{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T19:08:44Z","timestamp":1787252924616,"version":"build-2736575974"},"reference-count":56,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T00:00:00Z","timestamp":1751500800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Key R&amp;D Program of China","award":["2024YY21"],"award-info":[{"award-number":["2024YY21"]}]},{"name":"National Key R&amp;D Program of China","award":["2022YFC3300905"],"award-info":[{"award-number":["2022YFC3300905"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>5F-ADB, MDMB-4en-PINACA and ADB-4en-PINACA are three potent indazole-carboxamide synthetic cannabinoids (SCs) that have been widely abused in recent years. However, the pharmacological research on these compounds remains limited, especially in vivo research data. The purpose of the present study was to investigate the pharmacological effects of 5F-ADB, MDMB-4en-PINACA and ADB-4en-PINACA in mice, comparing their in vivo effects with those caused by \u03949-tetrahydrocannabinol (\u03949-THC), the main psychoactive substance in cannabis. We evaluated the cannabinoid-specific pharmacological effects of 5F-ADB, MDMB-4en-PINACA and ADB-4en-PINACA using the tetrad assay (locomotion inhibition, hypothermia, analgesia and catalepsy). Then we conducted conditioned place preference (CPP) and precipitated withdrawal assay to assess the rewarding effect and physical dependence, with \u03949-THC as a positive control. The results showed that all of the three SCs exhibited potential tetrad effects in a dose-dependent manner, with median effective dose (ED50) values ranging from 0.03 to 0.77 mg\/kg. In the CPP tests, they all exhibited a significant biphasic effect of conditioned place preference (CPP) and conditioned place aversion (CPA). A significant increase in paw tremors and head twitches was observed in the rimonabant-precipitated withdrawal assay, indicating that the repeated administration of these SCs can lead to potential physical dependence. All effective doses were lower than \u03949-THC. These findings strongly suggested that the three SCs exhibited similar but stronger cannabinoid-specific tetrad effects, rewarding effect and physical dependence compared with \u03949-THC, indicating their high abuse potential and possible threats to human health. The rank order of abuse potential for these drugs was 5F-ADB &gt; MDMB-4en-PINACA &gt; ADB-4en-PINACA &gt; \u03949-THC.<\/jats:p>","DOI":"10.3390\/ijms26136409","type":"journal-article","created":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T06:54:16Z","timestamp":1751525656000},"page":"6409","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Assessment of Abuse Potential of Three Indazole-Carboxamide Synthetic Cannabinoids 5F-ADB, MDMB-4en-PINACA and ADB-4en-PINACA"],"prefix":"10.3390","volume":"26","author":[{"given":"Yanling","family":"Qiao","sequence":"first","affiliation":[{"name":"School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China"},{"name":"Office of China National Narcotics Control Commission, China Pharmaceutical University Joint Laboratory on Key Technologies of Narcotics Control, Beijing 100193, China"},{"name":"Key Laboratory of Drug Monitoring and Control, Drug Intelligence and Forensic Center, Ministry of Public Security, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuesong","family":"Shi","sequence":"additional","affiliation":[{"name":"School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China"},{"name":"Office of China National Narcotics Control Commission, China Pharmaceutical University Joint Laboratory on Key Technologies of Narcotics Control, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaixi","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China"},{"name":"Office of China National Narcotics Control Commission, China Pharmaceutical University Joint Laboratory on Key Technologies of Narcotics Control, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixin","family":"Kuai","sequence":"additional","affiliation":[{"name":"School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China"},{"name":"Office of China National Narcotics Control Commission, China Pharmaceutical University Joint Laboratory on Key Technologies of Narcotics Control, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyu","family":"Li","sequence":"additional","affiliation":[{"name":"Office of China National Narcotics Control Commission, China Pharmaceutical University Joint Laboratory on Key Technologies of Narcotics Control, Beijing 100193, China"},{"name":"Key Laboratory of Drug Monitoring and Control, Drug Intelligence and Forensic Center, Ministry of Public Security, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Di","sequence":"additional","affiliation":[{"name":"School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China"},{"name":"Office of China National Narcotics Control Commission, China Pharmaceutical University Joint Laboratory on Key Technologies of Narcotics Control, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Xu","sequence":"additional","affiliation":[{"name":"Office of China National Narcotics Control Commission, China Pharmaceutical University Joint Laboratory on Key Technologies of Narcotics Control, Beijing 100193, China"},{"name":"Key Laboratory of Drug Monitoring and Control, Drug Intelligence and Forensic Center, Ministry of Public Security, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"109468","DOI":"10.1016\/j.drugalcdep.2022.109468","article-title":"Cannabimimetic Effects of Abused Indazole-Carboxamide Synthetic Cannabinoid Receptor Agonists Ab-Pinaca, 5f-Ab-Pinaca and 5f-Adb-Pinaca in Mice: Tolerance, Dependence and Withdrawal","volume":"236","author":"Wilson","year":"2022","journal-title":"Drug Alcohol Depend."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1097\/FBP.0000000000000618","article-title":"Behavioral Pharmacology of Five Novel Synthetic Cannabinoids","volume":"33","author":"Gatch","year":"2022","journal-title":"Behav. 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