Multiple tiny doses of a psychedelic chemical can improve depression-like symptoms and anxiety related to traumatic stress in rats, according to the first study of this treatment in animals. The microdosing approach may eventually offer a way to administer potent psychiatric drugs that, at larger doses, would have adverse hallucinogenic properties—if researchers can square away some strange side effects and translate the findings into people (ACS Chem. Neurosci. 2019, DOI: 10.1021/acschemneuro.8b00692).
Most current antidepressant drugs don’t work in at least one-third of people who need them. In recent years, psychiatric researchers have hailed ketamine, used since the 1960s as both an anesthetic and a party drug, as a promising therapy for depression, and on Tuesday, the US Food and Drug Administration approved the first ketamine-related medicine to treat depression that’s not relieved by other medicines. One big problem, however, is that ketamine can cause hallucinations at standard doses.
David Olson, a chemical biologist at the University of California, Davis, and his colleagues have been searching for compounds with ketamine’s therapeutic punch but without its side effects. They had previously found that N,N-dimethyltryptamine (DMT), a key component of an Amazonian tea called ayahuasca, has the same antidepressant and anxiety-relieving effect on rats as ketamine (ACS Chem. Neurosci. 2018, DOI: 10.1021/acschemneuro.8b00134). But DMT is also a powerful hallucinogen, so the researchers have now tried administering it in microdoses, using repeated doses each one-tenth of the single doses used in earlier work.
Most data on microdosing comes from survey studies, in which people given a series of small doses of psychedelic drugs are asked how they feel, Olson says. But such self-reports are confounded by the placebo effect, because subjects know that they have received a therapy and have the expectation—or at least the hope—that it will work. Animals don't have such expectations, he says, "so you can really get at the heart of the neurobiology.” The latest study is the first to show that “psychedelic microdosing might actually produce beneficial effects on mood and anxiety in animals,” Olson says.
The researchers injected 24 rats (half males and half females) every third day for 8 weeks. Half of the animals received sub-hallucinatory doses of DMT and half received saline solution. Starting 2 weeks in, the team gave the rats a series of behavioral and cognitive tests on the days they did not receive an injection, says Olson: “That way, we were not measuring the acute effects of drugs, just the long-lasting adaptations in neural circuits.” Then the researchers investigated how DMT affected the biochemistry and neural structure of the rats’ brain tissue.
In the behavioral tests, DMT microdoses did not affect the rats’ cognitive function or sociability, but they did improve their performance on two other assessments. In a standard test of antidepressants called the forced swim test, the rats were placed in a pool with no platform to stand on. Those microdosed with DMT continued swimming for longer than those that had only received saline, which is the expected outcome for an effective antidepressant drug. In a second test called cued fear extinction learning, a model for post-traumatic stress disorder, the researchers conditioned the animals to associate a sound with an electrical foot shock, eliciting fear that caused them to freeze. The animals who got DMT microdoses froze less often upon hearing the sound, suggesting that the compound could alleviate PTSD.
The researchers also compared the effects of microdoses with observations from their previous studies of larger doses that could cause hallucinations. A large dose initially made the animals anxious, but then had long-lasting positive effects. Microdosing eliminated the initial anxiety, says Olson, but still offered the same positive effects on the behavior tests.
The treatment had some drawbacks, however. Male rats who received the drug gained a significant amount of weight, although it was unclear what caused this. Female rats, meanwhile, experienced a loss of neuron structures called dendritic spines, which are involved in communication between neurons. These results show that a lot more work needs to be done to assess whether DMT microdosing is safe, Olson says.
The study is valuable because it suggests that microdosing has different biological effects that a single large dose, says Albert Garcia-Romeu, a psychopharmacologist at Johns Hopkins University. But “there are a lot of limitations on how much we can really translate from animal models to humans,” he adds, “so we don’t know if this holds up in people.”
This story was updated on March 6, 2019 to more accurately reflect the significance of rat studies in the context of the placebo effect.