Repeated Δ9-tetrahydrocannabinol exposure in adolescent monkeys: persistent effects selective for spatial working memory

Am J Psychiatry. 2014 Apr;171(4):416-25. doi: 10.1176/appi.ajp.2013.13030335.


Objective: Epidemiological findings suggest that, relative to adults, adolescents are more vulnerable to the adverse persistent effects of cannabis on working memory. However, the potential confounds inherent in human studies preclude direct determination of a cause-and-effect relationship between adolescent cannabis use and heightened susceptibility to persistent working memory impairments. Consequently, the authors examined the effects of repeated exposure to Δ9-tetrahydrocannabinol (THC) on performance of spatial and object working memory tasks in adolescent monkeys.

Method: Seven pairs of male adolescent rhesus monkeys, matched for baseline cognitive performance, received vehicle or THC intravenously 5 days/week for 6 months. Performance on spatial and object memory tasks was assessed 23 or 71 hours after drug administration throughout the study. In addition, acute effects on working memory were also assessed at the beginning and end of the 6-month period.

Results: Relative to the vehicle-exposed control animals, those with repeated THC exposure had a blunted trajectory of accuracy improvements on the spatial working memory task in a delay-dependent manner. Accuracy improvements on the object working memory task did not differ between groups. Relative to the acute effects of THC on working memory at the beginning of the study, neither sensitivity nor tolerance was evident after 6 months of THC exposure.

Conclusions: Because maturation of performance is later for spatial than for object working memory, these findings suggest that persistent effects of THC on cognitive abilities are more evident when exposure coincides with the developmental stage during which the underlying neural circuits are actively maturing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cannabinoid Receptor Agonists / pharmacology*
  • Case-Control Studies
  • Dronabinol / pharmacology*
  • Macaca mulatta
  • Male
  • Memory, Short-Term / drug effects*
  • Psychomotor Performance / drug effects*
  • Space Perception / drug effects
  • Spatial Behavior / drug effects*


  • Cannabinoid Receptor Agonists
  • Dronabinol