Ketamine—a powerful anesthetic for humans and animals that lists hallucinations among its side effects and therefore is often abused under the name Special K—delivers rapid relief to chronically depressed patients, and researchers may now have discovered why. In fact, the latest evidence reinforces the idea that the psychedelic drug could be the first new drug in decades to lift the fog of depression.



"We were trying to figure out what ketamine was doing to produce this rapid response," which can take as little as two hours to begin to act, says neuroscientist Ron Duman of the Yale University School of Medicine. So Duman and his colleagues gave a small amount of ketamine (10 milligrams per kilogram of body weight) to rats and watched the drug literally transform the animals' brains. "Ketamine… can induce a rapid increase in connections in the brain, the synapses by which neurons interact and communicate with each other, " Duman says. "You can visually see this response that occurs in response to ketamine."



More specifically, as the researchers report in the August 20 issue of Science, ketamine seems to stimulate a biochemical pathway in the brain (known as mTOR) to strengthen synapses in a rat's prefrontal cortex—the region of the brain associated with thinking and personality in humans. And the ketamine helped rats cope with the depression analog experience brought on by forcing the rodents to swim or exposing them to inescapable stress. "Preclinical and clinical studies show that repeated stress or depression can cause a decrease in connections and an atrophy of connections in the same region of the brain," Duman explains, noting that magnetic resonance imaging shows that some depressed patients have a smaller prefrontal cortex as a result. "Ketamine has the opposite effect and can oppose or reverse the effects of depression" for roughly seven days per dose.



Rats and humans have similar biochemical pathways. "There's a fair amount of similarity between the neurotransmitter systems and the way drugs act in the brains of rodents and humans. Biochemically, there is good correlation," Duman notes. "Behaviorally, it's much more difficult to know whether an animal is depressed and the drug is making it less depressed."



But ketamine is not alone among psychedelics in having potentially therapeutic effects. A review, published August 18 in Nature Reviews Neuroscience, of research on this grouping of drugs generally—ranging from dissociative anesthetics such as ketamine to naturally occurring hallucinogenic compounds such as the psilocybin in "magic mushrooms"— shows their efficacy at treating obsessive-compulsive disorders and addiction as well as depression and anxiety, among other disorders. (Scientific American is part of the Nature Publishing Group.)



In fact, ketamine has shown promise at reducing the risk of suicide and is currently being tested in humans for effectiveness in treating bipolar disorder and addiction. Psilocybin can decrease obsessive-compulsive behaviors, or even eliminate them entirely, for as long as a full day after treatment and is being tested to reduce anxiety and depression in terminal cancer patients. And even LSD—lysergic acid diethylamide-25—can combat inflammation, among other potential therapeutic uses. "The potency is about 300 times more potent than steroidal anti-inflammatories," says pharmacologist Charles Nichols of the Louisiana State University Health Sciences Center, who is working with the drug. "My lab is currently studying the ability of it to block or prevent inflammation in models of human inflammatory disorders, and the results are very promising so far."



The August 18 review, by psychiatrist Franz Vollenweider and neuropsychologist Michael Kometer of the University Hospital of Psychiatry in Zurich, proposes that various psychedelics' interaction with the receptors for the neurotransmitter serotonin may prove key to understanding their beneficial—and mind-bending—effects. "Psychedelics activate neuronal networks and the glutamate system that are implicated in the regulation of emotion," Vollenweider says, noting that their hallucinogenic effects can be impeded by blocking specific serotonin receptors in the brain (known as 5-HT2A). Psychedelics typically boost serotonin and may also boost the release of glutamate, according to the review authors, another neurotransmitter that has been linked to short-term but long-lasting brain functions such as learning and memory. More glutamate also has an impact on synapses. "This might result in an increased number and function of spine synapses in the prefrontal cortex," Vollenweider says.



That's exactly what Yale's Duman and his colleagues have now found, at least in the case of ketamine, though Duman is skeptical of a shared mechanism, given that ketamine and other hallucinogens affect different biochemical pathways. "There is evidence that the psychedelic agents enhance glutamate," he says. "I don't think the evidence is all that strong."



Regardless, it is unlikely that ketamine, psilocybin or any of these psychedelics would be used directly, because of their hallucinogenic and other side effects. According to Duman, several pharmaceutical companies have already begun the search for alternative compounds that target the same biochemistry or brain function, including some that his lab is testing. "We are testing other targets that we identified that we now know are potentially related and could impact pathways we have found to try to come up with novel targets and treatments that produce a ketamine-like effect with a better safety profile." In other words, a drug that treats depression the same basic way as a psychedelic but without any of the hallucinations and other mind-bending effects.