Tolerance but No Spontaneous Withdrawal Following Repeated THC Injections in Male and Female Rats
Christa M. Hickey, Casey Poling, W. Grimes, Alexa R Calvert, Michael M. Morgan
Cannabis and Cannabinoid Research December 1, 2025 DOI: 10.1177/25785125251404395 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Peer reviewed |
|---|---|
| Population | Male and female Sprague-Dawley rats |
| Intervention | Delta-9-tetrahydrocannabinol (THC) |
| Dose | 3 mg/kg, s.c., twice daily |
| Duration | 7 days of injections, 5 days of withdrawal assessment |
| Measures | Voluntary home cage wheel running |
| Topics | Cannabis |
| Key findings | THC (3 mg/kg) profoundly decreased voluntary wheel running and produced tolerance after repeated twice-daily injections for 7 days in both male and female rats, with no sex differences. However, spontaneous THC withdrawal produced no significant changes in wheel running over 5 days, suggesting that spontaneous THC withdrawal in rats is mild at best, in contrast to the pronounced changes seen with opioid withdrawal. |
Abstract
Introduction: Tolerance and dependence are known to occur with prolonged cannabis use. Few animal experiments on spontaneous withdrawal from delta-9-tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis, have been conducted. The experiments that have been conducted use extremely high doses and report relatively mild symptoms. The objective of the present experiment was to determine the magnitude and duration of spontaneous THC withdrawal in male and female rats using voluntary home cage wheel running as a sensitive, objective, and continuous measure of withdrawal.
Materials and Methods: Male and female Sprague-Dawley rats were injected with THC (3 mg/kg, s.c.) or vehicle twice daily for 7 days to induce tolerance and dependence. Spontaneous withdrawal was assessed for 5 days beginning 24 h after the day 8 tolerance test in which all rats received a THC injection.
Results: On day 1, THC profoundly decreased wheel running in male and female rats compared to vehicle-treated rats. On day 8, THC given to vehicle-treated rats produced a significantly greater decrease in running than in rats previously treated with THC, indicating tolerance development. There was no sex difference in the magnitude of the decrease in wheel running caused by THC injections or in the development of tolerance. There were no significant changes in wheel running associated with spontaneous THC withdrawal.
Discussion: These data suggest that spontaneous THC withdrawal in male and female rats is mild at best despite profound locomotor suppression and tolerance to repeated injections. The lack of spontaneous THC withdrawal contrasts sharply with the pronounced changes in wheel running produced by opioid withdrawal.