Synthetic cannabinoids - A clinical approach

Fundación CANNA has already published an article by Professor Koldo Callado on the subject in question, and I recommend reading it to complement the information I am going to share about synthetic cannabinoids (SC) with the intention of clarifying what they are and their impact on users.

As we already know, cannabinoids are modulators of the Endocannabinoid System, and THC is the molecule that led to the discovery of this important homeostatic regulatory system in many organisms. Phytocannabinoids, which, as their name suggests, are of plant origin, are molecules that interact with and modulate the Endocannabinoid System (ECS). This system can be modulated using various molecules, many of them of botanical origin, or tools as simple as exercise.

In order to study the Endocannabinoid System (ECS), synthetic molecules were legally created in university laboratories or research centres: these could be used in their study and would have a more effective and powerful effect on the receptors, with less bias than THC from the plant, which is not a very powerful agonist of the CB1 receptor, but is instead a partial agonist. The intention was also that some of these synthetic molecules could be used as medication, obviously after studying their use in humans.

It has to be said that plant-derived THC is much less potent than most synthetic molecules, and in the right doses is actually quite user-friendly when compared to the effect of most synthetic cannabinoids. It is because of this, and the low density of CB1 receptors in the brain stem, that botanical THC has never caused a fatal event related to acute poisoning from THC extract. There were no records in the medical literature of death directly caused by cannabis intoxication. For some years now there have been some such records, and this is something that I think is very important to clarify, because a large part of the population, and health professionals, can access reports in which the use of cannabis is related to fatal events, or serious adverse effects, without specifying what they are talking about.

Let's clarify three important concepts to understand the situation: there are cannabinoids of botanical origin, or phytocannabinoids; legal synthetic cannabinoids of pharmaceutical origin; and illegal synthetic cannabinoids, wrongly called cannabinoids, whose use in humans has not been tested in studies. In addition, information about all of them is confused, without correct details on what data we are dealing with: many cases just mention cannabis without specifying which, and this ends up in the hands of the reader or of the health professional.

As I said, there are legal synthetic cannabinoids whose use has been proven in humans: for example, THC from the pharmaceutical industry such as Marinol, Cesamet or Dronabinol. Evidence-based medicine studied these molecules and approved their use in humans. These molecules are very similar in structure to the THC found in the plant. They have been used in humans without problems, apart from possible adverse effects that can occur within treatments, which are predictable and easily solved by changing the dosage. They are tested and studied for use in humans. These synthetic cannabinoids are not a problem: Dronabinol has been used since 1985 without any serious events having been reported.

On the other hand, there are synthetic cannabinoids that are now found on the illegal market. They use the basic structure of plant-derived THC, but with many changes: there are many more carbon atoms and cyclic rings, and that is why they are much more potent in their effects – up to 100 times more than herbal THC.

Initially, they were used to act mainly on CB1 receptors, and to study the differences in affinity and potency compared to herbal THC. We now know that not only do they act on CB1 receptors, but that beyond binding to CB1R and CB2R, SCs can also mediate their action by targeting a number of non-cannabinoid receptors. Among these, G protein-coupled receptors GPR55 and GPR18, nuclear hormone receptors PPAR and ion channel TRPV1 are widely expressed in the central nervous system and are involved in modulating multiple intracellular signalling pathways, making it extremely difficult to predict the effects of these much more potent and unverified molecules on these receptors.

The exact date when SCs appeared on the illegal market is not known precisely, but we can estimate that it started in the late 1980s. Structure-activity relationship (SAR) studies conducted by Sterling Winthrop resulted in the identification of the full agonist of the CB1/CB2 receptors, WIN 55,212-2. Remember that THC is a partial, or weak, agonist of these receptors, and therefore its effect is less potent than most SCs. Based on the structure of WIN compounds, John W. Huffman and his colleagues at Clemson University synthesised the first set of naphtholylindole cannabinoids¹ in the 1990s.

These experiments were designed to develop a SC for the CB1 receptor and to compare the binding properties of SCs with those of THC. This was followed by the synthesis of other compounds of naphthoylindoles², naphthoylpyrroles³ and phenylacetylindoles⁴. Therefore, it is likely that, in the early 2000s, aminoalkylindoles and cyclohexylphenols⁵ were the most common SCs, and were found in K2/Spice products. These are probably the first SC products to be traded illegally: there is no control over these substances and their distribution, usually done via the internet or even in shops. Some of these SCs are up to 100 times more potent than herbal THC, which means that, without their dosages, pharmacokinetics and pharmacodynamics having been tested in humans, their use can potentially be lethal.

Not long ago I read an article entitled A Literature Review of Cannabis and Myocardial Infarction—What Clinicians May Not Be Aware Of, and was really surprised to see data on SCs under the umbrella of cannabis use, without clearly differentiating that these molecules have nothing to do with the adult or therapeutic use of plant extracts, which have never generated a fatal event. There is no clinical case in which acute intoxication by herbal THC is the cause of death. Now we can read articles relating serious, even fatal, events connected with the use of SCs: I believe that the accounts are not objective and can generate a very negative impact, especially when health professionals, who are now starting to use the plant therapeutically, read these articles about the toxic effects of SCs which are incorrectly attributed to the use of cannabis, and which only occur with the use of synthetic cannabinoids.

Currently, the most widely distributed SC families on the market are PINACAS and FUBINACAS (ADB or AMB), although other SC families are also available. These molecules keep getting synthesized and escaping possible analytical controls, even forensic ones.

There is actually very little information on the production and trafficking of ADB-FUBINACA and AMB-FUBINACA, probably because of limitations in the chemical detection of these substances. On the other hand, the detection of these substances in shipments seized by authorities in European countries suggests that AMB-FUBINACA and ADB-FUBINACA originate from chemical companies based in China (where these substances are not legally regulated), but are processed and packaged in the country of destination. SCs typically come in the form of a white or sometimes yellowish powder, which is dissolved in organic solvents and then sprayed on herbal products, allowing the user to consume it by inhaling the smoke after combustion, similar to smoking herbal cannabis in cigarettes.

It is important to note that this booming illegal SC market is very dangerous, as in most cases the user or buyer does not know that they are going to consume these substances, which are now sold in all forms. Recently, AMB-FUBINACA was also identified in liquid form, which facilitates its consumption through e-cigarettes and paper tabs, possibly in order to tailor formulations of these substances to the needs of users. ADB-FUBINACA was detected in samples of products labelled "Black Mamba", "VaperFi", "Freeze" and "Mojo", while its analogue AMB-FUBINACA has been detected in products marketed under the name "AK-47 Carat Gold", "Train Wreck2" and "Scooby Snax Limited Edition Blueberry Potpourri". These consist of herbal mixtures ready to be used in vaporisation devices, electronic cigarettes, inhalers, or even ingested orally. Note that by changing the route of administration, a faster or more potent effect can be achieved with the same dose. Inhalation generates a faster effect than the oral route, but is less potent at the same doses.

Δ9-THC has been consumed by humans for millennia and has low acute toxicity, but recent evidence indicates elevated toxicity from exposure to some SCs. For example, two case studies of confirmed poisoning with a new SC, hexahydrocannabioctyl (HHC-C8), have been published. In the first case, a young man was found deeply unconscious and hospitalised. The clinical picture was mainly neurological, with recurrent seizures and coma. The patient was in a coma for two days, with a slow gradual improvement over the next two weeks. In the second case, a woman was hospitalised after having slept for 14 hours and being found in a minimally responsive state. The patient suffered pronounced drowsiness and sedation for 3 days, after which she gradually recovered.

In the 15 years that I have been working with cannabis extracts, I have never encountered serious events such as those reported in many SC studies. Nor have other health professionals working with herbal products, with whom we have been in contact for years, ever shared with me a serious issue caused by the use of plant extracts.

In conclusion, the intention of this text is to warn about the use of these non-controlled substances, about which little information is available. New synthetic cannabinoids are continually being generated, without any data on their use in humans, and the data that is being published indicates that this situation will continue. We must be very clear that using plant extracts has never led to events such as those described: we have to think carefully about what the published articles or studies tell us, and what they are talking about – synthetic cannabinoids or phytocannabinoids – so that the information is objective and the conclusions clear. Erroneous data are being extrapolated that have nothing to do with the therapeutic use of the cannabis plant.

Bibliography:

1. JWH-007, JWH-018, JWH-201, etc.

2. AM-1220, AM-2201

3. JWH-30, JWH-145

4. JWH-203, JWH-250

5. CP-47, 947, CP-55, 940

Prolonged sedation and unconsciousness after intoxication with the novel semisynthetic cannabinoid hexahydrocannabioctyl (HHC-C8): Two case descriptions

Author links open overlay panel Ragnar Thomsen ^a, Tobias Melton Axelsen ^b, Nicoline Løkken ^b, Lisa Maria Gemmerli Krogh ^c, Nanna Reiter ^{d e}, Brian Schou Rasmussen ^a, Emilie Lund Laursen ^b Toxicology Reports Volume 14, June 2025, 101912

WHO critical review report: FUB-AMB (MMB-FUBINACA, AMB-FUBINACA) [(accessed September 22, 2020)]; Ser. Technical Representative of the World Health Organization. 2018 Toxicological reports Volume 14 ,June 2025, 191012

Trecki J., Gerona RR, Schwartz MD Synthetic cannabinoid-related illnesses and deaths. N. English. J. Med. 2015; 373: 103–107. doi: 10.1056/NEJMp1505328.

Alipour A., ​​Patel PB, Shabbir Z., Gabrielson S. Review of the many faces of synthetic cannabinoid toxicities. Mento. Clinical Health. 2019; 9: 93–99. doi: 10.9740/mhc.2019.03.093.

Adams AJ, Banister SD, Irizarry L., Trecki J., Schwartz M., Gerona R. Zombie outbreak caused by the synthetic cannabinoid AMB-FUBINACA in New York. N. English. J. Med. 2017; 376: 235–242. doi: 10.1056/NEJMoa161030

Adamowicz PME, Maslanka M. Fatal intoxication with the new synthetic cannabinoids AMB-FUBINACA and EMB-FUBINACA. Clinical. Toxic. 2019; 57: 1103–1108. doi: 10.1080/15563650.2019.1580371

Lam RTM, Leung S., Chong Y., Tsui M., Mak T. Supraventricular tachycardia and acute confusion following ingestion of e-cigarette liquid containing AB-FUBINACA and ADB-FUBINACA: a case report with quantitative analysis of serum drug concentrations. Clin. Toxicol. 2017; 55:662–667. doi: 10.1080/15563650.2017.1307385

Wood DM, Hill SL, Thomas SHL, Dargan PI. Using poison center data to assess acute harms associated with new psychoactive substances. Drug Test Anal. 2014; 6:850–60.

PMCID: PMC7801213 PMID: 33458628 A review of the literature on cannabis and myocardial infarction: what doctors may not be aware of Kimesh Chetty , MBBS, BSc, ^a, ∗ Andrea Lavoie , BSc, MD, FRCPC, ^by Payam Deghani , MD ^b

Di Marzo V, De Petrocellis L. Endocannabinoids as regulators of transient receptor potential (TRP) channels: yet another opportunity to develop new endocannabinoid-based therapeutic drugs. Curr Med Chem. 2010; 17:1430–49.

Iannotti FA, Vitale RM. The endocannabinoid system and PPARs: focus on their signaling communication, action and transcriptional regulation. Cells. 2021; 10:586.

The threat of synthetic cannabinoids: a review of health risks and toxicity Ayman Alzu'bi ,Fátima Almahasneh ,Ramada Khasawneh ,Ejlal Abu-El-Rub ,Worood Bani Panadero and Raed M. Al-Zoubi European Journal of Medical Research volume 29 , Article number: 49 (2024).