4 illegal drugs pushing through the treatment pipeline

All drugs approved by the FDA must be safe—but what does “safe” really mean, according to the agency? It doesn’t suggest that FDA-approved drugs are risk-free. Rather, “safe” means that “the benefits of the drug appear to be greater than the known risks.”

This definition tells us two key things. First, that all drugs—prescription and over-the-counter—can bring unwanted side effects. And secondly, it tells us that the FDA remains open to discoveries even after a ruling is made. In other words, while they judge drugs based on “known risks” and benefits, there are always unknowns that can tilt the scale later.

Those unknowns are what’s driving a renewed wave of research into drugs that are currently illegal under the Controlled Substances Act (CSA) of 1970, a piece of legislation passed by Congress under then-president Richard Nixon, a controversial figurehead widely known for initiating the War on Drugs and his claims that drug abuse was public enemy number one in America.

The CSA segmented drugs into five schedules based on their medical use, potential abuse, and safety or dependence liability. Drugs on Schedule I are those with “no currently accepted medical use and a high potential for abuse,” while those on Schedule V have very low potential for abuse and low risk of dependence.

However, the way the CSA scheduled drugs does not accurately reflect their risks and benefits, according to many in the scientific community. “It is likely that several drugs currently classified under Schedule I have important therapeutic potential for the relief of symptoms as well as for the management of the underlying chronic conditions,” a team of researchers from Mount Sinai wrote. “Without research, the potential benefits cannot be dispersed.”

Fortunately, a research “renaissance” into illegal drugs is underway. This new wave of clinical investigation focuses on clarifying the benefits and risks of illegal drugs through scientific study, and has already brought some promising results.

Here are four illegal drugs that new research is pushing through the treatment pipeline.

Lysergic acid diethylamide (LSD, acid)

LSD is a Schedule I hallucinogenic drug originally (and accidentally) synthesized by Albert Hofmann, PhD, in 1938 for the Sandoz pharmaceutical company. The drug is known for its ability to induce spiritual, mystical experiences and facilitate feelings of interconnectedness, which researchers hypothesize could help reduce the burden of psychiatric disease, including anxiety and addiction.

Beginning in the 1950s, psychiatrists across the United States gave LSD to thousands of people as treatment for alcoholism, as well as for depression and anxiety in patients with advanced cancers. Dozens of studies were published highlighting favorable risk-benefit ratios; however, clinical studies ceased once the CSA rendered the drug illegal in 1970.

The first recent study of LSD was launched more than 40 years later in 2007. The double-blind, randomized, placebo-controlled pilot study, which took place in Switzerland and was published in 2014, evaluated the safety and efficacy of LSD as an adjunct to psychotherapy in 12 patients with anxiety who faced life-threatening illnesses. Researchers dosed each patient in two supervised sessions and found that they experienced significant reductions in existential anxiety. No adverse events were reported, even those commonly attributed to LSD, like bad trips or flashbacks.

A 2020 systematic review of randomized controlled clinical trials of LSD, including 11 studies and 567 patients, concluded that LSD has potential as a psychiatric therapeutic, with strong evidence supporting its use for the treatment of alcoholism. Adverse events found in the review included acute states of anxiety, dysphoria, and confusion, as well as exacerbation of psychotic disorders and modest increases in blood pressure and heart rate, suggesting that LSD should be contraindicated during pregnancy, and with those with epilepsy and with paranoid personality traits.

New York-based drug development company Mind Medicine, which acquired the rights to eight clinical trials of LSD in April 2020, is looking to unearth more favorable data that can push LSD closer to FDA approval as a treatment for anxiety, ADHD, and other psychiatric conditions. However, the timeline for when that could happen remains unclear. What’s more, there are only eight ongoing studies of LSD according to ClinicalTrials.gov, including one for the treatment of cluster headache and another for major depression.

Psilocybin (Magic Mushrooms)

The hallucinogenic compound in magic mushrooms, the Schedule I drug psilocybin, has recently gained traction as a promising treatment for several psychiatric conditions, including depression, anxiety, and obsessive-compulsive disorder.

In a double-blind study of 51 adult patients published by researchers at Johns Hopkins University in 2016, a substantial majority of participants suffering from cancer-related anxiety or depression found relief from their symptoms for up to 6 months following just one large dose of psilocybin. Administered in a tightly controlled setting with the support of two clinically trained monitors, psilocybin decreased depressed mood, anxiety, and death anxiety, while increasing the quality of life, life meaning, and optimism of 83% of patients. What’s more, 67% of participants said their psilocybin experience was one of the top five meaningful experiences of their lives.

In November 2019, the FDA granted psilocybin a “breakthrough therapy” designation for the treatment of major depressive disorder—a designation used to expedite the development and review of drugs with clinical evidence that suggests the drug can demonstrate a substantial improvement over currently available options. The designation followed the launch of a phase 2 trial, PSIL201, which is currently ongoing and includes roughly 80 participants at seven US sites.

According to ClinicalTrials.gov, there are 22 ongoing trials of psilocybin, including as a treatment for addiction, anorexia, and depression.

Ketamine (Special K)

Originally developed as an anesthetic, emerging evidence suggests that ketamine, a schedule III drug that can produce dissociative, hallucinogenic effects, has clinical value as a pain medication and in treatment-resistant depression.

In March 2019, the FDA approved esketamine, a more potent version of ketamine, in nasal spray form for treatment-resistant depression. The drug’s efficacy was tested in three 4-week placebo-controlled clinical trials and one longer-term maintenance-of-effect trial. In one of the short-term trials, esketamine demonstrated a statistically significant improvement of depression symptoms, while the other two did not arrive at a statistically significant difference. In the longer-term study, patients in stable remission or with stable response who continued esketamine treatment plus an oral antidepressant experienced statistically significantly longer time to relapse of depressive symptoms than those on placebo.

According to ClinicalTrials.gov, there are 120 ongoing studies of ketamine in the United States, including as a treatment for mood disorders with suicidal ideation, chronic migraine, perioperative depression, for pain, and for general anesthesia.

MDMA (ecstasy or molly)

Widely known as a mood-altering party drug that increases pleasure, boosts energy, and intensifies feelings of empathy, the FDA granted 3,4-Methylenedioxymethamphetamine (MDMA, a Schedule I drug) breakthrough therapy designation for assisted psychotherapy for posttraumatic stress disorder (PTSD) in 2017. Since then, phase 3 trials have been underway and are expected to be completed in 2022.

“We are studying whether MDMA-assisted psychotherapy can help health the psychological and emotional damage caused by sexual assault, war, violent crime, and other traumas,” researchers wrote on the website of the Multidisciplinary Association for Psychedelic Studies (MAPS), a non-profit organization developing medical, legal, and cultural contexts for people to benefit from careful uses of psychedelics and marijuana. “We also sponsored completed studies of MDMA-assisted psychotherapy for autistic adults with social anxiety, and MDMA-assisted psychotherapy for anxiety related to life-threatening illness.”

According to ClinicalTrials.gov, there are 17 trials of MDMA currently ongoing, including those mentioned above, plus trials testing MDMA on startle response and even in healthy volunteers.

Following the evidence

As more evidence is gathered, our understanding of illegal drugs will become clearer. It’s likely that new data will lend support to efforts to reschedule some of these drugs, legalize others, and approve many more for additional medical uses. It all depends on whether the research uncovers new benefits that outweigh the known risks.