What Is A “Synthetic” Cannabinoid? Two Chemists Clarify the Science

This article discusses the controversial and widely misunderstood topic of so-called “synthetic” cannabinoids. This issue is important as legislatures across the country consider new hemp bills. 

I am grateful to chemists Mark Krause and Andrea Holmes for providing a clear scientific explanations about what constitutes a “synthetic” cannabinoid and how that differs from an “isomerized” or a “natural” cannabinoid. Mark is the principal scientist of Krause Analytical Labs and a noted expert witness on chemistry matters with over 45 years of wide-ranging experience in multiple disciplines in chemistry. Mark has addressed this issue in podcasts and writings. I am also grateful to Andrea Holmes, Professor of Chemistry Doane University, Scientific Consultant KD Pharma Group, Co-Owner CBD Remedies, and a respected expert witness for court cases and legislative sessions involving hemp matters. Their articles are below in their unedited format.

Thanks also to Cynthia Cabrera of Hometown Hero and the Hemp Industries Association for connecting me with Mark. 

Here’s Mark’s paper- 

Delta-8 THC is not a “synthetic” cannabinoid

In the USDEA Controlled Substances Act “synthetic cannabinoids” are prohibited. This refers to a series of compounds synthesized by John W. Huffman at the University of Clemson, all based on a chemical structure known as a naphthoylindole. Mr. Huffman called these compounds “synthetic cannabinoids” due to the effect they had in the human body, mimicking the effects of tetrahydrocannabinols. These compounds are fully synthetic; they do not occur anywhere in nature to the best of our knowledge. They are commonly referred to as K2 or spice, or occasionally bath salts.

These compounds are not tetrahydrocannabinols (THC); they have a completely different structure than the THCs. THCs, on the other hand, are not necessarily “synthetic” as they occur naturally in the plant Cannabis Sativa L. (as well as other plants). There are synthetic forms of THC; however, for the most part, THCs are chemicals known as phytochemicals, or chemicals that naturally occur in plants due to biosynthesis or other natural biochemical pathways.

The term “synthesis” has a specific meaning in chemistry. Synthesis in organic chemistry has a very well-defined meaning that involves the reaction of two or more compounds (reactants) to produce one or more new compounds with a differing mass (products). Isomerization, on the other hand, involves only one reactant and produces compounds of the same mass by moving chemical bonds into a more favorable energy state. This is also referred to as rearrangement since physically what is occurring is a rearrangement of the chemical bonds within the molecule.

Cannabidiol, or CBD, is a phytochemical. It is an isomer of THC; that is, it has the same molecular formula and the same molecular weight as THC. CBD in the presence of sunlight, heat, pressure or a combination of these will isomerize to THC; that is, bonds within the molecule move into a more energetically favorable state. This can, and does, happen in the absence of chemical catalysts and is a well-known phenomenon during the drying/curing cycle of hemp. While there are processes involving catalysts that radically accelerate the isomerization of CBD to THC these reactions are inherently non-synthetic since they do not involve two or more reactants and they do not produce a product of differing mass. Indeed, merely heating CBD in a flask will lead to nearly complete conversion to either delta-9 THC or delta-8 THC without involving any other chemicals, solvents, catalysts, etc. in the process.

The moving of bonds to achieve a more favorable energy state is true within the isomers of THC, as well. For example, delta-9 THC will isomerize to delta-8 THC in the presence of light and heat. This requires no catalyst; depending upon the frequency of the light and how much heat is present this reaction will occur somewhere between minutes and months. This is the likely pathway to delta-8 THC in the Cannabis Sativa L. plant, since the typical biochemical pathway from CBG to THC is through the production of delta-9 THC.

While there are well-documented synthetic pathways to the THCs isomerization is not synthetic, and delta-8 THC derived from hemp is not a synthetic compound. Delta-8 produced legally from hemp clearly falls within the definition of hemp as published by the USDA and accepted by the USDEA in their respective definitions of hemp.

[Editor’s note – Krause’s last statement regarding delta-8 THC legally falling within the definition of “hemp” under the 2018 Farm Bill is supported in rulings by both the 4th Circuit and the 9th Circuit Courts of Appeal.]

Here is Andrea’s paper- 

Natural versus Synthetic Cannabinoids

There is a lot of controversy around the “intoxicating synthetic cannabinoids.” The word “synthetic cannabinoids” is typically associated with designer drug molecules that are NOT occurring naturally in a plant or nature but bind to the same receptors as cannabis does. The term first arose with organic chemistry Professor John Huffman at Clemson University who worked on many new molecules and synthesized JWH-018 which later has shown to have very highly potent and negative health effects. Without Huffman’s knowledge, this drug was later introduced on the black market and was given the street name K2/Spice or bath crystals.  It is sold illegally as an herbal inscent plant type material and since then underground “cooks” have created hundreds of illegal substances by poaching procedures from publications and patents. These compounds are a big problem and health concern!

However, cannabinoids from federally legal hemp are NOT comparable to this type of synthetic designer drug molecules. They are completely different in chemical structure and the effect they have on the central nervous system. Furthermore, hemp derived THC isomers are prepared from naturally extracted CBD. It is important to distinguish these synthetic cannabinoids like K2/Spice from naturally occurring cannabinoids like delta 8 THC, its isomers, and other minor cannabinoids because the consumption of designer drugs can be dangerous while cannabinoids from cannabis has been consumed for hundreds even thousands of years for spiritual, religious, and health and wellness reasons. Furthermore, surveys have shown that consumers favor hemp derived cannabinoids like delta-8-THC because they can self-treat multiple conditions and have access to inexpensive natural alternatives to pharmaceutical prescription drugs.(1)

Innovations in science and technology is driven my mimicking what is happening in nature and in the case of hemp, chemists have learned how to reproduce chemical conversions that are happening in the plant. Compounds like delta-8-THC can be prepared in the lab by chemists by using legal hemp derived CBD and applying conditions such as heat, catalysts and solvents to isomerize CBD to THC. This is similar to what is happening in the plant in the presence of light, enzymes, and molecules that rearrange in molecular structure and electronic arrangements to achieve different states of stability. This is not novel to hemp. In fact, many naturally occurring compounds are now prepared or processed in the lab, including most vitamins, melatonin, biotin, vanilla flavoring, decaffeinated tea and coffee, aspirin, and much more. These controlled industrial processes are widely used in the pharmaceutical, food, and dietary supplement industry to allow access to pure compounds at high volumes and prices that would otherwise be prohibitive if these compounds were extracted naturally from the source material like hemp.

Insulin to treat diabetes is a perfect example to show how synthesis has improved human life. Diabetes used to be a death sentence. In the early days of discovery, insulin was extracted from the pancreas of dogs, cattle, and pigs. Only small quantities of insulin could be isolated from many animal sacrifices, and it was very expensive to treat patients and caused allergic reactions.  Innovation in science allowed chemists at pharmaceutical companies to insert a gene into a gut-flora bacteria called E-Coli and this organism was able to “synthesize” large quantities of human grade insulin at affordable prices.

Whether a cannabinoid is naturally extracted from hemp or prepared in the lab, the result is the same. A molecule is a molecule, and there is no difference between a synthetic or naturally derived cannabinoids. To assure consumer safety, CBD derived cannabinoids coming from legal hemp containing should be tested at third party labs to assure that they are compliant (less than 0.3% delta9-THC per g of dry mass), free of solvents, metals, pesticides, and microbial contaminants.  It is important to source these types of cannabinoids from reputable manufacturers with good manufacturing practices, process controls in place and standardized SoPs.

Research and scientific studies on delta 8 THC, its isomers, and minor cannabinoids are still limited when compared to other cannabinoids like CBD and delta-9 THC. The novelty of these compounds as well that the regulatory uncertainty has stifled academic research is this area. However, we do have some preliminary research that has shown promise of CBD derived synthetic delta-8-THC for nausea in pediatric cancer patients undergoing chemotherapy.(2) Other research has shown that delta-8THC has several therapeutic effects. (3, Table 2, 4) We also know the pharmacology of delta-8-THC. It is a much less potent cannabinoid than delta-9-THC due to a weaker binding to receptors in the brain, making this cannabinoid a preferred choice for some consumers who prefer a milder effect.  However,  research on delta-8 THC is largely anecdotal, and not many studies does not involve human subjects. (5)

Finally, in my personal experience and as an owner of three hemp dispensaries in Nebraska, I attest to the fact that my customers, many of whom get referred to us by physicians, purchase hemp derived compounds like THC isomers to help with sleep quality, feelings of anxiety, pain, sobriety, and mood disorders.

In conclusion, it is my view that reasonable laws and regulations are needed to mitigate the risks of using delta-8 THC, isomers, and minor cannabinoids, particularly around the quality of manufacturing practices, testing, packaging, dosages, labeling, marketing, and minimum purchase age.

1. https://pmc.ncbi.nlm.nih.gov/articles/PMC8725316/

Kruger JS, Kruger DJ. Delta-8-THC: Delta-9-THC’s nicer younger sibling? J Cannabis Res. 2022 Jan 4;4(1):4. doi: 10.1186/s42238-021-00115-8. PMID: 34980292; PMCID: PMC8725316.

2. https://pubmed.ncbi.nlm.nih.gov/7776837/

Abrahamov A, Abrahamov A, Mechoulam R. An efficient new cannabinoid antiemetic in pediatric oncology. Life Sci. 1995;56(23-24):2097-102. doi: 10.1016/0024-3205(95)00194-b. PMID: 7776837.

3. https://pubmed.ncbi.nlm.nih.gov/34797727/

Kruger DJ, Kruger JS. Consumer Experiences with Delta-8-THC: Medical Use, Pharmaceutical Substitution, and Comparisons with Delta-9-THC. Cannabis Cannabinoid Res. 2023 Feb;8(1):166-173. doi: 10.1089/can.2021.0124. Epub 2021 Nov 19. PMID: 34797727.

4. https://pubmed.ncbi.nlm.nih.gov/29450258/

Thapa D, Cairns EA, Szczesniak AM, Toguri JT, Caldwell MD, Kelly MEM. The Cannabinoids Δ8THC, CBD, and HU-308 Act via Distinct Receptors to Reduce Corneal Pain and Inflammation. Cannabis Cannabinoid Res. 2018 Feb 1;3(1):11-20. doi: 10.1089/can.2017.0041. PMID: 29450258; PMCID: PMC5812319.

5. https://pubmed.ncbi.nlm.nih.gov/36710464/

LoParco CR, Rossheim ME, Walters ST, Zhou Z, Olsson S, Sussman SY. Delta-8 tetrahydrocannabinol: a scoping review and commentary. Addiction. 2023 Jun;118(6):1011-1028. doi: 10.1111/add.16142. Epub 2023 Feb 13. PMID: 36710464.

January 23, 2025 [Updated March 10, 2025]

Rod Kight is an international cannabis lawyer. He represents businesses throughout the cannabis industry. Additionally, Rod speaks at cannabis conferences, drafts and presents legislation to foreign governments, is regularly quoted on cannabis matters in the media, and is the editor of the Kight on Cannabis legal blog, which discusses legal issues affecting the cannabis industry. You can schedule a call with him by clicking here.