A new chapter in the science of psychedelic microdosing: A study on rats offers the first evidence that small doses of hallucinogenic drugs could have therapeutic benefits. Zulu

The purported benefits of microdosing psychedelics are as numerous as the research is sparse. The technique, which involves ingesting small amounts of LSD, mushrooms, or other hallucinogenic drugs every three or four days, has made headlines for its popularity as a “productivity hack” among the Silicon Valley elite.

But anecdotal endorsements of microdosing claim that the routine can lead to a whole variety of benefits, including heightened emotional sensitivity, athletic performance, and creativity; and relief from symptoms of anxiety, depression, OCD, PTSD, and chronic pain—all without resulting in any sort of trip.

In a lab setting, meanwhile, these effects have hardly been studied. Microdosing straddles a line between homeopathic remedy and experimental biohacking as a promising tool that hasn’t yet made its way through the clinical system’s rigorous checks and balances. Now a new study published Monday in the journal ACS Chemical Neuroscience provides the first biological evidence that psychedelic microdosing could have unique therapeutic effects that differ from the effects of a full dose.

For David Olson, a professor in the chemistry and neuroscience departments at the University of California at Davis and one of the paper’s authors, it started with ketamine. Over the past few years, Olson watched as the formerly notorious anesthetic cum party drug was rebranded as an experimental miracle for treatment-resistant depression.

Ketamine has the ability to rebuild fraying connections between brain cells integral to networks that regulate emotions and mood, thanks to an effect known as neural plasticity. Olson suspected that the process by which ketamine promotes this type of plasticity could be activated by other substances as well, and in June his team published a paper showing that in rats, psychedelics such as LSD, ecstasy, and dimethyltryptamin, or DMT, mirror ketamine’s effects.

When the study ended, Olson began to wonder if the therapeutic benefits could also be achieved through microdosing. Along with the hallucinogenic effects of the drugs, he’d found that standard doses gave his rats fierce anxiety, which seemed like a high price to pay for an effective antidepressant. “I really wanted to answer the question as to whether or not the hallucinogenic effects of these compounds were necessary for the therapeutic effects,” Olson says.

At that point, there had only been four published studies on microdosing: three based on interviews with anonymous users who reported the effects, and one write-up of a conference where attendees ingested psychedelic truffles. (A fifth microdosing study, also interview-based but the first with an empirical setup, was published last month in the journal PLOS One.)

For the new study, Olson’s team calculated a dosage of DMT—which is chemically like a stripped-down version of LSD or psilocybin “magic” mushrooms—that was too small to produce any hallucinogenic effects. They gave it to the rats every three days. On off days, the animals completed tests, including two experimental proxies for human anxiety and depression, respectively: a repetitive fear exercise, and a forced-swim test that looks at whether the animal will simply give up when in danger.

Seven weeks later, the researchers found that even though the rats weren’t given enough DMT to hallucinate, their depression and anxiety scores still improved significantly. The uptick in anxiety associated with the higher dose of DMT was nowhere to be found in the rats that had taken intermittent microdoses. Olson says the study demonstrates that the therapeutic effects of psychedelics—in rats, at least—can indeed be harnessed independently of the hallucinogenic effects. It appears that each of DMT’s distinct effects can be activated only if the amount of the drug present crosses a certain threshold. For the benefits of neural plasticity, that threshold seems to be lower.

For most substances, a study like this could quickly prompt more research that would eventually open the door to clinical trials. But for psychedelics, which are highly illegal substances in the United States that fall among the most strictly regulated both in and out of labs, the progression of research can be slower.

“There has been a very big transformation of how psychedelics are perceived in society over the past 10 years,” says Balazs Szigeti, a researcher at the Icahn School of Medicine at Mount Sinai who is currently collecting data for a self-blinding study of microdosing. “Animal-model research is helpful in moving it forward, but the major hurdle to conducting a large-scale clinical study on microdosing is the money.”

In the 1950s and ’60s, tons of research funding in the United States and abroad was dedicated to studying the effects that psychedelics have on consciousness, creativity, and spirituality. But psychedelics were outlawed under President Richard Nixon’s Controlled Substances Act. Grant money for psychedelics research quickly dried up, and by the time researchers decades later became curious about the esoteric substances, most prior research had been rendered effectively useless by modern scientific standards. Grant money can still be hard to come by.

Noah Sweat, a program coordinator at the University of Alabama at Birmingham’s School of Public Health, claims that the specter of this politicization continues to influence psychedelics research. “People now that are in positions of authority, either over departments that would be researching [psychedelics] or over the grant-awarding processes, might not have any sort of political objection to the research, but just have kind of absorbed the ambient cultural attitude toward them,” he says.

Still, psychedelics have potential dangers. When Olson’s team first gave rats standard, non-micro doses of psychedelics, one potential benefit they observed was a boost in the growth of dendritic spines—small protrusions that boost the activity of communicatory cells—in the part of the brain that controls personality and social behavior.

The team expected to see the same effect from a microdose, but instead found almost the opposite. “In the male rats, we saw no change in neuronal structure; and in the females, we actually saw a decrease in dendritic-spine density,” Olson says. To his team, these results were concerning: In some cases, it looked almost like the DMT was having a cytotoxic effect, proving fatal to brain cells.

Olson hopes that by experimentally adjusting different elements of the study, he can figure out a safe way to determine the boundaries of microdosing’s benefits and harms. One factor he’s especially interested in looking into is age, which he says can greatly limit the degree to which a boost in neural plasticity is helpful. Microdosing “during neurodevelopment could be really, really bad,” Olson explains. “On the other hand, the aging brain is a little more susceptible to issues of cytotoxicity, and so that also could be very, very bad. There could be only a very narrow window of time in which they might work.”

Maybe microdosing is the perfect answer for treatment-resistant depression between the ages of 30 and 40, but harmful at any other age. The idea that a tiny psychedelic dose could damage the same brain structures that a full dose reinforces feels counterintuitive, but might be something committed microdosers should consider. So much of what is understood about how various substances work presumes a sort of graded spectrum of effects. Could microdosing, which we still know so little about, be an exception to the rule?

“There’s that saying,” Olson says, “that the difference between a medicine and a poison is the dose.”