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Research Articles

Appearance of hexahydrocannabinols as recreational drugs and implications for cannabis drug testing – focus on HHC, HHC-P, HHC-O and HHC-H

ORCID Icon, , &
Pages 125-132 | Received 04 Dec 2023, Accepted 13 Feb 2024, Published online: 15 Apr 2024

Figures & data

Figure 1. Chemical structures of delta-9-tetrahydrocannabinol (delta-9-THC), hexahydrocannabinol (HHC), its carboxylic acid metabolite (HHC-COOH), and the analogs hexahydrocannabiphorol (HHC-P), HHC acetate (HHC-O) and hexahydrocannabihexol (HHC-H).

Figure 1. Chemical structures of delta-9-tetrahydrocannabinol (delta-9-THC), hexahydrocannabinol (HHC), its carboxylic acid metabolite (HHC-COOH), and the analogs hexahydrocannabiphorol (HHC-P), HHC acetate (HHC-O) and hexahydrocannabihexol (HHC-H).

Figure 2. Chromatograms showing a patient urine sample testing positive for the carboxylic acid metabolite of delta-9-tetrahydrocannabinol (THC-COOH), a spiked urine standard for hexahydrocannabinol carboxylic acid (HHC-COOH), and a patient urine sample testing positive for HHC-COOH (22 µg/L).

Figure 2. Chromatograms showing a patient urine sample testing positive for the carboxylic acid metabolite of delta-9-tetrahydrocannabinol (THC-COOH), a spiked urine standard for hexahydrocannabinol carboxylic acid (HHC-COOH), and a patient urine sample testing positive for HHC-COOH (22 µg/L).

Figure 3. Monthly number of posts on hexahydrocannabinol (HHC) over two years until October 2023 on a Swedish open online discussion forum for psychoactive substances [Citation14]. After 11 July 2023 (broken line), when HHC was classified as a narcotic substance, the number of posts on the HHC thread decreased and eventually ended. Instead, new threads were started about the unregulated analogues HHC acetate (HHC-O) and tetrahydrocannabiphorol (THC-P).

Figure 3. Monthly number of posts on hexahydrocannabinol (HHC) over two years until October 2023 on a Swedish open online discussion forum for psychoactive substances [Citation14]. After 11 July 2023 (broken line), when HHC was classified as a narcotic substance, the number of posts on the HHC thread decreased and eventually ended. Instead, new threads were started about the unregulated analogues HHC acetate (HHC-O) and tetrahydrocannabiphorol (THC-P).

Figure 4. Test responses for A) delta-9-tetrahydrocannabinol (THC) and hexahydrocannabinol (HHC) and B) their carboxylic acid metabolites, THC-COOH and HHC-COOH, respectively, in immunoassay screening for cannabis use in oral fluid (OF) (THC Oral Fluid HEIA, Immunalysis Corp.) and urine (CEDIA Multi-Level THC Assay, Thermo Fisher Scientific), respectively. The substances were diluted in acetonitrile or methanol. Blanks with solvent only generated negative results.

Figure 4. Test responses for A) delta-9-tetrahydrocannabinol (THC) and hexahydrocannabinol (HHC) and B) their carboxylic acid metabolites, THC-COOH and HHC-COOH, respectively, in immunoassay screening for cannabis use in oral fluid (OF) (THC Oral Fluid HEIA, Immunalysis Corp.) and urine (CEDIA Multi-Level THC Assay, Thermo Fisher Scientific), respectively. The substances were diluted in acetonitrile or methanol. Blanks with solvent only generated negative results.

Figure 5. Frequency of urine samples testing preliminary positive for cannabis use (THC-COOH) in immunoassay screening, but confirmed negative by LC–MS/MS, among samples submitted for routine drug testing at the Karolinska University Laboratory (Stockholm, Sweden) in 2021–2023. On 11 July 2023, HHC was classified as a narcotic substance (broken line). The monthly number of samples that are screened for cannabis use is ∼10 000. Results are shown for urine samples confirmed to contain <5 µg/L THC-COOH, to exclude samples just below the 10 µg/L routine cut-off.

Figure 5. Frequency of urine samples testing preliminary positive for cannabis use (THC-COOH) in immunoassay screening, but confirmed negative by LC–MS/MS, among samples submitted for routine drug testing at the Karolinska University Laboratory (Stockholm, Sweden) in 2021–2023. On 11 July 2023, HHC was classified as a narcotic substance (broken line). The monthly number of samples that are screened for cannabis use is ∼10 000. Results are shown for urine samples confirmed to contain <5 µg/L THC-COOH, to exclude samples just below the 10 µg/L routine cut-off.

Figure 6. Test responses for hexahydrocannabinol (HHC), HHC acetate (HHC-O), hexahydrocannabihexol (HHC-H), hexahydrocannabiphorol (HHC-P) and delta-9-tetrahydrocannabiphorol (THC-P), in comparison with delta-9-tetrahydrocannabinol (THC), in immunoassay screening for cannabis use in oral fluid (OF) (THC Oral Fluid HEIA, Immunalysis Corp.). The substances were diluted in acetonitrile or methanol and spiked in three different blank oral fluid samples collected with the Quantisal device (Immunalysis Corp.). Results are the mean values. Blanks with solvent only generated negative results.

Figure 6. Test responses for hexahydrocannabinol (HHC), HHC acetate (HHC-O), hexahydrocannabihexol (HHC-H), hexahydrocannabiphorol (HHC-P) and delta-9-tetrahydrocannabiphorol (THC-P), in comparison with delta-9-tetrahydrocannabinol (THC), in immunoassay screening for cannabis use in oral fluid (OF) (THC Oral Fluid HEIA, Immunalysis Corp.). The substances were diluted in acetonitrile or methanol and spiked in three different blank oral fluid samples collected with the Quantisal device (Immunalysis Corp.). Results are the mean values. Blanks with solvent only generated negative results.