But largely absent from calls to action is the fact that some pharmacological treatments for mood disorders, including for depression and anxiety, can yield little to no benefit in certain individuals. Studies have found as many as 10% to 30% of patients with depression are treatment resistant, while 30% to 50% of patients do not fully respond to existing pharmacotherapies.
In addition to limited efficacy, some pharmacological treatments are also associated with patient adherence problems—as many need to be administered daily—and can have unwanted adverse effects such as weight gain and suicidal ideation, prompting a need for novel antidepressants with rapid and sustained benefits.
And despite the well-established benefits of psychotherapy for conditions like post-traumatic stress disorder (PTSD), a shortage of mental health professionals, in addition to insurance and cost barriers, prevent many from seeking care or receiving timely consultations.
“We have a supply-demand mismatch now. More people are seeking help than we have professionals,” said Ken Duckworth, MD, senior medical director for behavioral health and BCBS of Massachusetts, in an interview with The American Journal of Managed Care® (AJMC®) in May of 2021. “We need to figure out how to approach this from a public health point of view. We still have a very slow pipeline to develop practitioners.”
The consequences of delay reverberate, said another expert.
“Delays of care prolong suffering,” explained Jonathan DePierro, PhD, an assistant professor in the psychiatry department at the Icahn School of Medicine at Mount Sinai, New York. “So, when we identify people who are in distress, providing timely care can really be life altering and prevent someone having PTSD for 20 years. Untreated PTSD, untreated depression, crystallizes in the body in the brain, and it makes it even harder to treat down the road.”
Combined, these factors present a window of opportunity for alternative treatment options that have been gaining traction in recent years, thanks in part to the work of the Multidisciplinary Association for Psychedelic Studies (MAPS).
Since its inception in 1986, MAPS has funded and conducted numerous studies exploring the benefits of psychedelics for mental health illnesses—including major depressive disorder (MDD) and anxiety—in addition to substance use disorders and drug addiction.
In an interview with AJMC®, Ismail L. Ali, JD, the acting director of Policy and Advocacy at MAPS, noted this new focus on US mental health comes on the heels of an already heightened awareness that has permeated the national conversation in recent years.
“There aren’t that many families that haven’t been affected by addiction and suicide, depression, or something similar,” Ali said. “In general, there was already an openness that was emerging prior to COVID-19. The pandemic really put everything in relief, because you suddenly have this whole new class of people who have hard jobs as health care professionals already and are suddenly experiencing pretty severe trauma and burnout at a level that [some] have never seen before.”
According to Ali, this increased awareness will inspire a push towards more research into additional or alternative treatment options, such as psychedelic-assisted therapy. “But one big question I have right now is ‘How quickly can that move, especially with new innovative or alternative modalities like psychedelic therapy? What’s the balance between the stigma that already exists and where we need to go?’” he asked.
Studies on Psychedelics
Several studies have looked into the potential of psychedelics as treatment components for mental illnesses.
Results of one randomized clinical trial, published in 2020, found that among 24 individuals with MDD, those who underwent “immediate psilocybin-assisted therapy compared with delayed treatment showed improvement in blinded clinician rater–assessed depression severity and in self-reported secondary outcomes through the 1-month follow-up.”
Psilocybin, a classic hallucinogen commonly referred to as magic mushrooms, is generally not associated with long-term cognitive or neurological dysfunction and has been considered a novel antidepressant intervention. Unlike commonly used antidepressants taken daily, only a single or few administrations of psilocybin were required for patients to achieve sustained benefits.
In comparison with ketamine treatment—which is being studied as a therapy for treatment-resistant depression—results of the 2020 trial showed 71% of individuals maintained a clinically significant antidepressant response to psilocybin therapy for at least 4 weeks, whereas ketamine’s effects typically lasted from a few days to 2 weeks, researchers wrote.
Psilocybin was also revealed to have a low potential for addiction and a minimal adverse event profile, indicating its therapeutic advantages come with less risk for associated problems than ketamine, they added.
Notably, “the effect sizes reported in this study were approximately 2.5 times greater than the effect sizes found in psychotherapy and more than 4 times greater than the effect sizes found in psychopharmacological depression treatment studies.”
It is thought psilocybin has a transdiagnostic mechanism of action, in which patients could experience psychologically insightful experiences during a session that results in positive therapeutic effects. A larger study consisting of 100 participants is currently underway with results expected in 2022.
An additional study, published in May 2021 in Nature Medicine, outlined the benefits of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe PTSD.
A total of 90 patients were randomized to receive MDMA or placebo in addition to a series of therapy sessions. Researchers found “3 doses of MDMA given in conjunction with manualized therapy over the course of 18 weeks results in a significant and robust attenuation of PTSD symptoms and functional impairment as assessed using the Clinician-Administered PTSD Scale for DSM-5 and Sheehan Disability Scale, respectively.”
During the study window, treatment with MDMA significantly mitigated depressive symptoms and did not increase suicidality. The effect size of 0.91 between MDMA-assisted therapy and placebo with therapy was larger than those of sertraline and paroxetine—the FDA-approved first-line pharmacotherapies for PTSD.
Investigators hypothesized that use of MDMA may allow for a “window of tolerance” during which patients can revisit and process traumatic content without being overwhelmed by dissociative or hyperarousal symptoms.
“We may soon be confronted with the potentially enormous economic and social repercussions of PTSD, exacerbated by the COVID-19 pandemic,” authors wrote.
“Overwhelmingly high rates of psychological and mental health impairment could be with us for years to come and are likely to impart a considerable emotional and economic burden. Novel PTSD therapeutics are desperately needed, especially for those for whom comorbidities confer treatment resistance.”
Legislative Proposals Take Shape
Results of these and similar studies have prompted calls for loosening laws prohibiting possession and study of psychedelic substances in several states. In November of 2020, Oregon became the first state to decriminalize the possession of small amounts of street drugs including cocaine, methamphetamine, and heroin, and, via a referendum, voters approved an initiative to legalize therapeutic use of psychedelic mushrooms.
Although Oregon’s psilocybin program won’t be up and running until 2023, the Oregon Health Authority recently named a manager for the agency’s Psilocybin Services Section, while the state’s Psilocybin Advisory Board convened earlier this year, Oregon Public Broadcasting reported.
In California, a measure aimed at decriminalizing certain hallucinogenic substances passed in the state senate and assembly, but was recently delayed until next year.
However, decriminalization of certain substances for personal use and establishing systems for researching and using psychedelics as therapy are 2 separate initiatives, Ali stressed.
When it comes to the delay in California, “there is some research that would have come out of that bill, which is regarding the social impacts of and future recommendations [of decriminalization], that was a commission in California 519,” Ali said. He continued, “I do think that that’s a setback—that we’re going to have to wait another year for something to get passed and start doing that research, because we really want to know, ‘What does responsible access look like,’” in such an environment? But the pause does grant citizens more time to educate the legislature, Ali said.
In addition to California and Oregon, lawmakers in other states have proposed similar programs. A bill introduced in New York in June would require the state to establish an institute designated to research the therapeutic benefits of psychedelics, while the Committee of Veterans Affairs and Border Security in the Texas House of Representatives approved a bill focused on psychedelic therapy for PTSD in veterans.
At the national level, attitudes towards the potential therapeutic benefits of psychedelics have remained largely stagnant. “To me, government funding is probably the biggest key that’s missing at this point to really moving things forward,” Ali said.
But a report accompanying a recent US House appropriations bill signaled a potential shift in attitudes. Authors encouraged research on alternative therapies and psychedelics for veterans with treatment resistant PTSD and MDD, while also advising NIH and other agencies to undertake and expand research in this area.
Furthermore, in April of 2021, the NIH awarded its first grant dedicated to medicinal psychedelic research, but stopped short of funding an actual trial.
Federal funding is critical as current funding models for psychedelic research carry their own risks, Ali explained. “If it’s all going to happen through philanthropy and in non-profit, then you’re reliant on philanthropists, which has its own baggage, or you’re doing it in a business development—or drug development context, in a for-profit context—which also has its own baggage,” he said. “I think that either of those outcomes is going to limit the potential and benefit of psychedelic therapy.”
Psychedelic Push Back Exists
Calls for increased research on the therapeutic properties of psychedelics and for decriminalization are not without opposition. For some, legalization efforts have happened too fast, while for others, research supporting widespread therapeutic use is not sufficiently robust.
“The promise of therapeutic benefit from psychedelics is appealing, but overly rapid legalization and commercialization may short-circuit prudent legal reforms,” wrote William R. Smith, MD, PhD, and Paul S. Appelbaum, MD, in a recent viewpoint published in JAMA.
Relatively small and homogenous sample sizes mark limitations to many studies assessing the use of psychedelics for mental disorders, while Smith and Appelbaum argued adverse events and abuse potential are not yet fully understood.
“The current debate creates a sense of urgency for decriminalization and a promise of solving a mental health ‘crisis’ that may obscure potential harms of rapid implementation, largely unknown but potentially foreshadowed by prior experience,” they said. “Slowing the rush to legalization of psychedelics to clarify the evidence, giving policy makers and the public better information, and to develop careful regulatory policy would be wise.”
However, some posit this sense of urgency is warranted when it comes to care options for mental health conditions. “There is an inherent tension between urgency of need and quality of care,” said Ali in response to the authors’ critiques. “I agree with the concern that leaning too much into the urgency could undermine effective care and effective outcomes because of the desire for some sort of solution.”
But “I also think it’s a remarkably out of touch position to believe that there isn’t urgency, because I think that it’s quite obvious to most people who are paying attention to mental health that current treatments are not working,” he continued.
Pointing to the notoriously failed War on Drugs that resulted in excessive incarceration rates and disproportionately harmed communities of color in the United States, Ali stressed the importance of enacting decriminalization efforts independent of clinical research related to therapeutic benefits of certain drugs.
“Whether or not there’s a whole system of care that’s attached to these substances for specific indications, that to me is something that I think ought to be really well researched, have quality control, have supervision, and so on, because of the expectations that come with a medical system,” he stated. But ultimately the barrier to entry for personal adult recreational use of certain drugs is not going to be as high as the specific contexts warranted for therapeutic use.
For example, for individuals with multiple comorbidities or potential contraindications, more specialized care and more support will be necessary to ensure the beneficial therapeutic use of psychedelics.
Touching on the notion of unknown adverse events, Ali noted that, unlike the myriad new drugs produced and marketed each year for diseases, use of some psychedelics can be traced back decades or hundreds of years. “The idea that there’s suddenly going to be hundreds of surprise cases of something going horribly wrong, I think is a bit of a false flag,” he added.
Overall, “the medical system should not be rushing itself just because people see the urgency. In my opinion, there’s multiple tracks. We should be pushing for decriminalization; there should be a system of legal regulated adult use. Then, there also should be medical use and we just need to be mindful of which expectations are being played for which [track],” Ali said. “I do think that urgency is real, and the urgency shouldn’t undermine the quality.”
Under the Controlled Substances Act passed in 1970, psychedelics—including psilocybin and MDMA—are Schedule 1 drugs, meaning they are considered to have a high potential for abuse and have no current accepted medical uses, according to the DEA.
Currently, federal funds cannot be allocated to any activity that promotes the legalization of any Schedule 1 drug, according to restrictions put into place in 1996. In July, Representative Alexandria Ocasio-Cortez’s (D-NY) effort to allow federal research into the therapeutic role of psychedelics was rejected by the U.S. House of Representatives.
According to Ali, the only federal entity that has spent any money researching psychedelics is the National Institute on Drug Abuse, whose job is to uncover and report negative effects.
“For a long time, the drug policy movement was united against the War on Drugs, that was ‘We’re all against this thing,’” Ali explained. Now, we’re at a point where individuals in the field have to decide what they are collectively for and determine what should be the alternative to prohibition, he said.
In the next 5 years, Ali hopes to see progress made on several fronts when it comes to psychedelic-assisted therapy for mental illnesses. This includes a handful of states moving forward with policy changes, federal funding being unlocked for psychedelic research and therapy, and mental health becoming deeply incorporated into a unified health system.
Ali also called for a potential update to the Religious Freedom Restoration Act—under which psychedelics are sometimes used in religious or spiritual contexts—and all drug decriminalization at the state level.
“As much as I do think that psychedelics have a tremendous amount of potential, there’s no question to me that benefits…like decriminalization, ought to cover all drugs because I think that—wherever you land on whether or not drugs should be used, or how—the fact is that they are being used,” Ali said.
One way to reduce the harms or risks of drug use is decriminalization, he explained, noting legal interactions or interventions constitute part of the risk profile for some substances.
Overall, Ali feels there is a strong case for concurrent decriminalization and therapeutic use of certain substances. The United States has yet to transition out of a system like prohibition, but prohibition is the exception, not the rule, he stressed.
“We’ve only been experiencing prohibition of drugs for about the last 120 years, most concentrated in the last 50, during the War on Drugs.” Although careful iteration is needed, these things can coexist, Ali concluded. “I do believe that we’re trying to create something that’s different with drug policy that hasn’t been done before.”