Cannabidiol-Derived Cannabinoids: The Unregulated Designer Drug Market Following the 2018 Farm Bill
Department of Neural and Behavioral Sciences, Hershey, PA, USA
Department of Pharmacology, Penn State College of Medicine, Hershey, PA, USA
Abstract
Background
In this review, we summarize current scientific knowledge on psychoactive cannabinoids synthesized from cannabidiol (CBD) and sold in the semi-legal market established in response to the passage of the US Agriculture Improvement Act of 2018, commonly known as the 2018 Farm Bill. The discussion focuses on recent developments that suggest this unregulated market may be fertile ground for a potential health crisis.
Summary
Current research into CBD-derived cannabinoids is mainly limited to Δ8-tetrahydrocannabinol (Δ8-THC) products, with some recent publications beginning to explore O-acetyl-THC, a term describing the acetate ester of Δ8-THC or Δ9-THC, and its potential pulmonary toxicity. We advance the discussion on the CBD-derived cannabinoid market, shedding light on the introduction and associated dangers of novel cannabinoids, likely produced via fully synthetic routes using sidechain variants of CBD, with purportedly greater agonist activity at the human cannabinoid receptor 1 (as a source of euphorigenic activity) than Δ9-THC. We discuss the expanded incorporation of the acetate ester motif into other THC analogues. We also discuss the lack of regulatory oversight for the production of CBD-derived cannabinoids and the unlabeled presence of under-researched cannabinoids formed as reaction side products in the CBD-derived cannabinoid products being sold. Accordingly, we suggest approaches to monitoring the CBD-derived cannabinoid market and investigating the pharmacology of the cannabinoids being consumed. Finally, important epidemiological findings are discussed and future directions for research are suggested to call investigators to this critically understudied field.
Key Messages
The CBD-derived cannabinoid market is growing internationally, and the market has diversified to include potent synthetic cannabinoids. The products sold on this unregulated market are under-researched despite growing availability and consumer interest. Ernest investigation of the pharmacology of these novel cannabinoids and the contents of CBD-derived cannabinoid products is critical for monitoring this potential source of another vaping-related epidemic.
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Keywords: Delta-8-tetrahydrocannabinol, Tetrahydrocannabiphorol, Hexahydroxycannabiphorol, Ketene, O-acetyl-trahydrocannabinol-O
Article notes
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Received 2023 Aug 29; Accepted 2024 Jan 10; Collection date 2024 Jan-Dec.
Introduction
An unregulated market for novel psychoactive cannabinoids has proliferated in the wake of the passage of the US Agriculture Improvement Act of 2018, commonly known as the 2018 Farm Bill. The 2018 Farm Bill declared hemp legal, defining it as Cannabis sativa or any product of the plant with a Δ9-tetrahydrocannabinol (Δ9-THC) concentration of no more than 0.3 percent [1]. The bill’s passage led to the immediate mass production and over-the-counter marketing of cannabidiol (CBD) from hemp [1]. The resulting surplus of CBD, together with loopholes in the bill’s definition of hemp, created a market niche for the semi-synthetic production of cannabinoids with psychoactive activity by virtue of human cannabinoid receptor 1 (CB1R) agonism, with CBD serving as the reaction substrate [1, 2]. These products are sold online and at smoke shops and retail venues throughout the USA and the world [3]. The first product sold on this CBD-derived cannabinoid market was Δ8-tetrahydrocannabinol (Δ8-THC), with more potent cannabinoids following soon after, including CB1R full agonists.
According to the 1986 Analogue Act of the controlled substances act (CSA), all intoxicating cannabinoids should be considered schedule 1 compounds [4]. Indeed, this is the law that restricts the scientific community’s access to these compounds. However, Δ8-THC was ruled to fall within the definition of “hemp” under the 2018 Farm Bill by the Ninth Circuit Court of Appeals in May 2022. This ruling bolstered supplier confidence in the legal status of all CBD-derived cannabinoids. Research funded by the US government functions under the purview of the CSA, as enforced by the US Drug Enforcement Agency, and research access to schedule 1 compounds is heavily regulated. As the CBD-derived cannabinoid market operates under the interpretation that the 2018 Farm Bill exempts CBD-derived cannabinoids from the CSA, these contradictory pieces of legislation emboldened the CBD-derived cannabinoid market while limiting research on these novel cannabinoids and the possible dangers of the products which contain them.
A Potential Health Crisis
The unique risks posed by CBD-derived cannabinoid products are highlighted by research on reported adverse events. The first study to look at Δ8-THC case report data in the FDA Adverse Event Reporting System (FAERS) found that, since the passage of the 2018 Farm Bill, Δ8-THC adverse events have been reported at a rate 3 times greater than that for Δ9-THC [5]. The adverse event profile of Δ8-THC products was distinct compared to Δ9-THC, with respiratory events as the most frequently reported [5]. Currently, adverse events associated with other CBD-derived cannabinoids are unstudied.
Recent studies indicate that early evidence of the dangers of CBD-derived cannabinoid products may have been overlooked. In 2019, a national outbreak of acute lung injury, referred to as e-cigarette or vaping-use-associated lung injury (EVALI), resulted in over 2,800 confirmed cases and at least 68 deaths [6]. This epidemic was determined to be the result of adulterated cannabis vaping devices [7]. Investigators used gas chromatography-mass spectroscopy (GC-MS) to analyze vaping products obtained from EVALI patients [7]. Results found that while a majority of EVALI-associated samples contained cannabinoid profiles consistent with a typical cannabinoid extraction processes, a subset possessed profiles indicative of CBD-based semi-synthetic routes of production, such as high levels of Δ8-THC and olivetol [7]. Olivetol is known to cause respiratory irritation [1]. Evidence indicates vitamin E acetate (VEA), used as an excipient in unregulated cannabis vape cartridges, to be the most likely causative agent in the 2019 EVALI outbreak [7]. Accordingly, the authors’ findings do not necessarily evidence pulmonary harm from CBD-derived cannabinoids. Rather, the fact that CBD-derived cannabinoid products were combined with VEA (much like black market Δ9-THC cannabis products) underscores the dangers associated with the unregulated nature of this market.
Exploration of the endocannabinoid system has revealed its diverse roles throughout the body, including psychiatric, neurologic, immune, and metabolic functions [8, 9]. Subsequent to the surge in recreational use of synthetic cannabinoids in the early 2000s, the potential harm presented by highly potent full agonists of CB1R has gained attention. They are evidenced to cause acute pulmonary injury, psychiatric crises, seizures, and renal injury [10–13]. Additionally, cases of cannabinoid hyperemesis syndrome are reported to be on the rise and case reports of cannabinoid hyperemesis syndrome associated with synthetic cannabinoid use have appeared [14, 15]. Now that CB1R full-agonist ligands are available on the CBD-derived cannabinoid market, we must investigate how these cannabinoids may contribute to such pathologies.
CBD-Derived Cannabinoids
The first CBD-derived cannabinoid to reach commercial markets was Δ8-THC, produced through acid-catalyzed ring closure of CBD [1, 16]. In studies comparing it to Δ9-THC, Δ8-THC had a binding affinity at human CB1R ranging from Ki = 28.5 nm to 251 nm, while the binding affinity for Δ9-THC ranged from Ki = 18 nm to 32.3 nm, suggesting that Δ8-THC may be a weaker ligand (Table 1) [17]. Hexahydrocannabinol (HHC) reached markets soon after Δ8-THC. Hydrogenation of CBD-derived Δ8-THC or Δ9-THC forms a mixture of the 9R and 9S epimers of HHC [19]. The binding affinity at human CB1R for the racemic mixture has been reported as Ki = 149 nm, with in vivo evidence indicating the R epimer as more potent than the S epimer [19].
Early CBD-derived cannabinoid products such as Δ8-THC and HHC are less potent than Δ9-THC. Recently, more complex chemistry has been implemented to produce CB1R ligands of purportedly greater psychoactive potency than Δ9-THC, including Δ8 and Δ9 isomers of tetrahydrocannabutol (THCB), tetrahydrocannabiphorol (THCP) and tetrahydrocannabihexol (THCH), hexahydroxycannabiphorol (HHCP), and O-acetyl-THC (THC-O) (Table 1; Fig. 1).
Among these ligands, several display greater CB1R binding affinity in vitro and greater behavioral cannabimimetic activity in vivo compared to Δ9-THC, with some acting as full agonists at CB1R [18, 20, 21]. CB1R full-agonist ligands pose a risk for physiological, neurological, and psychiatric harm, and the emergence of such powerful ligands on the CBD-derived cannabinoid market necessitates research [10, 11].
Between 2019 and 2020, a research team discovered Δ9-THCB, Δ9-THCP, and Δ9-THCH after isolating them from the Italian medical cannabis strain FM2 [18, 20, 21]. In their reported human CB1R binding studies, Δ9-THC had a binding affinity of Ki = 40 nm, while Δ9-THCB and Δ9-THCP had binding affinities of Ki = 15 nm and 1.2 nm, respectively [18, 20]. This indicates that Δ9-THCB and Δ9-THCP, respectively, have roughly twice and 33 times the affinity for human CB1R compared with Δ9-THC [18, 20]. Moreover, behavioral testing of Δ9-THCP demonstrated a CB1R full-agonist profile [18]. The researchers liken Δ9-THCP’s CB1R activity to that of the full-agonist synthetic cannabinoid CP55,940. Considering that CP55,940 has been demonstrated to cause respiratory injury, this is cause for alarm [13, 18]. Pharmacological data for THCH are not yet available, but it is marketed as similar in psychoactive strength to THCP. While these cannabinoids were discovered as naturally occurring phytocannabinoids, the Δ8 and Δ9 isomers of these ligands sold on the CBD-derived cannabinoid market are produced synthetically. While there are no published data on the synthetic route employed, given the prohibitive nature of extending the 5-carbon tail of THC to form the 7-carbon tail of THCP, the THCP sold on the CBD-derived cannabinoid market is likely produced from synthetically derived cannabidiphorol produced in a manner similar to that employed by Citti et al. [18]. THCB and THCH are probably likewise produced from synthetic butol and hexol analogues of CBD. Briefly, the required CBD variants of differing sidechain lengths can be synthesized by reacting a stereospecific menthadienol isomer with resorcinol molecules of the desired sidechain lengths [18, 22]. As recently described, such resorcinol molecules can be efficiently synthesized by Wittig reaction of 3,5-dimethoxylbenzyl triphenylphosphonium bromide with aldehydes corresponding to the desired sidechain lengths, followed by Pd/C-catalyzed hydrogenation, then deprotection and hydrolysis of aryl methyl ether groups to hydroxyl groups by reaction with BBr3 [22]. Additionally, hydrogenation of Δ8- and Δ9-THCP forms the analogue HHCP [19]. No binding data are available for this compound, and it is not discussed in research; however, it is also marketed as having a similar psychoactive potency as THCP.
THC-O (Table 1; Fig. 1) first appeared on the market in 2020, although it was first synthesized in 1942 and tested as an incapacitating agent for military use during the Edgewood Arsenal experiments between 1948 and 1975 [2, 23]. THC-O is an acetate ester of either Δ9-THC or Δ8-THC formed by refluxing THC with acetic anhydride [24]. Binding data are not available, but users report it being twice as potent as Δ9-THC, longer in onset and duration, and it is marketed as possessing a more “psychedelic” quality compared to Δ9-THC [2]. Pharmacologic differences between Δ8- and Δ9-THC-O are unknown. THC-O is hypothesized to act as a prodrug that is hydrolyzed to the parent THC compound, explaining the delayed onset of THC-O compared to THC [19]. Of critical importance, researchers demonstrated, in 2023, that the aryl acetate moiety in THC-O can form a ketene (R2-C=C=O) when exposed to vaporization temperatures. Ketene-containing molecules possess significant pulmonary toxicity. In fact, ketene gas formation upon vaporization is hypothesized to be the pathologic mechanism by which VEA elicits the pulmonary injury as observed in the 2019 EVALI outbreak [24]. More recently, acetate esters of THCP, HHC, and HHCP have reached the market, labeled, respectively, as tetrahydrocannabiphorol-O-acetate, hexahydrocannabinol-O-acetate, and HHCP-O-acetate [19]. These compounds are likely to be at least as potent as their non-acetate precursors and are virtually unexplored in published research. No research is yet available regarding pulmonary toxicity of acetate esters of these cannabinoids, but as they grow in diversity and popularity, such data will be crucial. The DEA released a statement in February 2023 affirming Δ8-THC-O and Δ9-THC-O as schedule 1 controlled substances under the CSA; however, they are still widely retailed as of January 2024 [19, 25]. Additionally, the statement did not cover acetate esters of cannabinoids other than Δ8-THC and Δ9-THC.
It is important to recognize that pharmacologic data for CBD-derived cannabinoids are currently limited. The Ki values reported in this paper are obtained from numerous primary sources, rather than a single comparative study testing ligands under identical conditions. Moreover, EC50 values for most CBD-derived cannabinoids are unavailable. To advance CBD-derived cannabinoid research, we suggest that single laboratories test these novel ligands in the same systems and under the same conditions, to gather comparable data on EC50 values of these cannabinoids at cellular and behavioral levels, as well as more comparable Ki data.
CBD-derived cannabinoid products frequently include Δ9-THC as a reaction side product, often at levels exceeding the legally permissible 0.3%. In a study by the US Cannabis Council, 16 samples of products labeled as Δ8-THC were all found to have Δ9-THC levels above 0.3%, with the average of all samples having a Δ9-THC concentration 10 times the limit [26]. Additionally, CBD-derived cannabinoid products can include the undisclosed presence of numerous understudied cannabinoids and other reaction side products, which often lack the reference standards required for positive identification using MS techniques alone. Accordingly, thorough and accurate analysis of unlabeled cannabinoids and non-cannabinoid side products in CBD-derived cannabinoid products currently calls for a combination of NMR and MS techniques [27]. For example, one study performed 1H and 13C-NMR and GC-MS analysis of Δ8-THC-labeled products and found the undisclosed presence of Δ4(8)-isotetrahydrocannabinol, 9-ethoxyhexahydrocannabinol, and isotetrahydrocannabifuran (iso-THCBF). Iso-THCBF was unknown in the scientific literature prior to this discovery in Δ8-THC products in 2021 [27]. While these products included provider-supplied certificates of analysis, all were either inaccurate due to the use of analytical techniques such as HPLC-UV incapable of distinguishing side products such as iso-THCBF from Δ8-THC or falsified [27]. These cannabinoids possess unknown pharmacologic and toxicologic profiles necessitating further exploration. Analysis of novel, more potent CBD-derived cannabinoid products has not been performed. While Δ8-THC is synthesized in one step from CBD, newer cannabinoids such as THCP and tetrahydrocannabiphorol-O-acetate require more complex reactions, raising the possibility of even more undisclosed side products. Considering the presence of undisclosed and even undiscovered cannabinoids in Δ8-THC products, there is perhaps a cornucopia of unidentified cannabinoids yet to be discovered that are already being consumed by the public [27]. This production of unknown and untested CBD-derived cannabinoids has obvious parallels to the production of other designer drugs, with their attendant risks. For example, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine is a side product in some synthetic routes for the opioid 1-methyl-4-phenyl-4-propionoxypiperidine and causes acute-onset, permanent Parkinsonism if injected [1]. Similar concerns exist for understudied and undisclosed side products in CBD-Derived cannabinoids.
Non-Cannabinoid Side Products and Contaminants
The unregulated nature of the CBD-derived cannabinoid market is itself a source of risk. This is evident from the results of an investigation commissioned by CBDoracle that analyzed 51 Δ8-THC products from 44 different companies [28]. Results indicated that 76% of the products contained Δ9-THC at levels beyond the legally permitted 0.3%, and that most companies selling these products either do not analyze their products or, if they do, report only the potency of the desired cannabinoids, and not pesticides, heavy metals, excipients, or reaction side products, suggesting the use of insufficient analytic techniques for accurate reporting. They also found falsification of certificates of analysis to be a problem among Δ8-THC suppliers [28]. Peer-reviewed research corroborates the claims of this report, with 1H NMR and GC-MS analyses of 27 Δ8-THC products from 10 brands revealing excipients and side products unaccounted for by their producers and distributors, including undisclosed cannabinoids and olivetol, while inductively coupled plasma mass spectrometry revealed the undisclosed presence of heavy metals and silicon [27]. As mentioned earlier, olivetol inhalation is capable of causing respiratory irritation [1]. While not normally found in significant quantities in cannabis or processed products of cannabis, olivetol is rather a degradation product of the reactions used to synthesize Δ8-THC from CBD [7, 27]. The undisclosed presence of the highly potent, indazole-based synthetic cannabinoid MDMB-4en-PINACA has also been detected in CBD-derived cannabinoid products [19]. Overall, it is clear that consumers should not trust the packaging or supplier-provided certificates of analysis for CBD-derived cannabinoid products.
A Call for Research
Clearly, research must catch up to the current state of cannabinoid use. We believe this should be approached on two fronts: there needs to be an earnest analysis of CBD-derived cannabinoid products and pharmacological exploration of the cannabinoids on the market; there is also a need for observational studies of available human data. While observational studies regarding CBD-derived cannabinoid products are currently limited in quantity and scope, those that are available offer compelling findings that may inform future studies. The previously discussed research analyzing FAERS data on Δ8-THC products was effective in identifying the unique adverse event profile associated with their use. A similar approach can be implemented in future studies focusing on more potent CBD-derived cannabinoids, such as THCP and HHCP, and those hypothesized to be pulmonary toxicants, such as THC-O [5].
Recognizing the wealth of information available through online forums where CBD-derived cannabinoid users exchange information on the products, investigators analyzed the subreddit r/Delta8 for self-reported adverse events [29]. The authors found that between 2020 and 2022, there were 2,184 adverse events reported on r/Delta8, compared with only 326 reported to FAERS during the same period [29]. Moving forward, the subreddit r/altcannabinoids offers discussion on a greater diversity of CBD-derived cannabinoids than Δ8-THC alone and, accordingly, can be analyzed for adverse events related to novel, more potent cannabinoids.
As with other designer drug classes, research has struggled to keep pace with the production of novel CBD-derived cannabinoids. Innovative software can facilitate the first step in addressing this challenge: identification of cannabinoids currently discussed by consumers but unknown to peer-reviewed literature. A 2020 publication discusses implementation of a web crawling software called NPS.Finder to find information on novel synthetic cannabinoids [30]. NPS.Finder scours the web for mention of novel psychoactive substances. In this study, NPS.Finder identified 1,103 synthetic cannabinoids discussed online by recreational users. Of these, 863 synthetic cannabinoids were not mentioned in the novel psychoactive substance lists of the United Nations Office on Drugs and Crime, or the European Monitoring Centre for Drugs and Drug Addiction [30]. As the diversity of available CBD-derived cannabinoids increases, a similar approach may prove invaluable for informing the research and clinical monitoring of these compounds.
Such web-based studies can provide the earliest insights into novel cannabinoids in use, as well as the cannabinoids and brands most associated with adverse events. These data can inform market surveillance utilizing the multiple analytic approaches required for identification and quantification of unlabeled cannabinoids and other reaction side products, excipients, and contaminants, such as a combination of 1H-NMR, GC-MS, and inductively coupled plasma mass spectrometry. Such web-based data can also inform the production of reference standards of emerging cannabinoids to facilitate their identification with MS techniques without the need of NMR. Understudied cannabinoids indicated by web data and confirmed via market surveillance should become the focus of preclinical research to determine their pharmacology and toxicology. In addition to studying these novel cannabinoids themselves, their metabolites should also be investigated. An understanding of the pharmacology and toxicology of such metabolites will inform our understanding of the health impact of these novel cannabinoids, and identification of any unique metabolites that can indicate which cannabinoid was consumed would offer great clinical utility in events of adverse consequences following drug ingestion. Should a widely available cannabinoid, its metabolite, or reaction side product demonstrate a toxic profile, the capacity to screen for it via blood or urine metabolite-specific immunoassay would be invaluable for rapid diagnostic purposes and initiation of appropriate care.
Finally, epidemiological research for CBD-derived cannabinoid use is nascent. A 2021 publication provides a foundation for future studies. Briefly, researchers analyzed Google queries to understand trends in public interest for Δ8-THC. They found that global searches for Δ8-THC increased 257% from 2019 to 2021, and 705% from 2021 to 2022 globally [3]. They also found that Δ8-THC search rates are 10 times higher in the USA than in any other country. Moreover, among US states and territories, they found a significant correlation between the degree of Δ9-THC prohibition and the number of Google queries for Δ8-THC. Search rates for Δ8-THC were 2.8 times higher in states prohibiting both medicinal and recreational cannabis compared to states with legal cannabis. The authors also point out that states with no legal cannabis infrastructure are havens for the production of CBD-derived cannabinoids, as there are no state laws in place to regulate the quality or distribution of cannabis products [3]. While usage rates cannot be gleaned from these findings, such data on regional interest in CBD-derived cannabinoids provide a hypothetical framework for relative usage and potential mediating variables such as degree of Δ9-THC prohibition. These reports can then inform more in-depth observational research. Hospital emergency department records can be analyzed for instances of adverse events resulting from CBD-derived cannabinoid use. Moreover, it is standard practice in the USA for healthcare providers to inquire about drug use while taking a patient history, and should inquire about the use of CBD-derived cannabinoid products. Such information may prove clinically relevant to pulmonary or psychiatric concerns, and anonymized data from electronic medical records could provide an understanding of usage statistics for these products. Identification of metabolites unique to specific CBD-derived cannabinoids could offer biomarkers for wastewater-based epidemiology via liquid chromatography tandem mass spectrometry.
Conclusion
Addressing the risks associated with the emergence of the CBD-derived cannabinoid market poses a unique and multifaceted set of challenges. Contradictory laws have bred a cavalier attitude for the mass production, diversification, and distribution of increasingly potent cannabimimetics, while dampening the scientific community’s capacity to research them. As the variety of CBD-derived cannabinoids expands, so may the dangers. Within these products are risks posed by potent CB1R agonism, pulmonary exposure to ketene gases and olivetol, unstudied cannabinoids, undisclosed reaction side products, and potentially toxic contaminants and excipients. The unregulated nature of this market enhances the dangers. False laboratory reports on the contents of the products underscore deceptive sales practices. Supplier claims of these products being derived from organic sources, coupled with their “legal” status, create a sense of safety and, accordingly, a broader appeal than would likely exist if the public was better informed on the production and associated dangers of these products. Research into CBD-derived cannabinoids is crucial to avoid another vaping-related epidemic.
Conflict of Interest Statement
J.E.N. is the recipient of funding from the NIH (R35 GM146774) and the Congressionally Directed Medical Research Program (CDMRP, W81XWH-21-1-0870). K.E.V. and the Penn State College of Medicine are the recipients of research support from PA Options for Wellness (a state-approved medical marijuana clinical registrant) and the NIH (R01 AT012053). The funding sources had no involvement in study design, data collection, analysis and interpretation; writing of the report; or the decision to submit the article for publication.
Funding Sources
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Funding Statement
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
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