The Origins of 'Spice' and Synthetic Cannabinoids

The Origins of 'Spice' and Synthetic Cannabinoids

There is a lot written in the media at the moment about the widespread consumption of Synthetic Cannabinoids, often generically known as 'Spice' (although, as will be seen below, 'Spice' is to synthetic cannabis in the same way as 'Hoover' is to vacuum cleaners'). As I have always been enthralled by trivia, this post looks at the history of synthetic cannabis (or Synthetic Cannabinoid Receptor Agonists to give them their proper name).

There are two key characters in the history of Synthetic Cannabis products: Dr. John W. Huffman and Professor Alexandros Makriyannis.

John Huffman is now Emeritus Professor of Organic Chemistry at Clemson University, South Carolina.

He lists his principal research interests as “the synthesis of analogues and metabolites of delta-9-tetrahydrocannabinol THC), the principal active component of marijuana. The long term goals of this research are two-fold and include the potential development of new pharmaceutical products and an exploration of the geometry of both the cannabinoid brain (CB1) and peripheral (CB2) receptors. Cannabinoid receptors are found in mammalian brain and spleen tissue, however, the structural details of the active sites are currently unknown. Marijuana metabolites are used in drug testing and THC analogues show promise for the treatment of nausea, glaucoma and as appetite stimulants”.

Alex Makriyannis works at Northeastern University, Boston, Massachusetts, and is the Founder and Director of the Center for Drug Discovery.

According to his CV he is “a highly successful medicinal chemist and is well recognized nationally and internationally for his important contributions in endocannabinoid research. This relatively newly characterized biochemical system, where he played an important role in its discovery, regulates many physiological functions including pain, neuroprotection, addiction, immunomodulation and cognition. Over the past four decades, his laboratory has designed and synthesized some of the key pharmacological endocannabinoid probes that are widely used and serve as leads for the development of new medications. He has also made important contributions aimed at understanding the molecular basis of cannabinoid activity.”

Huffman is credited with synthesising the Synthetic Cannabinoid Receptor Agonist (or SCRA) that was identified in the first version of 'Spice Gold' and Makriyannis is credited with creating the SCRA found in the original version of Black Mamba. The active ingredients of both were changed over time as constituent ingredients became illegal and laboratories 'copied' the branding often used their own 'version' of the active ingredient.


Why create synthetic cannabinoids in the first place?

There are at least three main reasons. Firstly, you cannot patent something natural (whole plant cannabis products), so in order for pharmaceutical companies to make money, they needed to create something new (such as a product made from a specific and unique extraction process). Secondly, the synthesis of SCRAs can (and did) provide a better understanding of how receptors in the brain operate and the effects of manipulating them), Thirdly was the perceived medical value of organic cannabis. For instance, in the UK cannabis and it’s derivatives are currently regulated as Schedule 1 under the Misuse of Drugs Regulations 2001. Drugs belonging to this schedule are thought to have no therapeutic value and therefore cannot be lawfully possessed or prescribed and also include LSD and MDMA (ecstasy). Schedule 1 drugs may be used for the purposes of research, but a Home Office licence is required, and these are not easily acquired. Cannabis has previously been listed as a Schedule 1 substance in the U.S. and under the United Nations Convention on Psychotropic Substances. Therefore, a pharmacologist seeking to harness the effects of THC to produce a medicine such as Sativex™ (used to control neuropathic pain and muscle spasms in people with Multiple Sclerosis - and does contain extracts from the cannabis plant itself) may find synthesising a synthetic version easier, as was the case with Dronabil (Marinol™) used to enhance appetite and reduce nausea in people with anorexia or undergoing chemotherapy.

Huffman named each one with his initials – the first to be identified in Spice Gold in Germany was JWH-018 - as did Makryannis (AM-2201 for example).


How did these ‘get out’?

Huffman and Makriyannis (and other psychopharmacologists working for Universities) needed to raise grant funding to support their research, and in the academic world, this meant publishing their results. Prior to the advent of the internet, someone wishing to view these articles would have to look at a paper copy of the journal in a library. Post-internet, they could look on line and someone with an organic chemistry degree could probably figure out how to replicate it quite easily.

The SCRAs were sprayed onto inert plant matter and sold as ‘herbal incense’ in an attempt to circumvent laws around medicines and drug use. Part of their appeal was therefore that possession was not illegal, and their use did not show up on standard drug tests.

The brand "Spice" was released in 2004, and from 2006 rapidly gained popularity, particularly throughout Europe. Initial tests of Spice Gold and other ‘herbal incense’ or ‘herbal smoking mixtures’ found no illegal substances and forensic toxicologist were not able to detect active ingredients that could explain the ‘high’ they produced in users, although tests also were unable to detect most of the herbs the products were supposed to contain. On December 15, 2008, it was reported by the German pharmaceutical company THC Pharm that JWH-018 was found as one of the active components in at least three versions of the herbal blend Spice, which had been sold as an incense in a number of countries around the world since 2002. An analysis of samples acquired four weeks after the German prohibition of JWH-018 took place found that the compound had been replaced with JWH-073. Huffman created hundreds of these SCRAs, though not all of them would be psychoactive. Makriyannis has also synthesised many new compounds with cannabinoid activity, such as AKB48 and AM-2201 (the active ingredient in the original ‘Black Mamba’).

A similar story is evident with some other ‘New Psychoactive Substances’ such as Benzo Fury.

The substance later packaged and sold as Benzo Fury (6-APB) was first synthesised by Dr. David Nichols, a pharmacologist and medical chemist at Purdue University in Indiana and is a specialist in hallucinogen amphetamines (such as MDMA, MDEA) and he held a US government licence to make and research Schedule 1 drugs for research purposes for over 40 years. However, information in academic papers he published were later used by ‘Grey-Market Chemists’ to create new psychoactive substances.

Nichols has worked in the field of psychoactive drugs since 1969. While still a graduate student, he patented the method that is used to make hallucinogenic amphetamines including MDMA, MDEA. Among pharmacologists, he is considered to be one of the world's top experts on psychedelics and is still carrying out legitimate research on the chemistry of psychedelics.

He has published approximately 250 scientific reports and book chapters, all describing the relationship between the structure of a molecule and its biological effects (often referred to as a Structure-activity relationship, or SAR). A number of compounds included in Alexander Shulgin's PIHKAL were actually first synthesized in Nichols's lab.

Nichols is one of the few people who has published legitimate research on the chemistry and pharmacology of LSD in the last 25 years, and first reported that several LSD analogues, including ETH-LAD, PRO-LAD, and AL-LAD, were more potent than LSD itself. Other notable research he helped carry out includes extensive studies Nnicholsof the structure-activity relationships and mechanisms of action of MDA and MDMA, during which he helped to discover many novel analogues including such compounds as 5-methyl-MDA, 4-MTA and MDAI. Nichols has said that "he believes grey-market chemists used information from papers he published on 4-methylthioamphetamine (MTA) in the 1990s to synthesize the drug, which they sold in tablets nicknamed "flatliners" as a substitute for MDMA (Ecstasy)."

For those wishing to read a more scientific article on the history of SCRAs have a look here.



About Hugh Asher


Hugh is an author, practitioner, trainer, researcher and consultant.

He keeps rare breed sheep and cows.

He also shares his house with the world’s largest puppy, called Charlie.

Although he was told from a young age that “Life isn’t fair” he has refused
to give up on his goal to make other people’s lives as happy as he can.

His vision for a better world involves giving people the skills and
confidence to make a positive change to other people’s lives.

To learn more about Hugh and the mission of Soma, click here.​






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