The FDA and Botanical Drug Pathway

December 16, 2021

The societal toll of the global mental health crisis cannot be overstated. There are nearly 1 billion people with mental health and substance use disorders globally – 15% of the world population – a proportion that has been stable or rising since 19901. Despite this, effective and novel medical mental health treatments have been in short supply in the last 30 years. For instance, the current gold standard for depression, Selective Serotonin Reuptake Inhibitors (SSRI’s), have a long latency period, unwanted side effects, and sub-optimal efficacy – up to a third of patients do not respond at all2. Fortunately, in recent years, clinical trials have begun for what could prove to be a renaissance for mental health care: psychedelics.

Since 2000, there have been 327 clinical trials globally investigating the use of psychedelics in mental healthcare (See Figure below). There are currently 38 Phase 1 and 26 Phase 2 trials for the use of psilocybin in mental health treatment. Results have been promising, with the largest randomized-controlled double-blind psilocybin study showing rapid and sustained positive response to psilocybin and its concurrent therapy.

Figure: Total number of clinical trials since 20003

To date, the majority of psychedelic trials are using synthetic variants. The reasons for this include, but are not limited to:

  1. Ease: Synthetic variants are single compounds which makes them easy to work with and measure.
  2. Patents: As long as they are modified from naturally-occurring molecules, novel single compounds are easier to patent than complex multi-compound natural preparations.
  3. Purity: They contain minimal impurities that could interact with the active ingredient or be harmful on their own.
  4. GMP: It is believed that synthetic processes more easily achieve GMP compliance.

From a pharmaceutical development perspective, the above considerations make synthetic variants an attractive option – but is it the only option that should be pursued?

Botanical Drug Pathway

Botanical drugs consist of natural material, which can include plants, algae, and fungi, and come in a variety of forms. Since they are classified as drugs, they must be intended for use in the diagnosis, cure, mitigation, treatment, and prevention of disease in humans.4

Botanical drugs are unique because they are:

  1. Derived from natural sources; and
  2. Made up of a complex combination of multiple active compounds, rather than one single compound.

The botanical drug pathway is particularly promising for psychedelics and has several distinct advantages:

  1. History: human consumption of natural psychedelic substances throughout history is evidence of their safety and efficacy, including first-generation psychedelics. New synthetic analog compounds created in laboratories require significant investment in preclinical, toxicology, and other testing to assess second-gen compound safety and efficacy.
  2. Intellectual Property: because they contain multiple active compounds and consist of complex mixtures, the formulations and processes used in their development are only known to the manufacturer and are therefore difficult to replicate5.
  3. Entourage Effect: there is the potential for better outcomes due to the presence of multiple secondary metabolites. After all, human receptor sites are not one size fits all – they are natural and are variable6.

The botanical drug pathway contrasts with the typical pharmaceutical development process wherein a novel chemical entity is patented – a process that is efficient, but can be replicated relatively easily by others over time once the patent has expired.

Given that drug development requires time and money, how does one go about protecting a complex mixture of natural molecules?

Take the example of Premarin, a naturally-derived menopause drug. It was developed in 1942 and for many years it was the only hormone replacement therapy drug derived from a natural source on the market. In a short time, it quickly became the most widely prescribed drug in the US and Canada7. One company, Wyeth, was the only supplier of Premarin for decades. Several patents were filed on the drug in the 1940’s, but after their expiration, no generic competitors entered the market. How could this be? The answer is the fact that Wyeth kept the manufacturing process a tightly-held trade secret the whole time – opting for secrecy over IP patent protection. The extraction process itself, given the multiplicity of naturally-occurring compounds in the final product, was complex enough to avoid duplication so long as the manufacturing process remained a secret.

This story has implications for the current psychedelics industry. At present, most psychedelics companies are developing single-compound isolated products. In the case of unpatentable first-gen molecules, they are gaining protection through strategies like speed to market (to gain marketing exclusivity) and creating novel, patentable delivery methods. In the case of novel synthetic analogs of natural compounds, they are able to patent the compound itself. Patenting single-compounded molecules, although efficient, opens up the possibility for relatively easy duplication – especially once the patents run out.

Both of these scenarios have difficulties. In the first, companies are faced with low protectability. In the second they are faced with a large preclinical testing burden as well as significant competition from other analog manufacturers. An alternative scenario is to leverage the advantages of both by citing the established safety and efficacy of natural compounds but creating unique and protectable IP used to produce them. Layer on top of that the complex nature of the product, and the trade secrets of the composition and manufacturing, and you have a very compelling case. This third path is the one that we at Filament Health have chosen.

Filament Health

Filament Health is the first company to practically pursue botanical psychedelics. We have done this by overcoming challenges including developing stabilized doses, manufacturing technologies, and the FDA approval process.

Standardized Doses
One of the greatest impediments to developing botanical drugs is the production of the standardized doses required to create pharmaceutical-grade medicines8. Standardization requires proper and safe control of the raw material quality and manufacturing processes9. Through our innovative technology, we have developed a method for controlling the relative amount of psilocybin and psilocin produced during the extraction process. Additionally, the technology accounts for the inherent instability of the psilocin molecule. This work has culminated in producing three leading botanical drug candidates: PEX010, PEX020 and PEX030. PEX010 is a standardized 25 mg dose of natural psilocybin designed to provide the standard clinical dose, PEX020 is a dose-withheld oral delivery of psilocin and PEX030 is a dose-withheld sublingual delivery of psilocin.

Manufacturing Technologies
The heterogeneous nature of botanical drugs can make it difficult to determine if the constituents are active. Without consistency, therapeutic potential is limited. We are able to combat this by ensuring the control of the botanical raw materials through a facility that adheres to current Good Manufacturing Processes (GMP). Filament has a 3,500 sq. ft. GMP-certified facility and a Health Canada Dealer’s Licence held by our wholly-owned subsidiary Psilo Scientific, where we can produce several thousand high doses of psilocybin per month. These batches of psilocybin are pharmaceutical-grade and used in clinical trials. The facility conforms to Health Canada’s Directive on Physical Security Requirements for Controlled Substances and GMP manufacture.

FDA Approval Process
The unique aspects of botanical drugs described above require special consideration and adjustment during the FDA approval process. Compared to synthetic variants which are single compounds and have a more simplified approval process, the complexity of natural molecules makes this process challenging. This is one of the reasons why the FDA has only approved two botanical drug candidates to date. Despite this, Filament has been successful with efforts towards ultimately achieving an FDA-approved botanical medicine: on November 2, 2021, we announced FDA authorization of a Phase 1 clinical trial which will be the first FDA trial using naturally-sourced psychedelic substances and the first direct administration of psilocin rather than its prodrug psilocybin.

  1. PSYCH (2021). The Psychedelics as Medicine Report. Third Edition. Blossom. [Online] [Nov 25, 2021].
  2. [Internet]. Cologne, Germany: Institute for Quality and Efficiency in Health Care (IQWiG); 2006-. Depression: How effective are antidepressants? [Updated 2020 Jun 18]. Available from:
  3. Ibid
  4. What is a Botanical Drug. U.S. Food and Drug Administration.
  5. Further reading on the botanical drug example, Premarin.
  6. Further reading on the Entourage Effect. ​​
  8. Liu Y, Wang MW. Botanical drugs: challenges and opportunities: contribution to Linnaeus Memorial Symposium 2007. Life Sci. 2008 Feb 27;82(9-10):445-9. doi: 10.1016/j.lfs.2007.11.007. Epub 2007 Nov 29. PMID: 18177674.
  9. Eisner, S., 2001. Guidance for Manufacture and Sale of Bulk Botanical Extracts. Silver Spring, MD, American Herbal Products Association