Repeated THC Produced Wheel-Running Tolerance Without a Detected Spontaneous Withdrawal Effect in Rats
A rat study detected clear tolerance to THC-related suppression of wheel running but no significant wheel-running change during spontaneous withdrawal. The two results show why tolerance and withdrawal should be measured separately.
The study followed both sexes continuously
Male and female Sprague-Dawley rats received THC or vehicle twice daily for seven days. THC strongly reduced voluntary home-cage wheel running initially. A later THC challenge suppressed running more in previously vehicle-treated animals than in previously THC-treated animals, indicating tolerance. The study detected no sex difference in the reported acute suppression or tolerance.
Withdrawal was assessed on the same behavioral measure
Researchers observed running for five days, beginning after the tolerance-test period. They found no significant running changes associated with spontaneous withdrawal. Unlike antagonist-precipitated models, this part of the experiment did not use receptor blockade to provoke signs.
The null finding belongs to the endpoint and regimen
A sensitive continuous activity measure can still leave other possible symptoms unmeasured. The result does not prove that all physiological adaptation was absent, particularly because tolerance was demonstrated. Nor does it invalidate withdrawal findings from different compounds, doses, exposure durations or measurement methods.
The study supports a narrow but important conclusion: repeated THC did not produce a detected spontaneous wheel-running withdrawal signal in this rat protocol. It cannot establish that people do not experience cannabis withdrawal, or that every tolerant individual necessarily has clinically meaningful withdrawal symptoms.
Related: interpreting cannabis tolerance claims.
Research cited
Hickey CM; Poling C; Grimes W; Calvert AR; Morgan MM. Tolerance but No Spontaneous Withdrawal Following Repeated THC Injections in Male and Female Rats. Cannabis and cannabinoid research (2026). doi:10.1177/25785125251404395. Findings discussed from the study abstract.
