Delta-8, a Cannabis-Derived Tetrahydrocannabinol Isomer: Evaluating Case Report Data in the Food and Drug Administration Adverse Event Reporting System (FAERS) Database (2024)

Data Source and Collection

The FAERS database structure adheres to the international safety reporting guidance issued by the International Conference on Harmonization, ICH E2B.Adverse events and medication errors are coded using terms in the Medical Dictionary for Regulatory Activities (MedDRA) terminology.15 Reports can be submitted by healthcare professionals and consumers through the “MedWatch” program.16–18 The original FAERS system was started in 1969. In 1997, it underwent a major revision resulting in an increase in reporting.19,20 To date, the FAERS is the largest repository of spontaneously reported AEs in the world with more than 22 million total reports.19,20 The FDA releases these data to the public. Public access allows external researchers to explore these data through pharmacoepidemiologic/pharmacovigilance analyses. It has also evolved to allow broader public health utilization, as Healthcare Professionals (HCP) and consumers can report AEs/side effects from any medication or product.

There are a series of tables available in the FDA FAERS dataset including: case demographics (sex, age, weight), suspect drug, and a list of all suspect drugs; report to the FDA dates, outcomes, reactions (AE), indications for use, reporter (consumer, healthcare provider, not specified) administrative information (DEMO), drug/biologic information (DRUG), a, drug therapy start and end dates (THER). The drugs in the DRUG table are assigned as any of primary suspect, secondary suspect, concomitant, or interacting. The AEs in the REAC (reaction) table are coded using the preferred terms (PTs) in MedDRA. FAERS permits the reporting of random drug names, including trade names and abbreviations. Spelling errors and drug combinations of interest were reviewed by the authors. A case can have multiple events reported, and each event or AE will be listed; therefore, the number of events will be greater than the number of cases.

For simplicity, system organ class (SOC) will be used to represent the “reaction group”/body system. Preferred Term (PT) will represent the “reaction” or AE that was reported. D8-THC will be used to represent all formulations/combinations of D8-THC identified in FAERS.

Descriptive data analyses (total number of cases and percentages) were performed. Subset analyses were performed and evaluated as a case series where we analyzed AEs caused by drugs, not by disease state. Disproportionality analysis was performed using the relative odds ratio (ROR) to detect unexpected (spontaneous) signals. Our approach allows for the detection of increased frequencies of drug-related AEs21 using a case/no case method. “Cases” are defined as a person who reported exposure to a specific drug and who also reported a specific AE, while all other possible pairs are “non-cases”. The calculation for ROR uses a two-by-two contingency table reporting event counts for each specific drug and all other drugs. ROR represents the odds that an outcome will occur given a particular exposure and is a measure of an association between an exposure to a drug, and the odds a specific outcome will occur.22 The Yates Correction is recommended when expected cell frequencies are below 10 or even 5. For these data, none of the expected cells were below 10 and given the large sample size of the FAERS database and the Yates correction was not applied. We did, however, have circ*mstances where there were 0 cases in the observed. For this, we assigned a 0.5 to the cell per the Cochrane handbook.23 All data processing and statistical analyses were performed using Excel (version 2201).

An ROR signal is defined positive if the lower limit of the 95% confidence interval (CI) is greater than 1.24 The 95% CI gives an indication of the precision of the estimate of the ROR. As with proportional reporting ratios, an ROR value equal to 2 or greater can be used as a threshold; however, the lower bound of the 95% CI is preferred. For this analysis, the odds of reports of the pre-specified event with the product of interest (D8-THC) are 2x (two times) higher than the odds of the event occurring among all other reports in the database (FAERS).

ROR = (a*d)/(c*b)

95% CI = Lower 95% CI = eln(OR) – 1.96√(1/a + 1/b + 1/c + 1/d) and

Upper 95% CI = eln(OR) + 1.96√(1/a + 1/b + 1/c + 1/d)

This reference risk is believed to reflect the baseline risk of the reported event in a person exposed to that product provided there is no specific association between the product and the event of interest. A possible limitation is if the reference risk provides an accurate estimate of the baseline risk of an event for a person receiving a product since the rate is calculated by using a group of medications (products) that include treatments that may be known for the event of interest. It has been theorized that the ROR may have an advantage over the proportional reporting ratio by estimating the relative risk. Both are disproportionality measures and do not allow for risk quantification. These measures and analytical tools assist in the possibility of identifying an indication of the strength of a signal.25

Analyses of the data extracted from the FAERS database included all cases with suspect drug D8-THC. The first data extraction was performed on March 11, 2021, and it included data from 2011 to December 2020. A subsequent data extraction was performed with the last being September 14, 2021 and included data up to June 30, 2021. For this analysis, the specific drug search terms in this evaluation included D8-THC; D8-THC/device/herbals; D8-THC/device/herbals/nicotine; D8-THC/herbals. Prior to data mining, all duplicate reports were deleted according to the FDA’s recommendation by utilizing the most recent case number. There were no duplicates identified. The number of reports remained at 183.

Descriptive Results on D8-THC Cases

Main Findings

To our knowledge, this is the first study to analyze AEs related to D8-THC products, reported in a national database (ie, FAERS) in the United States. Overall, the findings demonstrate that the FAERS database captured almost triple the number of cases where D8-THC was listed as a suspect product compared to D9-THC products.26 This has remained consistent as of Jan 3, 2022.

Our data show that, since 2018, the increases of D8-THC AEs occurred in mostly males aged 18 to 65 years in the US when compared to D9-THC products.26 The most frequent events occurred in the respiratory and nervous system organ class (SOC, ie, body systems). When the most common AEs (eg, dyspnea, respiratory disorder, and seizure) with D8-THC were compared to all cases of dyspnea, respiratory disorder, and seizure events reported in the FAERS database, the RORs were consistently and significantly greater than 2 from 2019 to 2021. This represents a doubling indicative of a potential safety signal. The respiratory event profile in the D8-THC cases appears to be unique for products labeled as D8-THC derived from CBD or hemp and not for D9-THC or cannabis. D8-THC products are not approved by the FDA.

D8-THC in Case Reports and Health Advisories

The most urgent and important concern is the possible association of D8-THC labeled products causing respiratory and cardiac issues from public health-related data sources (ie, case reports, poison control centers, AEs databases, etc.). A few case reports highlighting this possible public health issue are described below. The first case report is that of acute encephalopathy in a 2-year-old-female in Kentucky ingesting approximately 15mg/kg of D8-THC gummies.27 The patient was minimally responsive with a noted Glasgow Coma scale (GCS) of three and a heart rate of 136 beats per minute; the patient was intubated using fentanyl and ketamine. Since D8-THC is not included in the typical drug screen, the hospital collaborated with the DEA toxicology division to confirm the presence of D8-THC. Parents estimate that the child ingested about 9 gummies, an estimated total dose of 225 mg of D8-THC. The child was extubated after 10 hours, and GCS returned to a 15, a score generally associated with a mild head injury. The patient was discharged after 24 hours of observation and mental impairment resolved.27

Another case report documented an instance of a potentially life-threatening heart rhythm disorder after exposure to D8-THC, known as a Brugada electrocardiogram pattern (BEP; type III to type I).28 A healthy 31-year-old male in Texas presented with sudden onset of chest pain with associated pallor and dyspnea 20 minutes after ingesting a hemp D8-THC gummy. The chest pain was non-specific and non-exertional, substernal, and not relieved with rest or nitroglycerin. Abnormal EEG and BEP persisted for 16 hours post D8-THC ingestion. The Brugada pattern resolved upon one month of follow-up.28

The Michigan Poison Control Center reported two cases of severe AEs to D8-THC in children who ingested an adult’s hemp D8-THC-infused gummies obtained from a vape shop.29,30 The children experienced deep sedation and slow breathing with increased heart rate that progressed to a slow heart rate and decrease in blood pressure.29,30 The West Virginia Poison Control Center has reported cases of AEs in adults who mistakenly ingested a hemp D8-THC product, presuming it did not contain intoxicants.

Based on the totality of data, (case reports, data from this FAERS analysis and the warnings from the FDA and CDC) D8-THC containing products or exposure to D8-THC seems to be associated with significant risks of experiencing an AE. Many of these AEs seem to resolve; however, there have been some reports about a D8-THC product that was a possible factor associated with a death.26

D8-THC Animal Toxicology Data

D8-THC toxicity has clinical features of hypothermia, bradypnea, rapid weight loss, inactivity, ataxia, muscle tremors, prostration, lethargy, drowsiness, and depressive behavior.31,32 Histopathologic changes from toxic doses of D8-THC were observed in rats but not dogs or monkeys.32 Sagratella and Wada reported similar characteristics in baboons and in rabbits.33,34 In light of modern evidence, it does not appear that the doses administered by these investigators produced the aforementioned D8-THC effects as seen in FAERs.

D8-THC in Population-Based and Clinical Trial Studies

There is limited, if any, meaningful population-based information on modern D8-THC uses in humans. Our results appear to be in direct contrast to a D8-THC consumer survey published by Kruger (2021); participants were provided with CBD and D8-THC products by a manufacturer and no side effects were reported.35 The respondents also perceived D8-THC products to be safer than prescription cannabinoids (ie, Epidiolex™, Marinol™, etc.) and the FDA approved prescription drugs.35 There is a discrepancy between consumer reported perceptions of the “immaculate” safety of D8-THC and the AE data that are available.5,13

Decades ago, three small clinical trials2,6,7 compared the effects of oral doses of D8-THC to D9-THC. Hollister et al (1973) investigated D8-THC (20, 40 mg) and D9-THC (20 mg) in a small sample (n = 6), and intravenous (IV) doses of D8-THC (n = 3) and D9-THC (n = 4).2 Results indicated that oral D8-THC and D9-THC produced a similar profile of typical cannabinoid agonist effects which can include euphoria, dry mouth, red eyes, dizziness, vision that is blurred, relaxation, and small increase in heart rate (7–12 bpm). Symptom onset occurred 30–90 min after administration, with peak effects at 2.5–3.5 h (with some effects still present at 5 h). Results from the IV administration of THC and its isomer were comparable, with dose-dependent increases in tachycardia (9–41 bpm) and faster onset (ie, peak effects at 20–60 min). The authors concluded that D8-THC is slightly less potent than D9-THC.2

Years later, Gong et al evaluated the bronchodilation effect of 4 gel capsule cannabinoids: D8-THC (N = 8), D9-THC (N = 18), cannabinol (CBN) (N = 14) and CBD (N = 10). Effects of BP, heart, respiratory rates, and specific airway were measured.6 D8-THC subjects’ heart rate increased similarly to D9-THC. Level of intoxication was measured using a VAS 0 to 7, with a 7 being the highest high they have ever experienced. Oral D8-THC was rated as a 3 and 2 for 50mg and 75mg, respectively, whereas D9-THC 20mg rated a 4. No change in BP or other side effects were reported. Abrahamov et al evaluated the antiemetic effects of D8-THC without a placebo or comparable drug, in 8 children (10 m to 13yrs) with hematologic cancers.7 D8-THC (18mg/m2) was administered as oil drop on tongue for 6 hours for 24 hours. A total of 480 treatments were administered. None of the children were reported to have vomited while receiving D8-THC treatment. The treatment was well tolerated, and 2 patients were reported to experience irritability and one euphoria.

Babalonis et al summarized the current understanding regarding the comparison of D8-THC to D9-THC.1 The author states that clinically distinguishing D8-THC ingestion from D9-THC ingestion by hospital toxicology laboratories is difficult and does not seem to have changed medical management of cannabinoid-related adverse events.1 Currently, symptomatic, and supportive care without any antidotal therapy is indicated for acute intoxication. An article by Richards et al is consistent with the data found in FAERS, such as respiratory issues and severe sedation are more common in children and after high-dose exposure in adults.36

In the FAERS data, we found that the types of AEs reported in D8-THC cases had a different profile compared to those reported in the D9-THC cases. More respiratory-related AEs were reported with D8-THC than for any other cannabis or hemp product during the observation period used for this analysis.

Strengths and Weaknesses of the Methods

The main limitations of our investigation are related to the FAERS data source. At a national level, the rate of reporting an AE for an FDA approved, marketed product is about 6%. We speculate that the reporting rate could be significantly lower for non-FDA approved cannabis and hemp-derived products in FAERs. Each state cannabis program has a reporting system designated in their regulations (eg, usually local poison control centers). There is no such requirement for hemp programs. Given the overall low rate of reporting AEs and decentralization of safety data collection – simply being able to detect D8-THC safety signals in FAERS is concerning.

Data mining does not provide adequate evidence for causation. In many of the reports, there were multiple medications listed as suspect. However, in greater than 50%, D8-THC was the only suspect product listed. Given that the only data available to healthcare providers are case reports, we believe this paper will generate discussion both between and among healthcare workers and consumers. The public needs to be aware that not every product available to them has been standardized or deemed safe for consumption.

Rothman et al discuss the advantages of a reporting odds ratio over a proportional reporting ratio.22 It is stated that given the weaknesses of a spontaneous reporting database like FAERS, the data can be treated as a case–control study. For this reason, our ‘case series’ approach focuses on the importance of an appropriate choice of controls for the comparison. This is challenging and thereby highlights weaknesses in spontaneous reporting case data. In drug safety assessments and surveillance, these approaches are considered exploratory and for the purposes of identifying signals. A disproportionality ratio greater than 2 for a drug should lead to an investigation of all available data that includes a comprehensive literature review, a review of current and past animal toxicology, pharmacology, case reports and randomized clinical trials. An epidemiologic assessment may include the initiation of a case–control or cohort study to confirm the signal.

It is the body of evidence and strong pharmacovigilance assessments that allow for the complete evaluation of a potential signal. No one method (experimental data, clinical trials, spontaneous notifications, case–control studies, cohort studies and data mining) should be considered definitive when evaluating drug risk. It is the level of evidence that is generally used for evaluating drug efficacy and safety. Safety is and should be monitored for the lifetime of a product. This is true for FDA approved products. The authors believe that a product is obligated to demonstrate that it works (efficacy) and is safe in order to get on the market, however it is the safety data that keeps the product on the market. Therefore, all methods and available data are of interest and considered in an evaluation of an AE signal.

Knowledge and attitudes of consumers and healthcare professionals are important as educational intervention improves the reporting of AEs in FAERs.37–39 Increased publicity for the FAERS database and/or education should be considered to increase consumer and patient reporting.40 Many AEs may go under reported if an individual or healthcare professional does not take the time to submit a report to FAERs. Further, precise exposure to the product in question is generally unknown and limits analysis as these signal detection tools do not imply causation. The strength of FAERS is its ability to generate early signal detection for serious public health issues. Additionally, the analysis of ROR is an accepted and a standard reporting disproportionality measure of association between a product and an AE.

Public Perceptions and Public Health Implications

D8-THC products are procurable in many formulations: cookies, gummies, vaporizer cartridges, hemp flower, tinctures, and other food-like products. Yet, hemp-derived D8-THC products do not follow any standards expected of basic food items found in a grocery store, such as a loaf of bread, dairy products, or a product known to contain allergens. In effect, D8-THC, allegedly derived from hemp, is an unregulated intoxicant that can be purchased by any individual without age restrictions or proper food safety labeling.

It is theorized that the rise of access to this product and other newly obtainable isomer (THC-O acetate; D10-THC, etc.) compounds are attributed to an oversupply of CBD. Oversupply pushed producers to seek alternative products that could be profitable. Synthesizing illicit substances from CBD continues to be profitable and remains federally prohibited without licensure or approval from the DEA or other applicable regulatory bodies. Even if the chemical process was legal, regulated, and standardized, the resulting product in this case, D8-THC, can be intoxicating.41

In closing, D8-THC and other THC-isomer sales have been rising, and the perception of the public is that if a packaged product is in a storefront, then it must be safe or at least deemed safe by an authority (eg, FDA).3,35 It is unclear if D8-THC is directly responsible for the events reported in the FAERS database, or are they due to other adulterants, or due to misleading packaging.26,30,42

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