Psychedelics & Cannabis, Gaining Clinical Acceptance

Small studies are demonstrating value for individuals with depression, alcohol use disorder, and chronic pain. States and localities are showing a willingness to loosen restrictions. But the path to medical coverage is long, narrow, and currently blocked by government agencies.

Cannabis and hallucinogenic usage reached an all-time high in 2021 among young adults, according to a report¹ from the National Institutes of Health. Researchers say that the increase is due to disparate factors, including mental health effects of the pandemic, the growing availability of legal marijuana, and increased acceptability of the use of psychedelics to treat depression, post-traumatic stress disorder, alcohol use disorder (AUD), and other conditions.

The spotlight on psychedelics and cannabis extends to research centers, statehouses, and city halls across the country. Small studies and meta-analyses are showing the clinical value of certain compounds, and state and local officials are loosening restrictions on them. In New York state, efforts are underway to mandate that state-sponsored health plans cover cannabis treatment.

Researchers have published several studies this year, assessing the potential benefits of psilocybin and cannabis. While the research points to promise using these compounds, the studies tend to be small, and investigators note that additional assessment is needed before the treatments are recommended for widespread clinical use.

Additionally, these compounds still face challenges at the regulatory level from the US Food & Drug Administration (FDA) and the Drug Enforcement Administration (DEA) but their clinical value could pave a path forward.

Can psilocybin coupled with psychotherapy decrease the number of heavy drinking days in those with AUD?

Researchers sought to answer that question by conducting a double-blind randomized clinical trial² involving 95 individuals. Participants had experienced at least 4 heavy drinking days in the month prior to screening for the trial. All received 12 weeks of psychotherapy and were randomly assigned to receive either high-dose psilocybin (n=49) or placebo (n=46) at weeks 4 and 8. Investigators assessed the percentage of heavy drinking days following the initial medication administration. They found participants receiving psilocybin averaged 10% heavy drinking days over the study period vs 24% for the diphenhydramine group—a difference of 14%. The results support further study of this compound to treat AUD.

Is psilocybin-assisted therapy efficacious among patients with major depressive disorder?

Researchers at John Hopkins University’s Bayview Medical Center conducted a randomized, waiting list–controlled clinical trial³ involving 27 individuals with major depressive disorder. Participants were randomized to receive 2 psilocybin sessions as part of supportive psychotherapy either immediately (n=15) or after an 8-week delay (n=12).

Investigators looked at depression severity using the GRID-Hamilton Depression Rating Scale (GRID-HAMD) scores at baseline and then at weeks 5 and 8 after the delayed treatment group enrolled. This assessment period corresponded to weeks 1 and 4 following treatment for the immediate treatment contingent. Among the results:

• Average GRID-HAMD score at baseline was 22.8 for all participants
• Weeks 1 and 4 GRID-HAMD score in the immediate treatment group averaged 8.0 and 8.5, respectively
• Weeks 5 and 8 GRID-HAMD score in the delayed treatment group averaged 23.8 and 23.5, respectively

The researchers concluded that psilocybin-assisted therapy leads to large, rapid, and lasting antidepressant effects. Moreover, even though the effect is similar to what has been reported with ketamine, psilocybin’s efficacy appears to be longer-lasting and may be less addictive. They noted that larger, placebo-controlled trials are needed to further demonstrate efficacy.

Investigators conducted a systematic review⁴ of 18 randomized, placebo-controlled trials and 7 cohort studies involving 1740 and 13,095 individuals, respectively. The studies were mostly short-term, assessing patients for 1 to 6 months. Some of the key results include the following:

• Synthetic products containing more than 98% tetrahydrocannabinol (THC) appear to be linked with moderate improvement in pain severity. They are also associated with an increased risk for sedation and dizziness
• Extracted products with high THC-to-Cannabidiol (CBD) ratios are linked with a higher rate of study withdrawal due to dizziness and other adverse events

Sublingual spray with equal amounts of THC and CBD may be linked with a slight improvement in pain severity and overall function, but also a large increased risk for dizziness and sedation and a moderate increased risk of nausea

Researchers concluded that these products may provide short-term benefit from chronic pain, but that longer-term studies and evaluation of additional product formulations are needed.

While the researchers continue to assess the benefits of psilocybin and cannabis and their potential role in the clinical setting, at least one state is moving to mandate coverage of medical marijuana. In June, the New York State senate approved a bill⁵ that would cover medical marijuana under Medicaid and other state public health plans. Coverage by commercial plans would be optional. However, if the commercial plan is providing coverage under public health plans, such as Medicaid managed care plans, coverage would be required.

The legislation did not advance to the state assembly for passage, meaning it will need to be reintroduced in the 2023 legislative session. Still, a similar bill did not make it out of committee in 2018, suggesting that steady progress may result in the bill becoming law next year.

Meanwhile, some states appear to be loosening restrictions on psychedelics, adopting a strategy like the one that paved the way for legalizing cannabis at the state level. Oregon led the way by voting to legalize and regulate psychedelics. Politico reports⁶ that efforts are underway in Washington state to allow psilocybin use in adults under supervision. Some cities have loosened enforcement of laws governing use of psychedelic compounds. And now states both red and blue politically are considering doing the same, including Utah, Missouri, Connecticut, New Jersey, Texas, and California.

Despite the apparent momentum in both the clinical and legislative/political settings, coverage of psychedelics and cannabis cannot occur as long as these compounds remain unapproved by the FDA. The Controlled Substances Act classifies them as Schedule 1 narcotics because they are highly addictive and lack medical applications. The experts we spoke with largely concurred that coverage is not likely anytime soon. If there is a potential pathway, it is a very narrow one.

William Rogers, MD, chief medical officer at Applied Policy in Washington, DC, stated it plainly: “Until the DEA lifts its prohibition against use there can be no discussion of coverage by an insurance company.”

Norm Smith, a principal payer market research consultant in Philadelphia, PA, expanded on Dr Rogers’ frank assessment. “For starters, there is no pot of money to support the clinical development of these compounds. Second, without federal approval, psychedelics will experience a similar fate as marijuana: variation among states laws and legal commercialization. Third, a method to measure the potency of these compounds, along with standards for indications, must be created. Finally, after the opioid epidemic, it will take a courageous group of legislators to approve laws making psychedelics legal. I am not holding my breath.”

Larry Hsu, MD, medical director at the Hawaii Medical Service Association in Honolulu, HI, is not holding his breath either, but neither is he discounting the possibility that a path exists. “There is a lot of interest and research assessing use of psychedelics and cannabis. So, I wouldn’t say there is no chance these compounds would ever be covered.” Cannabis might blaze the trail, he noted, given researcher interest in evaluating it and increasing public acceptance of it. Adoption, however, will be slow, Dr Hsu admitted.

David Marcus, director of employee benefits at the National Railway Labor Conference in Washington, DC, agreed. “The road to coverage is a long one and could vary depending on the compound. Some sort of coverage for THC would likely occur prior to coverage for hallucinogens.”

Mr Smith acknowledges that as certain states and localities increasingly become more tolerant of individuals experimenting with psychedelics and cannabis, acceptance will grow. “Still, I am not convinced that any payer, private or public, will want to include these compounds on their approved lists.” Mr Marcus noted that state and local initiatives involving psychedelics would likely follow a similar path as THC. Acceptance will grow, restrictions will loosen, but likely halt there. “I don’t see federal support as part of the calculus.”

Edmund J Pezalla, MD, founder and chief executive officer of Enlightenment Bioconsult in Hartford, CT, agreed that activity at the state and local level will not play much of a role. “This is not within the state’s purview. Medicaid can only cover FDA-approved drugs.”  He added that any pathway to coverage would require the DEA and FDA to come into alignment on a compound. “Drugs are scheduled based on a combination of abuse potential and whether they have a currently accepted medical use. If the FDA approves a drug, that would qualify as accepted medical use. Then both agencies would agree and the drug would no longer be illegal and, thus, can be covered.”

Dr Rogers noted it is important to distinguish between whether a substance is FDA approved as a prescription drug or just not banned and therefore available in some way. “I see the market initially opening up for: 1) psychedelics for clinician administration for depression under prescription, and 2) cannabis over the counter primarily for nausea due to chemotherapy and weight loss.”

The opioid crisis is reason enough for any pharmaceutical company to steer clear of developing and commercializing these compounds. Still, the drugs could someday represent a revenue stream that pharmaceutical companies would find difficult to ignore. If that becomes the case, “it will be important to have behavioral health experts involved in order to address potential misuse or addiction,” noted Mr Smith. Mr Marcus thinks pharmaceutical companies will resist for a different reason—“potential loss of market share” of existing therapies.

As far as gaining federal buy-in/approval, Mr Marcus explained there would need to be “rigorous clinical study of the effects of these compounds. The early work is promising, but small.”

Dr Pezalla agreed: “Really convincing research will be needed to gain acceptance for psychedelics.” Trials will need to demonstrate either superiority over current treatments, such as antidepressants, or that the treatment works for patients who failed on standard care. “The studies will need to be randomized and compare the psychedelic with current treatments head-to-head.” And it will be many years before results from such trials are published, noted Mr Marcus.

Dr Pezalla returned to the potential for addiction. If clinical administration is ever deemed appropriate, “Administration by a health care provider would very likely be needed,” similar to the way methadone is administered in clinics, and how esketamine is self-administered under the supervision of a clinician.