Delta-8 tetrahydrocannabinol, delta-10 tetrahydrocannabinol, and tetrahydrocannabinol-O acetate exposures reported to America's Poison Centers.

INTRODUCTION: Since the passage of the Farm Bill in 2018, the availability of synthetic tetrahydrocannabinols has increased, including delta-8 tetrahydrocannabinol, delta-10 tetrahydrocannabinol, and tetrahydrocannabinol-O acetate. The objective of this study is to investigate the characteristics of delta-8 tetrahydrocannabinol, delta-10 tetrahydrocannabinol, and tetrahydrocannabinol-O acetate exposures reported to United States poison centers from 2021 to 2022. METHODS: National Poison Data System data were analyzed, including year, individual demographics, substance category and type, reason for exposure, highest level of health care received, and medical outcome. United States Census Bureau data were used to calculate population-based rates. RESULTS: There were 5,022 reported cases involving delta-8 tetrahydrocannabinol, delta-10 tetrahydrocannabinol, and tetrahydrocannabinol-O acetate as the primary substance reported to United States poison centers from 1 January 2021 to 31 December 2022. The rate of exposure per 100,000 United States population increased by 89.1 percent from 0.55 in 2021 to 1.04 in 2022. Children less than 6 years old accounted for 30.1 percent of cases, with a mode at age 2 years (representing 8.9 percent of cases). Most cases involved delta-8 tetrahydrocannabinol (98.1 percent), were single-substance exposures (94.3 percent), or occurred in a residence (95.9 percent). Ingestions accounted for 94.2 percent of cases, including 95.1 percent among children less than 6 years old. The leading reason for exposure was unintentional-general (40.2 percent), followed by abuse (33.1 percent). The most common related clinical effects were mild central nervous system depression (25.0 percent), tachycardia (23.0 percent), and agitation (15.6 percent). More than one-third (38.4 percent) of cases experienced a serious medical outcome, and 10.3 percent were admitted to a noncritical care unit and 5.3 percent to a critical care unit. DISCUSSION AND LIMITATIONS: The National Poison Data System is limited by its passive surveillance design. Delta-8 tetrahydrocannabinol, delta-10 tetrahydrocannabinol, and tetrahydrocannabinol-O acetate have toxic effects, and reports to United States poison centers increased from 2021 to 2022. Unintentional ingestions by young children are of particular concern. CONCLUSIONS: Opportunities exist to improve regulation, with accompanying enforcement, of these products and to educate the public about their potential toxicity.

Cannabidiol-Derived Cannabinoids: The Unregulated Designer Drug Market Following the 2018 Farm Bill.

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.

Behavioral Effects of Vaporized Delta-8 Tetrahydrocannabinol, Cannabidiol, and Mixtures in Male Rats.

Background: The popularity of delta-8 tetrahydrocannabinol (THC) and cannabidiol (CBD) products has seen a sharp increase in use during recent years. Despite the rise in use of these minor cannabinoids, there are little to no pre-clinical behavioral data on their effects, with most pre-clinical cannabis research focusing on the behavioral effects of delta-9 THC. The current experiments aimed to characterize the behavioral effects of delta-8 THC, CBD, and mixtures of these two drugs using a whole-body vapor exposure route of administration in male rats. Methods: Rats were exposed to vapor that contained different concentrations of delta-8 THC, CBD, or CBD/delta-8 THC mixtures during 10 min of exposure. Following 10 min of vapor exposure, locomotor behavior was monitored, or the warm-water tail withdrawal assay was conducted to measure the acute analgesic effects of the vapor exposure. Results: CBD and CBD/delta-8 THC mixtures resulted in a significant increase in locomotion across the entire session. Although delta-8 THC alone had no significant effect on locomotion across the session, the 10 mg concentration of delta-8 THC had a hyperlocomotion effect in the first 30 min of the session followed by a hypolocomotor effect later in the session. In the tail withdrawal assay, a 3/1 mixture of CBD/delta-8 THC resulted in an immediate analgesic effect compared to vehicle vapor. Finally, immediately following vapor exposure, all drugs had a hypothermic effect on body temperature compared to vehicle. Conclusion: This experiment is the first to characterize the behavioral effects of vaporized delta-8 THC, CBD, and CBD/delta-8 THC in male rats. While data were generally congruent with previous research investigating delta-9 THC, future studies should explore abuse liability and validate plasma blood concentrations of these drugs following administration through whole-body vapor exposure.

Using Transformer-Based Topic Modeling to Examine Discussions of Delta-8 Tetrahydrocannabinol: Content Analysis.

BACKGROUND: Delta-8 tetrahydrocannabinol (THC) is a psychoactive cannabinoid found in small amounts naturally in the cannabis plant; it can also be synthetically produced in larger quantities from hemp-derived cannabidiol. Most states permit the sale of hemp and hemp-derived cannabidiol products; thus, hemp-derived delta-8 THC products have become widely available in many state hemp marketplaces, even where delta-9 THC, the most prominently occurring THC isomer in cannabis, is not currently legal. Health concerns related to the processing of delta-8 THC products and their psychoactive effects remain understudied. OBJECTIVE: The goal of this study is to implement a novel topic modeling approach based on transformers, a state-of-the-art natural language processing architecture, to identify and describe emerging trends and topics of discussion about delta-8 THC from social media discourse, including potential symptoms and adverse health outcomes experienced by people using delta-8 THC products. METHODS: Posts from January 2008 to December 2021 discussing delta-8 THC were isolated from cannabis-related drug forums on Reddit (Reddit Inc), a social media platform that hosts the largest web-based drug forums worldwide. Unsupervised topic modeling with state-of-the-art transformer-based models was used to cluster posts into topics and assign labels describing the kinds of issues being discussed with respect to delta-8 THC. Results were then validated by human subject matter experts. RESULTS: There were 41,191 delta-8 THC posts identified and 81 topics isolated, the most prevalent being (1) discussion of specific brands or products, (2) comparison of delta-8 THC to other hemp-derived cannabinoids, and (3) safety warnings. About 5% (n=1220) of posts from the resulting topics included content discussing health-related symptoms such as anxiety, sleep disturbance, and breathing problems. Until 2020, Reddit posts contained fewer than 10 mentions of delta-8-THC for every 100,000 cannabis posts annually. However, in 2020, these rates increased by 13 times the 2019 rate (to 99.2 mentions per 100,000 cannabis posts) and continued to increase into 2021 (349.5 mentions per 100,000 cannabis posts). CONCLUSIONS: Our study provides insights into emerging public health concerns around delta-8 THC, a novel substance about which little is known. Furthermore, we demonstrate the use of transformer-based unsupervised learning approaches to derive intelligible topics from highly unstructured discussions of delta-8 THC, which may help improve the timeliness of identification of emerging health concerns related to new substances.

Pharmacokinetics of Two Nanoemulsion Formulations of Δ8-Tetrahydrocannabinol in Rats.

The use of Δ8-tetrahydrocannabinol (Δ8-THC) has increased in recent years. Given that the oral absorption of cannabinoids in oil formulations is typically slow and variable, nanoemulsions may be an improved delivery vehicle. Therefore, we characterized the pharmacokinetics (PK) in Sprague-Dawley rats following the administration of three different oral formulations containing 10 mg/kg Δ8-THC: a translucent liquid nanoemulsion, a reconstituted powder nanoemulsion, and a medium chain triglyceride (MCT) oil solution for comparison. Δ8-THC was also administered intravenously at 0.6 mg/kg. Plasma samples were quantified for Δ8-THC and two metabolites, 11-hydroxy-Δ8-THC (11-OH-Δ8-THC) and 11-carboxy-Δ8-THC (COOH-Δ8-THC). Non-compartmental PK parameters were calculated, and a PK model was developed based on pooled data. Despite a smaller median droplet size of the translucent liquid nanoemulsion (26.9 nm) compared to the reconstituted powder nanoemulsion (168 nm), the PK was similar for both. The median Tmax values of Δ8-THC for the nanoemulsions (0.667 and 1 h) were significantly shorter than the median Tmax of Δ8-THC in MCT oil (6 h). This resulted in an approximately 4-fold higher Δ8-THC exposure over the first 4 h for the nanoemulsions relative to the MCT oil solution. The active 11-OH-Δ8-THC metabolite followed a similar pattern to Δ8-THC. The non-compartmental bioavailability estimates of Δ8-THC for the nanoemulsions (11-16.5%) were lower than for the MCT oil solution (>21.5%). However, a model-based analysis indicated similar bioavailability for all three oral formulations. These results demonstrate favorable absorption properties of both nanoemulsions, despite the difference in droplet sizes, compared to an MCT oil formulation.

Pharmacokinetics of Oral Minor Cannabinoids in Blood and Brain.

Introduction: Minor cannabinoids are increasingly being consumed in oral formulations (i.e., edibles, tinctures) for medical and nonmedical purposes. This study examined the pharmacokinetics (PKs) of cannabinoids tetrahydrocannabivarin (THCV), cannabichromene (CBC), cannabinol (CBN), and delta-8-tetrahydrocannabinol (D8-THC) after the first and last oral dose during a 14-day administration period. Materials and Methods: Sprague-Dawley rats (N=6 animals/dose, 50% female) were given an assigned dose of one of four cannabinoids (THCV=3.2-100 mg/kg, CBC=3.2-100 mg/kg, CBN=1-100 mg/kg, or D8-THC=0.32-10 mg/kg) or vehicle (medium-chain triglyceride oil) through oral gavage once daily for 14 days. Blood was collected 45 min and 1.5, 3, and 24 h following the first dose (day 1) and the last dose (day 14) of repeated oral cannabinoid treatment for PK analysis. Outcomes of interest included time to maximum concentration (Tmax), maximum concentration (Cmax), and area under the concentration versus time curve (AUClast). Dose-normalized (DN) Cmax and DN AUClast were also calculated. Brain tissue was collected 24 h post-administration of the first (day 1) and the last (day 14) dose of each cannabinoid to determine concentrations in brain. Results: All cannabinoids tested were detectable in plasma after single and 14-day repeated dosing. DN Cmax and DN AUClast were highest for D8-THC, followed by CBC, CBN, and THCV. There was no sex difference observed in cannabinoid kinetics. Accumulation of D8-THC in plasma was observed after 14 days of administration. THCV levels in plasma were lower on day 14 compared to day 1, indicating potential adaptation of metabolic pathways and increased drug elimination. Cannabinoids were detected in brain tissue 24 h post-administration of the first and the last dose of 17-100 mg/kg THCV, 3.2-100 mg/kg CBC, 10-100 mg/kg CBN, and 10 mg/kg D8-THC. Conclusions: THCV, CBC, CBN, and D8-THC produced detectable levels in plasma and translocated to brain tissue after the first dose (day 1) and the last dose (day 14) of repeated oral dosing. Examination of PKs of these minor cannabinoids in blood and brain provides a critical step for informing target dose ranges and dosing schedules in future studies that evaluate the potential effects of these compounds.

Δ8-THC Induces Up-Regulation of Glutamatergic Pathway Genes in Differentiated SH-SY5Y: A Transcriptomic Study.

Cannabinoids, natural or synthetic, have antidepressant, anxiolytic, anticonvulsant, and anti-psychotic properties. Cannabidiol (CBD) and delta-9-tetrahydrocannabinol (Δ9-THC) are the most studied cannabinoids, but recently, attention has turned towards minor cannabinoids. Delta-8-tetrahydrocannabinol (Δ8-THC), an isomer of Δ9-THC, is a compound for which, to date, there is no evidence of its role in the modulation of synaptic pathways. The aim of our work was to evaluate the effects of Δ8-THC on differentiated SH-SY5Y human neuroblastoma cells. Using next generation sequencing (NGS), we investigated whether Δ8-THC could modify the transcriptomic profile of genes involved in synapse functions. Our results showed that Δ8-THC upregulates the expression of genes involved in the glutamatergic pathway and inhibits gene expression at cholinergic synapses. Conversely, Δ8-THC did not modify the transcriptomic profile of genes involved in the GABAergic and dopaminergic pathways.

Self-reported adverse events associated with ∆8-Tetrahydrocannabinol (Delta-8-THC) Use.

BACKGROUND: There is an expanding unregulated market for a psychotropic compound called ∆8-Tetrahydrocannabinol (delta-8-THC) that is being derived from hemp, but a summary of adverse events related to delta-8-THC has not been publicly reported. METHODS: This case series assessed adverse events reported by delta-8-THC users on the Reddit forum r/Delta8 and compared these to delta-8-THC AEs in the US Food and Drug Administration Adverse Event Reporting System (FAERS). Delta-8-THC and cannabis AEs reported in FAERS were also compared. The r/Delta8 forum was selected because it includes a large sample of 98,700 registered individuals who publicly discuss their experiences using delta-8-THC. All r/Delta8 posts were obtained from August 20, 2020, through September 25, 2022. A random sample of r/Delta8 posts was drawn (n = 10,000) and filtered for posts in which delta-8-THC users reported an adverse event (n = 335). FAERS reports that listed delta-8-THC (N = 326) or cannabis (N = 7076) as a suspect product active ingredient were obtained. Adverse events claimed to result from delta-8-THC use were coded using Medical Dictionary for Regulatory Activities to system organ class and preferred term categories. RESULTS: The absolute number of delta-8-THC adverse event reports (N = 2184, 95% CI = 1949-2426) and serious adverse event reports (N = 437; 95% CI = 339-541) on r/Delta 8 were higher than the adverse event reports (N = 326) and serious adverse event reports (N = 289) to FAERS. Psychiatric disorders were the most frequently cited system organ class in r/Delta8 adverse event reports, mentioned in 41.2% (95% CI = 35.8%-46.3%) of reports, followed by respiratory, thoracic and mediastinal disorders (29.3%, 95% CI = 25.1%-34.0%) and nervous system disorders (23.3%, 95% CI = 18.5%-27.5%). Anxiety (16.4%, 95% CI = 12.8-20.6), Cough (15.5%, 95% CI = 11.9-20.0) and Paranoia (9.3%, 95% CI = 6.3-12.5) were the most frequently cited preferred terms in adverse event reports. The overall prevalence of AEs reported for cannabis and delta-8-THC on FAERS were also similar when analyzed by system organ class (Pearson's r = 0.88). CONCLUSIONS: The findings of this case series suggest that most of the adverse events reported by delta-8-THC users are like those reported during acute cannabis intoxication. This finding suggests that health care professionals follow similar treatment and management protocols, and that jurisdictions should clarify whether delta-8-THC can be sold as a hemp product.

Delta-8-THC association with psychosis: A case report with literature review.

Background: Cannabis (Δ9-THC) is the most commonly consumed illicit drug. The Agricultural Improvement Act of 2018 removed hemp, a strain of Cannabis sativa, as a controlled substance. This law allowed the plant to be processed into its components, which contain <0.3% Δ9-THC. As a result, delta-8-tetrahydrocannabinol (Δ8-THC), a federally unregulated substance, grew in popularity in 2020. Δ8-THC is readily available in most gas stations or head shops and may be considered harmless by patients. However, an increasing number of patients admitted for psychiatric hospitalization report use, with limited literature on the effects. Case presentations: This case report describes three individual cases of patients who required admission to a university psychiatric hospital after the regular use solely of Δ8-THC. All three patients developed psychotic and paranoid symptoms concurrently with the use of Δ8-THC, with a severity exceeding their previous historical presentations. The presenting psychotic symptoms were also atypical for all three patients. New-onset violence and visual hallucinations were noted in two of the patients, one patient with no previous psychiatric history and one patient while on a therapeutic dose of his antipsychotic. In the third case, a new onset of bizarre, fixed delusions of puppies dissolving in the bathtub developed. Conclusion: This report adds to the limited body of evidence on Δ8-THC documenting a temporal association between Δ8-THC use and the development of psychotic symptoms. A strong body of research already correlates the continued use of Δ9-THC with psychosis, and Δ8-THC acts at the same CB1 and CB2 receptors as Δ9-THC. Therefore, it is hypothesized that Δ8-THC may have similar adverse psychiatric effects as Δ9-THC. These conclusions are not without speculation, due to the need for self or collateral-reporting of Δ8-THC use as urine drug screening cannot distinguish Δ8-THC from Δ9-THC, and the patients' symptoms could be explained by medication non-adherence and primary psychotic disorders. However, physicians should be encouraged to gather a specific history of Δ8-THC use and treat patients with Δ8-THC-related intoxication and symptoms.

Delta-8, a Cannabis-Derived Tetrahydrocannabinol Isomer: Evaluating Case Report Data in the Food and Drug Administration Adverse Event Reporting System (FAERS) Database.

Purpose: The aim of this study was to characterize the frequency of adverse effects where delta-8 tetrahydrocannabinol (D8-THC) was identified as a possible suspect drug in the FDA Adverse Event Reporting System (FAERS) database. Methods: A case-series design was used. Results: A total of 183 cases listed D8-THC as a suspect drug in FAERS as of June 30, 2021. The most common events included dyspnea, respiratory disorder, and seizure. The reporting odds ratios were consistently and significantly greater than 2, a 2-fold increase from 2019 to 2021, indicating a potential safety signal. Conclusion: The first report of D8-THC, in the FAERS database, as a suspect drug appears to be in 2011. Overall, there are 183 total cases listing D8-THC as a suspect drug in the FAERS database as of June 30, 2021. Of the 183 cases, most were respiratory in nature.

Delta-8 gummies causing visual snow: a case report.

A 26-year-old man developed visual snow syndrome (VSS) after consuming a little less than half of a delta-8 gummy (estimated at 4 mg of delta-8 tetrahydrocannabinol). Secondary VSS and hallucinogen-persisting perception disorder (HPPD) are discussed, and clinicians who evaluate patients with VS and VSS should ask about delta-8 gummies as an etiology of secondary VSS.

Δ8-THC: Legal Status, Widespread Availability, and Safety Concerns.

Delta-8-tetrahydrocannabinol (Δ8-THC) is chemically and functionally similar to delta-9-tetrahydrocannabinol (Δ9-THC) (the primary psychoactive cannabinoid in the cannabis plant) and is currently widely available "over-the-counter" across the United States due to unregulated sales. However, these products have a questionable legal status based on current U.S. laws, as Δ8-THC is considered a Schedule I drug by the federal Drug Enforcement Administration (DEA). Despite this designation, Δ8-THC products (e.g., gummies, edibles, oils, and vapes) are largely unregulated and are sold in gas stations, online, and other marketplaces (most often outside of authorized dispensaries) and are marketed as legal hemp products. This problem arises from a purposeful misinterpretation of the 2018 Farm Bill, which some interpret as legalization of non-Δ9-THC cannabinoids (notably, Δ8-THC). The widespread availability of Δ8-THC products has not been without health consequences. The lack of regulation means that there are no required warning labels or packaging protections in place and no mandated laboratory analysis to assure label accuracy or product purity. As Δ8-THC produces physiological and toxicological effects that are similar to Δ9-THC, high-dose exposure of Δ8-THC (e.g., consuming a full bag of Δ8-THC gummies) has resulted in recent reports of medical emergencies, including calls to poison control centers and presentations to emergency departments, with some pediatric patients arriving unconscious and unresponsive. Several states and regulatory agencies have called for legislation to regulate Δ8-THC, but little progress has occurred nationally thus far.

Oral Cannabidiol Does Not Convert to Δ8-THC or Δ9-THC in Humans: A Pharmacokinetic Study in Healthy Subjects.

Introduction: Recent studies have suggested that cannabidiol (CBD) could interconvert into Delta-8- and Delta-9- tetrahydrocannabinol. Materials and Methods: Thus, we tested the plasma samples of 120 healthy human subjects (60 male and 60 female), 60 in fasting and the other 60 under normal feeding conditions after acute administration of an oral solution containing CBD 300 mg. To do this, we developed a bioanalytical method to determine CBD and the presence of THC in plasma samples by Ultra-High Performance Liquid Chromatography Coupled to Tandem Mass Spectrometry. Results: The results showed that THC was not detected in plasma after the administration of CBD, and those study participants did not present psychotomimetic effects. Conclusions: The findings presented here are consistent with previous evidence suggesting that the oral administration of CBD in a corn oil formulation is a safe route for the administration of the active substance without bioconversion to THC in humans.

Cannabidiol in medical marijuana: Research vistas and potential opportunities.

The high and increasing prevalence of medical marijuana consumption in the general population invites the need for quality evidence regarding its safety and efficacy. Herein, we synthesize extant literature pertaining to the phytocannabinoid cannabidiol (CBD) and its brain effects. The principle phytocannabinoid Δ9-tetrahydrocannabinol (Δ9-THC) and CBD are the major pharmacologically active cannabinoids. The effect of CBD on brain systems as well as on phenomenological measures (e.g. cognitive function) are distinct and in many cases opposite to that of Δ9-THC. Cannabidiol is without euphoriant properties, and exerts antipsychotic, anxiolytic, anti-seizure, as well as anti-inflammatory properties. It is essential to parcellate phytocannabinoids into their constituent moieties as the most abundant cannabinoid have differential effects on physiologic systems in psychopathology measures. Disparate findings and reports related to effects of cannabis consumption reflect differential relative concentration of Δ9-THC and CBD. Existing literature, notwithstanding its deficiencies, provides empirical support for the hypothesis that CBD may exert beneficial effects on brain effector systems/substrates subserving domain-based phenomenology. Interventional studies with purified CBD are warranted with a call to target-engagement proof-of-principle studies using the research domain criteria (RDoC) framework.