Semi-Synthetic Cannabinoids: new perspectives for the regulation of industrial hemp in Brazil

Semi-synthetic cannabinoids represent an emerging frontier in the universe of compounds derived from cannabis. The increase in availability and diversity of these products has raised growing concerns related to public health, regulatory challenges, and difficulties in monitoring in several countries.

What Are Semi-Synthetic Cannabinoids?

Semi-synthetic cannabinoids, also known as intoxicating derivatives of hemp, are chemically modified forms of cannabinoids found in the cannabis plant, developed specifically to mimic, enhance, or alter the psychoactive effects of compounds like Delta-9-THC (tetrahydrocannabinol). They are created by altering the molecular structure of naturally extracted cannabinoids, such as CBD (cannabidiol), through specific chemical reactions.

Unlike fully synthetic cannabinoids, which are entirely created in a laboratory without using plant components, semi-synthetics retain part of the original structure of the natural cannabinoid. This distinction is important because it influences the pharmacological properties, legal status, and health implications.

The market for semi-synthetic cannabinoids has been rapidly expanding, with various compounds gaining popularity. These products are often marketed as legal alternatives to traditional cannabis, taking advantage of regulatory loopholes in several countries, particularly in jurisdictions where the legal framework indiscriminately allows any hemp derivative.

Key Semi-Synthetic Cannabinoids and Cannabidiol (CBD) as a Precursor

Delta-8-THC and Delta-10-THC

Delta-8-THC and Delta-10-THC are isomers of Delta-9-THC, the main psychoactive component of cannabis, and are naturally present in small amounts in cannabis plants. Both are considered less potent than Denta-9-THC and are usually synthesized from cannabidiol (CBD) through an isomerization process. This process involves the application of strong acids, such as hydrochloric or sulfuric acid, to the CBD distillate extracted from hemp flowers, converting CBD into delta-8-THC and/or delta-10-THC.

Hexahydrocannabinol (HHC) and Derivatives (Hexahydrocannabinol Acetate (HHC-O) and Hexahydrocannabiforol (HHC-P))

Although present naturally in cannabis in minimal traces, commercially available Hexahydrocannabinol (HHC) is predominantly obtained via semi-synthetic means. The main production method involves the catalytic hydrogenation of THC isomers (Delta 8, Delta 9, and Delta 10), derived in turn from the conversion of CBD.

Hexahydrocannabinol (HHC) has emerged as a psychoactive alternative to THC, marketed as a milder and more stable option, often under the designation of "light cannabis." However, its development has significantly evolved with the creation of more potent derivatives. Through acetylation, HHC-O (hexahydrocannabinol acetate) is obtained, a version with greater molecular stability and amplified intoxicating effects. Even more impactful is HHC-P (hexahydrocannabiforol), resulting from the addition of a carbon chain to the HHC structure - a cannabinoid estimated to be 30 times more potent than its acetylated precursor, rivaling the strongest synthetic analogs available on the market.

This chemical progression demonstrates how relatively simple structural modifications can generate substances with dramatically different activity profiles.

Tetrahydrocannabiforol (THC-P) and Tetrahydrocannabidiol (H4-CBD)

First isolated in 2019 by Italian scientists and present in minimal quantities, tetrahydrocannabiforol (THC-P) shows structural similarities to delta-9-THC, with much higher narcotic potential and greater affinity (up to 33 times more) for CB1 receptors. Synthesized from CBD, using processes similar to those used to produce delta-8-THC, it has been gaining popularity and has been found in various commercial products.  

Tetrahydrocannabidiol (H4-CBD), also known as hydrogenated CBD, is a semi-synthetic compound produced from CBD. Although it recently entered the market, it is far from new, as it was first synthesized in 1940. Few studies are available, but it is known that H4-CBD activates both CB1 and CB2 receptors, enhancing the effects of CBD.
 

The global explosion of semi-synthetics

The production of semi-synthetic cannabinoids has been made possible by the abundance of CBD derived from hemp in the market, reducing raw material costs and driving the development of higher value-added products. A noteworthy example is the Delta-8 THC market, which was introduced in 2019 and by 2023 already represented 44% of the US market for semi-synthetic cannabinoids derived from hemp, with sales reaching $1.2 billion in the same year.

According to the UNODC (UNITED NATIONS OFFICE ON DRUGS AND CRIME), of the 40 varieties of synthetic cannabinoids identified in seized material between 2022 and 2024, nearly half (18 substances) belong to the new class of semi-synthetic cannabinoids. Hexahydrocannabinol (HHC) emerged as the most widespread substance, detected in 34 countries and territories, followed by HHC-P (17 countries) and H4-CBD (15 countries). 

Concurrently, a Californian study revealed alarming data: in 104 hemp-derived products (from 68 different brands), 95% contained prohibited synthetic cannabinoids, including samples with THC concentrations 32 times higher than the legal limit. Particularly concerning was the detection of THC-P - a semi-synthetic cannabinoid with 30 times the potency of natural THC - in almost half of the analyzed products.

In addition to the increasing product diversification and their heightened psychoactive potential, there is also an expansion in the presentation and commercialization of these items. A striking example is the practice of spraying semi-synthetic cannabinoids on natural cannabis flowers, a technique that aims to intensify the effects under the guise of a 'natural' product.

An increasing number of countries are reporting toxicological incidents associated with the use of synthetic and semi-synthetic cannabinoids, a situation exacerbated by the lack of proper labeling and accurate information about these products. This reality not only exposes consumers to serious risks but also undermines the credibility of the regulated market, which ends up being unfairly associated with these issues.

Countries that have already regulated Semi-Synthetic Cannabinoids

Faced with a significant increase in concerns related to safety and public health, several countries have adopted specific regulatory measures for semi-synthetic cannabinoids. This wave of emerging regulations represents a coordinated response to the complex challenges that these substances are posing to global health surveillance systems and drug policies.

Japan
Japan implemented a series of specific controls on various cannabinoids, including THC-P and HHC in March 2022, and expanded controls in subsequent years to include delta-8-THC-O and HHC-O, among others.

Switzerland
Switzerland controlled HHC in March 2023 and HHC-P, delta-8-THC, THC-P, and H4-CBD in October 2023, as well as introducing generic control and designating olivetol as a chemical precursor.

Denmark
Denmark controlled HHC in May 2023, followed by H4-CBD, HHC-P, and all seven THC-P isomers in January 2024. In September 2024, they introduced a generic control covering any THC and HHC derivatives not specifically listed.

France
France regulated HHC, HHC-O, and HHC-P in June 2023. In June 2024, they controlled H2-CBD (dihydrocannabidiol) and H4-CBD (tetrahydrocannabidiol), as well as introducing broad generic control on THC and HHC variants.

Italy
In July 2023, Italy controlled HHC, HHC-O, and HHC-P, followed by the regulation of HHCH and THC-P in March 2024.

Sweden
Sweden controlled HHC, HHC-P, HHC-O, delta-8-THC, and THC-P in July 2023, along with delta-8 and delta-9-THC acetates.

Germany
Germany introduced an extremely broad generic control over THC and HHC variants, covering a wide range of semi-synthetic cannabinoids under a single regulatory framework.

Canada
Health Canada issued guidance stating that products containing "intoxicating cannabinoids other than delta-9-THC" are subject to the same legal requirements as those containing delta-9-THC. This includes limits on the total amounts of active materials per unit.

Czech Republic
In March 2024, the Czech Republic controlled HHC, HHC-O, and THC-P. In June 2024, they expanded this control to include THC-B, THC-H, THC-C8, HHC-P, HHC-H, HHC-B, and HHC-C8.

Malta
In September 2024, Malta announced the prohibition of the sale of products containing HHC due to concerns about their appeal to children, particularly in the form of colorful edibles.

Considerations for the regulation of industrial hemp cultivation in Brazil

The global market for cannabis derivatives - whether synthetic, semi-synthetic, legal, or illicit - clearly demonstrates a constant capacity for innovation to circumvent regulations, with new products and formulations continuously emerging. Among international experiences - the example of the US after the 2018 Farm Bill - highlights the critical need for precise definitions of industrial hemp derivatives.

 Legal ambiguity in the US allowed intoxicating semi-synthetic derivatives to gain legal status, creating challenges for public health and regulation. However, beyond these compounds, it is essential to consider the entire chain of derivatives, as there are direct natural derivatives (flowers, leaves, seeds, stems, and roots); secondary derivatives (post-extraction biomass, distillation by-products) and industrial derivatives (biomaterials, fibers, biofuels). 

Effective regulation should establish objective criteria for classification (origin, processing, and intoxicating potential), differentiating standards for commercial and scientific use - ensuring both quality control and consumer safety, as well as space for research and industrial innovation.

On the other hand, it is crucial to recognize that these semi-synthetic cannabinoids also present promising, yet unexplored, medicinal applications. Chemical modifications in their structure can confer not only greater potency but also greater molecular stability and selectivity for specific receptors - valuable characteristics for therapeutic purposes. Although this research is in its early stages, its development should be encouraged.

The evolving landscape requires a reassessment of control mechanisms, with a primary focus on the final products marketed, as strict oversight of cultivation proves ineffective in the face of the complexity of new derivatives. The regulatory obsession with THC limits (such as the 0.3% in Brazil) has lost practical relevance with the emergence of semi-synthetic cannabinoids - many synthesized from CBD but with psychoactive effects up to 30 times more potent than natural THC.

During my recent participation in CannMed 25 - a global event with representatives from 12 countries, on the panel about semi-synthetic cannabinoids, there was a scientific consensus on the need to regulate cannabis as a single species, rejecting the artificial division between "hemp" and "marijuana." 

This outdated dichotomy, based solely on THC content, has proven not only scientifically inconsistent but also counterproductive from a public health standpoint. 

The most sensible approach would be to regulate and control the production of all natural cannabinoids, ensuring consumers access to safe, standardized, and properly monitored products. This strategy is infinitely preferable to the current situation, which ends up pushing users towards the risks of the illegal market - full of unregulated synthetic products, without any quality control or monitoring.