain noticeable behavioral changes in other environments.

In a test that involves placing the mice in a cylinder of water, the treated animals spent more time floating motionlessly rather than actively swimming. In a separate observation test, the treated mice were less likely to rear up on their hind legs to explore a new enclosure. The researchers interpreted these reduced activity levels as signs of mild depressive and sedative side effects.

While the compound demonstrates a powerful ability to block facial pain, its sedative and depressive side effects present hurdles for daily medical use. The mind-altering properties of the plant, which are heavily documented at higher doses, also complicate its potential development into a standard therapeutic drug.

Future research will likely focus on evaluating the chemical in different models of nerve damage. Scientists will also need to test modifications of the compound to see if they can isolate the pain-relieving benefits while reducing the unwanted psychological effects.

The study, “Antinociceptive effect of salvinorin A from the extract of Salvia divinorum in formalin-evoked trigeminal pain behavior in mice: Underlying mechanisms,” was authored by Geovanna Nallely Quiñonez-Bastidas, Eva Daysi Tixta-Ramírez, José Luis Balderas-López, Paola Andrea Vargas-Durán, Araceli Pérez-Vásquez, and Andrés Navarrete.