Psychedelics moving into pharmaceutical mainstream

Mind-altering psychedelic drugs such as LSD, “ecstasy”, and “magic mushrooms” are moving into the pharmaceutical mainstream and creating substantial opportunities for CMOs with controlled substance handling qualifications. Regulators have recently approved clinical trials and even marketing authorizations for these chemicals, as doctors incorporate them into regimens for widely prevalent indications such as post-traumatic stress disorder (PTSD). Physicians hope their use will help reduce opioid prescriptions to combat the addiction epidemic. The potential market for psychedelics is huge: according to GlobalData’s Epidemiology database, there were 29.2 million cases of PTSD alone in 2020 across the 16 major markets.

Psychedelics (also known as serotonergic hallucinogens) are compounds with appreciable serotonin 2A receptor agonist properties that can alter consciousness in a marked and novel way. Naturally occurring psychedelics are DMT, mescaline, psilocybin, THC, and LSD. Synthetic psychedelics also exist. These substances tend to also be classed by their structure: tryptamines (structurally resembling serotonin), phenethylamines (structurally resembling epinephrine and norepinephrine), and ergolines (derived from ergot).

Amphetamine-based psychedelics
Amphetamine-based psychedelics such as Adderall (amphetamine aspartate + amphetamine sulfate + dextroamphetamine saccharate + dextroamphetamine sulfate) have long been used as therapeutics, and now researchers are exploring other psychedelics, either repurposing illicit drugs or by altering the chemical structures of marketed pharmaceuticals to produce safer and more predictable results.

In the latter category, the FDA and EMA approved Johnson & Johnson’s Spravato (esketamine) in 2019 for treatment-resistant depression, their first approval of a psychedelic treatment for a psychiatric disorder in both the US and EU. Esketamine is derived from the anesthetic ketamine. In August this year, the FDA approved Axsome Therapeutics’ Auvelity, (bupropion hydrochloride + dextromethorphan) for major depressive disorder. Clinical trial results suggest Auvelity works faster than traditional antidepressants, which can take weeks to have an effect.

Related psychedelics are not far behind. Avanir Pharmaceuticals is developing a Phase III NMDA receptor antagonist, deudextromethorphan hydrobromide + quinidine sulfate, for schizophrenia and traumatic brain injuries. Similarly, the nontoxic and nonhallucinogenic chemical cousin of ibogaine, named DLX-7, has shown success in preclinical studies by Delix Therapeutics for anxiety, depression, and addiction.

LSD and mushrooms
Drugs such as MDMA (midomafetamine), psilocybin, and LSD have long been taken recreationally but are increasingly being used in medical research. GlobalData’s Clinical Trials database shows at least 51 trials were initiated for psilocybin, 10 for MDMA, and six for LSD during 2019–2021. The closest to market is MDMA, in Phase III for PTSD and Phase II for social anxiety disorder, sponsored by the non-profit Multidisciplinary Association for Psychedelic Studies. AWAKN Life Sciences has an MDMA product in Phase II for alcohol addiction. MindMed’s LSD product is in Phase II for major depressive disorder, attention deficit hyperactivity disorder (ADHD), cluster headache, and anxiety disorders.

Psilocybin is the active constituent in what are commonly known as ‘magic mushrooms,’ a naturally occurring chemical compound that is increasingly seen as highly safe and effective in treating many forms of mental illness and substance use disorder. It is currently in Phase II development for multiple psychiatric indications by Braxia Scientific, Tryp Therapeutics, Compass Pathways, Ceruvia Lifesciences, Revive Therapeutics, and a Copenhagen psychiatric hospital.

Even if these drugs are approved, their accessibility and the scalability of the regimen to all patients will be an obstacle that could reduce use among any potential treatment population. Studies so far suggest that for the greatest level of benefit, psychotherapy is needed alongside psychedelics. That creates an additional requirement that will limit scalability in the marketplace compared to traditional treatment models, which only require the patient to consume medicines.

Legal obstacles – but CMO opportunities
Imprisonment for psychedelic possession in the US increased after 1986, when President Reagan signed the Anti-Drug Abuse Act. This allotted $1.7 billion to the War on Drugs, and established mandatory minimum prison sentences for specific drug offenses. Many of the strict legal and social stances formed against psychedelic drugs in the 1980s have begun to relax. On January 11, 2022, the launch of the International Therapeutic Psilocybin Rescheduling Initiative (ITPRI) occurred, a global coalition working to promote and secure a rescheduling of psilocybin under the 1971 United Nations Convention on Psychotropic Substances.

CMOs have already secured manufacturing agreements for marketed psychedelics such as Takeda Pharmaceuticals’ Mydayis ER (amphetamine aspartate + amphetamine sulfate + dextroamphetamine saccharate + dextroamphetamine sulfate) for which Cambrex Corp is producing the API and Patheon (owned by Thermo Fisher Scientific) is manufacturing the finished dosage form.

Authorisations for manufacturers to produce controlled substances require very strict security for the production and storage of the active substance, and vetting of the personnel involved in the active substance manufacture. In the US the Drug Enforcement Administration (DEA) classifies chemicals into five schedules depending upon the drug’s acceptable medical use and the drug’s abuse or dependency potential. The abuse rate is a determinate factor in the scheduling of the drug; for example, Schedule I drugs have a high potential for abuse and the potential to create severe psychological and/or physical dependence with no currently accepted medical use. Examples of Schedule I drugs include heroin, LSD, cannabis, MDMA, methaqualone, and peyote. If any of these substances were to become FDA-approved then their associated DEA schedule would have to be lowered. Perimeter fencing, steel vaults, and electronic monitoring are the kinds of requirements an API manufacturer of a Schedule II drug would need to provide.

GlobalData’s Contract Service Provider database shows there are 245 contract manufacturing organisations with 386 facilities worldwide permitted to handle DEA-scheduled products (excluding pharmaceutical companies that also offer contract services). Only 152 of these sites can carry out Schedule I manufacture, and 272 facilities able to carry out production of Schedule II or III substances.

Controlled substance capabilities and facility requirements can be prohibitively expensive. Smaller pharma companies are not able to possess or purchase these kinds of sites, so CMOs have a good chance to generate business by owning controlled substance capabilities.