Cohen’s Brain Bits: Magical Mystery Medicine

Med Page Today – by Joshua Cohen MD, MPH

When President Richard Nixon signed the Controlled Substance Act (CSA) in 1970, a wide array of substances, natural and manufactured, instantly became illegal. Categorized as Schedule I drugs, they are those substances determined by the Drug Enforcement Agency (also created by the CSA) to have a high potential for abuse, no currently accepted medical use in treatment in the U.S., and a lack of accepted safety for use under medical supervision.  

This model creates considerable conundrums. First, the DEA has interpreted the CSA criteria of “high potential for abuse” as “at least some potential for abuse,” recognizing that the potential for abuse of many of the Schedule I substances is currently unknown. Additionally, once substances are placed on Schedule I, performing medical research into their risks and benefits becomes extremely difficult, preventing determination of whether there could be “accepted medical use” and “accepted safety.”

Hence the current debate over medical marijuana — data is still insufficient to provide guidance on the potential for abuse, medical benefit, and safety. However, as the volume of medical studies has grown, especially showing a variety of compassionate uses for marijuana, so too has public support for a change in its classification. In 1996, California became the first state to legalize the use of marijuana for medical purposes, and 22 states and the District of Columbia have since followed suit. The culmination of that process may be here, as a bipartisan bill that would reschedule marijuana to Schedule II was introduced in the Senate last week.

Recently, attention has turned to another group of substances on Schedule I, the so-called “psychedelics,” or “classic hallucinogens,” including lysergic acid diethylamide (“LSD” or “acid”) and psilocybin (the active ingredient in “magic mushrooms”). In the last year alone, there have been hundreds of medical studies evaluating these agents, their epidemiology, pathophysiology, sociology, potential therapeutic uses, and much more.

These hallucinogens function as agonists at serotonin 2A (5-HT2A) receptors, producing the positive symptoms of schizophrenia like hallucinations and thought disorder. By stimulating postsynaptic 5-HT2A receptors on pyramidal cells deep in the prefrontal cortex, they increase glutaminergic synaptic activity and thereby modulate prefrontal network activity.

The neuromodulatory effects of LSD and psilocybin have been shown to have profound potential for therapeutic intervention. Downregulation of prefrontal 5-HT2A receptors with repeated use of these agents can treat depression, anxiety, and chronic pain. Prefrontal 5-HT2A receptors also are associated with anxiety, and downregulation of these structures by the hallucinogens may define the pathophysiologic basis by which they can help in treatment of anxiety.

The potential therapeutic benefits of the psychedelics do not stop there. Dozens of studies have demonstrated their efficacy in treating addiction, especially alcohol dependence, and a large meta-analysis found significant reduction in alcohol abuse with use of LSD with an odds ratio of 1.96. Other studies have shown these agents to reduce symptoms of OCD, and psychedelics have been demonstrated to treat depression and anxiety in terminally ill patients. This month, a study found that use of psychedelics can decrease psychological stress and suicidality.

Benefits are also not limited to psychiatry. A number of studies have shown benefits of psychedelics in the treatment of cluster headaches, also known as “suicide headache.” Psilocybin affects blood flow to the hypothalamus and also acts as an agonist at 5-HT1B/1D receptors, much like triptan medications. It has been shown to both abort individual cluster headache attacks as well as turn off a cluster headache cycle.

Interestingly, studies have failed to demonstrate any significant concerns regarding abuse or safety. Neither psilocybin or LSD have ever been associated with a risk of addiction — neither induce any withdrawal symptoms with prolonged use, and neither activates the mesolimbic dopaminergic pathway responsible for the reward system implicated in addiction. Likewise, both substances are well tolerated, have no genotoxic or mutagenic effects, and do not affect liver or kidney function. While there are some sympathomimetic stimulant effects that might prompt caution against use in those with cardiovascular disease, the magnitude of this effect is not significantly different from that noted with the triptan medications and is likely due to the same 5-HT1B/1D effects.

As the public and legislators call for a re-examination of the scheduling of marijuana, it might be time to take a critical look at the rationale behind the scheduling of all Schedule I substances. If the psychedelics hold much promise for difficult-to-treat disease and are safe and without risk of abuse, those suffering from psychiatric and neurologic disease may truly benefit from a new approach to drug policy.

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