Building on the Shulgin Approach

How did a chemist working for the Dow Chemical Company become known as the godfather of psychedelics? 

Alexander Shulgin, a formally trained chemist, fascinated with the interaction between the mind and molecular matter, is credited with bringing MDMA into the field of psychotherapy as a potential form of treatment as well as creating over 200 psychoactive compounds. His mission? To improve on the psychedelic properties of existing psychedelics such as MDMA and diisopropyltryptamine (a derivative of DMT) to help treat various mental health disorders. Contrary to his meticulous chemical synthesis, his lax biological ‘studies’ would never allow his molecules to be developed into paradigm changing medicines. 

These compounds were tested on none other than his wife and himself while documenting their experiences in a series of books. In actual fact, drug development is a rigorous endeavor that requires robust, placebo-controlled studies proving a drug is both safe and effective at treating a disease in a patient. Companies today such as MagicMed Industries are building on what Shulgin started but in a much larger and more scientifically rigorous way. Compared to Shulgin’s 200 compounds, the team at MagicMed aims to synthesize thousands of novel compounds of known psychedelics such as psilocybin, DMT, and MDMA.  

By partnering with pharmaceutical companies, some of these novel compounds will go through the rigorous drug development process to become a next-generation therapeutic that will help patients around the world. This article will explore the work of Alexander Shulgin and how MagicMed is inspired by and improving on his approach of novel psychedelic compound development for the treatment of brain and mental health indications. 

Introducing MDMA and New Psychedelics to the World

A gifted student, Shulgin started his studies of chemistry at Harvard University at the age of 16 but with World War II disrupting the world, he joined the Navy in 1943. Eventually he would complete his studies, ultimately obtaining his PhD in biochemistry at UC Berkley. During the 1950s, he experimented with mescaline, which ignited his fascination with the mind and how chemical matter can alter it. When discussing the mind and his experience with mescaline he once stated:

“I understood that our entire universe is contained in the mind and the spirit. We may choose not to find access to it, we may even deny its existence, but it is indeed there inside us, and there are chemicals that can catalyze its availability.” 

While working for the Dow Chemical Company, Shulgin first synthesized MDMA and although he did not invent the compound, he soon would introduce it to the world of psychotherapy. Interestingly, Merck patented MDMA in the early 20^th century only to block a compound synthesis route for one of their other compounds. They never investigated its effects.  It was not until the mid 1970s when one of his students told him about the psychoactive properties of MDMA that Shulgin started synthesizing it for himself. Although he did not find the effects of the drug to be powerful, Shulgin enjoyed it and called MDMA his ‘low-calorie martini”.

He thought it would be useful in therapy and started giving the drug to his friend’s including psychotherapist Leo Zeff. Along with Shulgin, Zeff believed that MDMA hindered the human’s fear response allowing increased communication during therapy sessions for several disorders including substance abuse, autism, premenstrual syndrome, and other psychiatric disorders.

Wanting to improve and expand on the effects of psychedelics, Shulgin started synthesizing novel analogs of various psychedelics in his home laboratory. Synthesizing safer and more effective compounds using what nature has created is a common practice in the pharmaceutical industry. Shulgin’s work created new classes of compounds including the 2C and Dox family of compounds which were more metabolically stable and potent than naturally occurring psychedelics. He published his findings in two books: “Phenethylamines I have Known and Loved” and “Tryptamines I have Known and Loved”. In these books he discussed the synthesis, bioassays, dosages, and their psychedelic effects. Shulgin’s work is far reaching. His books are used by amateur chemists who want to synthesize these psychedelics and benefit from them. Compounds he created such as DOM are also commonly used in research labs today to study the 5-HT receptor and thus have contributed greatly to the advancement in our understanding of the mind. 

Why Shulgin’s Approach Decreases the Chance of Creating a New Medicine

The ultimate goal of drug development is determining if it is safe and effective at treating a specific condition. Progressing a drug from lab bench to patient bedside is an extensive and heavily regulated process with patient safety being prioritized first and foremost. Shulgin’s sentiment of wanting everyone to benefit from his psychedelics was performed with good intentions but his approach is impossible for most psychedelic companies. 

First, Shulgin created these compounds in a lab in his garage. Government regulatory bodies, such as the FDA, have strict guidelines dictating how products meant for human use are to be manufactured (Good Manufacturing Practice; GMP) and how experiments must be conducted (Good Laboratory Practice; GLP). These guidelines ensure safety for any patient that will be exposed to the drug. Shulgin himself was not synthesizing his compounds in GMP settings thus exposing anyone who took the drugs to great risk. By not following GMP standards, the compounds cannot be consistently reproduced leading to structure variances due to the lack of quality control.  Compounding these risks were the inexperienced chemists who attempted to synthesize these compounds themselves after reading his books. Secondly, before entering clinical trials there must be a wealth of data surrounding the drug indicating its efficacy and safety in the in vitro lab models and in lab animals. The FDA has many requirements for what is known about the drug and thoroughly reviews this data before allowing testing in humans.  

This brings us to the third point regarding Shulgin’s approach: clinical trials must be scientifically robust and statistically powered.  Scientific robustness comes from well-planned placebo and double-blinded controlled clinical trials. The placebo effect is an unexplainable event where a treatment, even if truly ineffective, will exhibit results simply because the recipient believes it will. Sugar pills are a common placebo treatment in drug trials. Double-blinded means that both the doctor administering the drug and the patient receiving it do not know whether the drug they received is the placebo or the real treatment. Double-blinded, placebo-controlled trials are the gold standard in scientific experimentation and are especially important when testing the effect of a drug on someone’s perceived state such as in pain and depression studies. Administering the drug to yourself, as was the case in Shulgin’s experiments, is not scientifically valid and he likely saw an improved effect in some of his drugs simply because he believed they should be better. Additionally, drugs must be tested on hundreds, if not thousands, of patients from diverse backgrounds before being approved by the FDA. Due to differences in genetics and a number of other factors, some people will not respond while others will respond more to certain drugs, and it is important to understand the factors that dictate these populations of response. Again, Shulgin failed to do this as he only tested his drugs on himself, his wife and his friends.  

With the vast number of regulations and data required to get a drug from bench to bedside, immense amounts of money are required. In fact, the average cost to bring a drug to market is estimated to be $985 million USD (Journal of the American Medical Association, 2020). Pharmaceutical companies obtain this money from investors who only invest if they believe they will make a return on their investment as the drug gets approved. A drug that cannot be patented is not a safe investment since another company can easily copy what is being developed. By publishing his compounds in books, they became public domain, cannot be patented and thus will never attract investors to help develop them into effective medicines. Philanthropy can only go so far when costs and risks are as high as they are in biotechnology and pharmacology. 

MagicMed’s Approach 

Despite the limitations to his approach, Shulgin’s sentiment was in the right place. He stated in 2001 that he was “quite confident there will come a time when Ecstasy will be recognised for its medical value”. Indeed, Shulgin was correct, and this is now coming to fruition with companies like MagicMed looking to lead the innovation. Much like Shulgin, MagicMed believes psychedelics will be the next frontier used to treat various neurological diseases and psychological disorders. Their mission is focused on the discovery and early development of novel drug candidates, structurally related to the classic psychedelics but with vastly improved pharmaceutical characteristics and commercial potential.  Contrary to Shulgin’s small scale approach that at times lacked scientific rigor, MagicMed is taking a robust, scientific approach to generate many novel analogs in the patented compound library, the Psybrary, which is poised to become an essential building block from which industry partners can develop new patented drugs. Using a mix of synthetic biology, medicinal chemistry and artificial intelligence (AI), these novel compounds can be specifically curated towards desired drug characteristics, improved safety profiles and enhanced efficacy.  With pharmaceutical partners, high quality and robust scientific experiments – on the lab bench, in lab animals and eventually in humans – will be conducted following the rigorous guidelines set by health regulatory bodies providing the best opportunity for these psychedelics to become the next frontier of innovative medicines. 

References:
Bennett, Drake (2005-01-30). “Dr. Ecstasy”. New York Times Magazine. New York Times. Archived from the original on November 17, 2011.

Romero, Dennis (1995-09-05). “Sasha Shulgin, Psychedelic Chemist”. Los Angeles Times. Archived from the original on 2007-03-26. 

This article is written by Sean Vandersluis for MagicMed