Avoiding the Mistakes of the War on Drugs

Back in the 1960s, hippies rejected mainstream society and promoted a peace-loving, anti-war, pro-“drugs, sex and Rock ‘n Roll” mindset. This era also saw the rise in recreational use of psychedelic drugs amongst those who embraced a counterculture lifestyle. Simultaneously, early psychological researchers unveiled a new use for these drugs as potential therapeutics for mental illnesses like addiction.

However, after a few highly publicized “bad trip” reports, mixed with the political climate at the time, the infamous and widely ineffective War on Drugs was implemented. Aimed at combating the use and distribution of illegal drugs, the Controlled Substances Act of 1971 placed psychedelics and many other drugs under strict restrictions.

This legislature categorizes substances into five schedules based on medical use, potential for abuse and safety. Drugs like LSD, psilocybin and marijuana were placed into Schedule 1—defined by high potential for abuse, no medical use and lack of accepted safety. In addition to banning these drugs from public use, this law made research on psychedelics incredibly difficult, ultimately leaving initial findings on the clinical use of psychedelics dormant for decades.

The days of psychedelics embodying the symbol for hippie counterculture are long past. The recent positive shift in the climate of public opinion on psychedelic drugs has largely been due to a renaissance of scientific research on these substances. New preclinical and clinical studies have shown impressive results suggesting significant promise for various psychedelics as therapeutics for neuropsychiatric disorders. In fact, the Food and Drug Administration (FDA) has recently designated multiple psychedelic drugs as breakthrough therapies for the treatment of certain neuropsychiatric disorders including PTSD, anxiety and depression. 

"The recent positive shift in the climate of public opinion on psychedelic drugs has largely been due to a renaissance of scientific research on these substances."

-- Anna Tsyrulnikov

Despite promising data supporting the need for continued research on these drugs, history appears to be repeating itself. At the end of 2023, the U.S. Drug Enforcement Administration (DEA) proposed a rule to categorize two psychedelic drugs—2,5-dimethoxy-4-iodoamphetamine (DOI) and 2,5-dimethoxy-4-chloroamphetamine (DOC)—as Schedule I controlled substances.

But why should we care about the classification of DOI and DOC?

For decades, scientists have used DOI in basic preclinical research to understand the function of serotonin and its signaling throughout the body. DOI strongly activates a specific serotonin receptor in the brain, the 5-HT2A receptor. Importantly, scientists believe that the action of classical psychedelics like psilocybin or lysergic acid diethylamide (LSD) at the 5-HT2A receptor is responsible for many of their therapeutic effects. The 5-HT2A receptor not only mediates the “trip” from psychedelic substances but has a variety of other roles in the body, from normal neurological functions like learning and memory, to disorders like schizophrenia and depression.

DOI’s selectivity for this important receptor makes it a unique and valuable tool for researchers. Due to its hallucinogenic effects and receptor specificity, DOI is currently used by labs across the country to investigate what changes in the brain might be causing the therapeutic effects of psychedelics seen in clinical trials. Using DOI to target the 5-HT2A receptor may provide researchers with important insights that may improve the safety and efficacy of psychedelic therapies in the future.

DOI is one of the only unscheduled molecules that is widely available for researchers to characterize the effects of 5-HT2A activation. Moving these substances from unscheduled to Schedule I would create significant restrictions to their use in these critical preclinical studies. To use any Schedule I compound in a lab setting, researchers must acquire a Schedule I license—a process that can take months—and comply with the DEA’s strict regulations for the use, storage and security of the substance.

So why does the DEA want to schedule DOI and DOC anyway? The main factors that the DEA states qualify DOI and DOC as Schedule I substances are safety concerns, a high potential for abuse and a lack of accepted medical use.

Safety
Any substance, whether scheduled or not, can pose serious safety concerns and public health risks. For DOC, the DEA refers to global data that indicates a total of 16 intoxication reports between 2008 and 2017, three of which resulted in adverse effects with one leading to death. Further, there are currently no medical reports of adverse effects or deaths due to DOI alone.

These statistics may seem surprisingly low. That’s because they are. DOI and DOC are rarely used recreationally by humans, mainly due to the long duration and strength of their hallucinatory effects which may last over 24 hours.

To really put these reports into perspective, over 8 million people die from using tobacco—an uncontrolled substance—each year. Although potential risks should be properly acknowledged for any substance, the rate of harm attributed to DOI and DOC appears minimal in comparison with other commonly used and legal drugs in the U.S.

Abuse
The DEA assessed the liability for abusing DOI and DOC by comparing their effects to other Schedule I hallucinogens, like 2,5-dimethoxy-4-methylamphetamine (DOM), N,N-dimethyltryptamine (DMT) and LSD. The assumption is that because these drugs have relatively similar structures and some overlapping effects they are equally as addictive.

However, it’s well known by neuroscientists that classical psychedelic drugs, like LSD and DMT, are non-addictive because they do not induce any physical dependence. In fact, researchers are currently investigating the use of psychedelics like psilocybin for the treatment of substance use disorders. This points towards a potential therapeutic role of psychedelics in reducing addiction rather than promoting it.

Medical Use
There is currently no known medical use for DOI or DOC, which the DEA uses to support their scheduling. However, this may be due to a lack of research on potential medical uses of DOI or DOC.

By comparing the therapeutic effects of related psychedelics, it’s evident that psychedelics show promise for treating multiple neuropsychiatric disorders. Therefore, it seems premature to disregard any potential therapeutic use of DOI and DOC.

Ultimately, there remains a significant gap in research on DOI and DOC, and imposing a Schedule I classification would greatly limit future investigation with these substances. More research is needed to clearly define any risks associated with DOI and DOC and to understand how similar psychedelic compounds promote such profound improvements in neuropsychiatric disorders. Although recent findings supporting a therapeutic role of psychedelics has been encouraging, progress has been slow for those that suffer daily from mental illness and have not seen improvements from typical treatment options.

Now is not the time to increase restrictions on scientific research into the therapeutic benefits of various psychedelics. Rather, this is a crucial turning point that necessitates support for psychedelic science in order to avoid repeating the mistakes of the War on Drugs.