Novel Psychoactive Substances - A Brief History

Natural psychoactive substances, such as Psilocybin found in “Magic” Mushrooms, THC in Cannabis, or Nicotine in Tobacco, have been used by humans for thousands of years. However, novel psychoactive substances, or synthetic compounds, require some chemistry for their creation, usually in a laboratory setting, and are a much more recent phenomenon.

Some well-known examples of synthetic compounds include MDMA, Ketamine, and Aspirin.

But when were these synthetic compounds first discovered, where did they come from, and why do they exist?

To best answer these questions perhaps a timeline is useful.

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Most chemistry from the late 18th century was based on plant extracts. Opium was one of the more important extracts at the time, likely for its ability to induce euphoria and eliminate pain. The isolation of Morphine from Opium occurred between the years of 1803 and 1817 by Friedrich Wilhelm Adam Sertürner [7], revolutionizing the field of pharmaceutical chemistry forever.

For the most part, up until this time, humans were dependent on whatever herbs, roots, or fungi that had been discovered to treat medical ailments. One of the first synthetically derived substances was Chloral Hydrate. Even though it was first synthesized in 1832 [3], it was not until 1869 that the substance was available for use in medicine [3][6]. It was classified as a sedative-hypnotic, with its primary use as a treatment for insomnia. 

After the element Bromine had been successfully isolated from seaweed, Charles Lockock soon discovered its anticonvulsant and sedative properties. This led to the development of Potassium Bromide, and in the latter half of the 1800’s, the substance was frequently used for sedation and the control of anxiety and convulsions. Bromides came with a host of toxic side effects, such as mental dullness, weight loss, and delirium [2].

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Diamorphine (Heroin) was first synthesized with the original intent to be a less addictive form of Morphine (ha).

In 1898, the Bayer pharmaceutical company began to aggressively market Heroin as a treatment for Bronchitis, tuberculosis, and other cough-inducing illnesses, and as a replacement to Morphine. It was initially claimed that Heroin was not at all addictive, and so was prescribed to treat people suffering from Morphine addiction. This led to some 200,000 people becoming addicted to Heroin in New York City before the Harrison Narcotics Act was passed in 1914.

Cocaine was isolated from the Coca Leaf, and the extract was marketed as a topical anesthetic in toothache drops to be sold over the counter. Cocaine was legally sold in this manner for decades. Coca-Cola also contained small amounts of cocaine during this period, although exactly how much is unknown.

The clinical introduction of Barbiturates began when the Bayer Company brought Diethyl-Barbituric Acid into the world of pharmacology. Barbiturates were seen as more effective than previously discovered sedatives, and when patients were given the appropriate dose, it improved their general prognosis where before they had seemed untreatable. Over 2500 Barbiturates were synthesized in the 20th century, with about 50 reaching clinical use [8]. 

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MDMA was first synthesized by Merck, though it apparently was not sampled in humans, and thus did not attract the attention of chemists until much later[9].

Methamphetamine was first synthesized by Japanese chemist, Akira Ogata [4].

While working with an ergot fungus in his laboratory, Albert Hofmann accidentally creates (in 1938) and ingests (in 1943) the well-known psychedelic compound, Lysergic Acid Diethylamide (LSD). The altered effects on his perception were profound and he envisioned the substance having potential use psychotherapeutically. Over the next few decades, the substance made its way into the far reaches of the world. It has since become among the most famous and influential novel psychoactive substances.

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Methamphetamine was first marketed in the United States under the brand names Desoxyn and Methedrine to treat narcolepsy, obesity, and depression [4].

There was a great need at the time to develop an anesthetic compound for use during surgery. After much careful research, Parke-Davis and Company developed Phencyclidine (PCP). While the anesthetic and analgesic effects were potent, there were also a variety of side effects that were less than desirable. Occasionally, patients would emerge from anesthesia with delirium, hallucinations, and overall chaotic behavior. This motivated chemists to explore other novel psychoactive substances [10].

In 1962, after exploring PCP and some of its analogs, chemist Calvin Stevens at Parke-Davis synthesized Ketamine for the first time [10]. The researchers were quite pleased with the effects as it appeared to be the most effective dissociative anesthetic agent they had seen so far.

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Mescaline, found naturally in some species of South American cactus, had been explored as a potential psychotherapeutic agent, however, the hallucinatory effects and cognitive alterations were extreme at times and made therapy difficult. It was at this time that MDA began to be tested as a possible alternative because intensified emotional states were achieved, but with much less hallucinatory effects [11]. 

The 1960’s was a tumultuous time for Americans. The Civil Rights Movement, Vietnam War protests, and growing counter-culture led to an explosion of new art, music, and political expression. With this activism, many individuals began sampling various psychoactive compounds, such as LSD, STP, MDA, and Mescaline, which drew the attention of the media. 

4-AcO-DMT (Psilacetin) and other analogs of Psilocin, one of the psychoactive compounds in Psychedelic Mushrooms, were patented by Sandoz Ltd. Albert Hofmann was again a major contributor to the success of these chemicals.

Alexander Shulgin introduced MDMA as a psychotherapeutic agent and shared it with psychotherapists he knew well. It was not long before underground psychotherapy sessions began with the use of the substance [11]. Due to its potent and highly euphoric pharmacological effects, it soon began to be used as the popular street drug, Ecstasy.

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Charles Pfizer of Pfizer Pharmaceuticals develops CP 47,497, a Synthetic Cannabinoid intended for medicinal use. The need for a Synthetic Cannabinoid spawned from the fact that Cannabis was made illegal and thus, it was very difficult to do medical research into the plant. Just another example of prohibition leading to the creation of new novel psychoactive substances.

Due to the rising popularity of powdered Cocaine in the 1970’s, a new form of “rock” Cocaine was spread throughout many cities in America. It was made to be smoked, and because of the crackling sound it made while ignited, was named “Crack Cocaine”. Crack was notorious for decimating impoverished neighborhoods at the time.

The DEA scheduled MDMA due to its rising popularity as a recreational substance, despite having numerous alleged benefits as a psychotherapeutic agent.

John W. Huffman, the creator of the JWH series of Synthetic Cannabinoids, such as JWH-018, JWH-019, and JWH-122, documents his findings on the potential medical use of his compounds.

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Publication of PiHKAL (1991), and TiHKAL (1997). These books were written and published by Alexander (Sasha) Shulgin and his wife, Ann Shulgin. The first half of each book includes stories from Sasha Shulgin’s life, while the second halves include directions for the synthesis of 234 novel psychoactive substances. Having tested the compounds on himself on various occasions, there are detailed reports of what effects these substances can have. 

Due to how detailed these books were, these writings undoubtedly inspired countless chemists and researchers to further elaborate on Shulgin’s work. They were also a catalyst in the research chemical/novel psychoactive substances boom of the early 2000s until the present day.

Although Mephedrone was originally synthesized in 1929, the compound was not made popular until the early 2000’s when curious individuals synthesized the compound as an experiment. It was said to provide an Ecstasy-like high and quickly became one of the most popular novel psychoactive substances of that time. [5].

In Europe, products containing Synthetic Cannabinoids such as JWH-018 or CP 47,497, emerged on consumer markets. These products became known as “Spice”. They were designed to be smoked and marketed as alternatives to Cannabis. Effects were often very different from that of traditional Cannabis, with many very negative side effects.

Spice, K2, and other herbal smoking blends that contained Synthetic Cannabinoids began to appear in the United States.

Articles surface about a “cannibalistic” class of compounds called “Bath Salts” that allegedly caused an individual to try to eat the face of another person. This has largely been debunked as sensationalized news that was intended to generate hysteria [14]. Regardless of the validity of the claims, many stories were published supporting this narrative, causing some negative public opinion of Research Chemicals that still persists until today.  For reference, the term Bath Salts referred to a class of euphoric stimulant compounds called cathinones, namely Methylone (bk-MDMA), Mephedrone (4-MMC), and Methylenedioxypyrovalerone (MDPV), that allegedly caused Cocaine or Ecstasy-like effects. 

The FDA approves Ketamine as a treatment for treatment-resistant depression. Many individuals who had undergone multiple lines of traditional treatment, such as various prescriptions of antidepressants, are now able to alleviate many of their depressive symptoms quickly and effectively.

As of December of 2019, over 950 unique research chemicals (NPS) have been identified by the United Nations Office on Drugs and Crime (UNODC). The emergence of these chemicals was most popular in the United States, Canada, the United Kingdom, Germany, Poland, Russia, China, and Japan [13]. These substances are broken down as such: 36% Stimulants, 31% Synthetic Cannabinoids, 15% Hallucinogens, 8% Opioids, 3% Dissociatives, 3% Sedative-Hypnotics, and the rest are unassigned [13].

To describe the full history of synthetic psychoactive compounds would take volumes of books. What you see above are some important events that hope to explain some of the reasons why these psychoactive compounds have been sought after and discovered. Ergo, for medicinal purposes. Whether it was PCP and Ketamine for the purpose of anesthesia, Barbiturates for the purpose of tranquilization, or MDMA and LSD for the purpose of psychotherapy, the reason for the creation of these compounds can almost always be mapped to something medicinal. The inevitable consequence is that many of these beneficial compounds come with pleasurable effects, leading to recreational users, which results in governments attempting to impose bans and the medicinal potential of many of these compounds unrealised.

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One of the troubling discoveries I made while researching the history of these synthetic compounds was that some of these substances, especially in the case of the Synthetic Cannabinoids, were only developed because the parent substance (Cannabis) was illegal. Perhaps, if Cannabis was not made illegal, then there would have been no need for Synthetic Cannabinoids to be developed in the first place. This may have saved governments and lawmakers from the sociological fallout that began happening in the early 2000s, when herbal smoking blends that contained Synthetic Cannabinoids flooded the markets of the world, wreaking havoc on unsuspecting individuals. The same could be said for the rise of Methylone and Mephedrone in the early 2000s. These substances had characteristics of Amphetamines and MDMA, but likely only ever became popular because those similar compounds had been made illegal decades prior. These are just a couple of examples of recently made (and very popular) substances that illustrate the problem at hand. It seems that this trend to develop new psychoactive compounds will only continue as the years progress. 

In conclusion, I believe a paraphrased quote by Dr. David Nichols, who has been studying psychedelic neuroscience for the better part of the last 50 years, best describes this dilemma: “Make one compound illegal, and several new compounds will emerge more dangerous than the last”. Indeed, that seems to be the situation we are faced with today. This is why it is more important than ever to be informed!

Remember, if you decide to study a new and unfamiliar chemical, whether for medicinal purposes or otherwise, please do adequate reading and research! Be safe! 

Master Horus is the Author of Drugs of The Universe, a FREE harm reduction and education handbook you can read here.

Diamorphine (Heroin) was first synthesized with the original intent to be a less addictive form of Morphine (ha).

In 1898, the Bayer pharmaceutical company began to aggressively market Heroin as a treatment for Bronchitis, tuberculosis, and other cough-inducing illnesses, and as a replacement to Morphine. It was initially claimed that Heroin was not at all addictive, and so was prescribed to treat people suffering from Morphine addiction. This led to some 200,000 people becoming addicted to Heroin in New York City before the Harrison Narcotics Act was passed in 1914.

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