Daily intraperitoneal injections of THC in 30- to 43-day-old mice—a time that roughly corresponds to human adolescence [54]—cause a marked dampening of the animals’ weight-gain trajectory [52]. This effect was obtained with a THC dose (5 mg/kg) that exerts only modest physiological and behavioral effects in adolescent mice, most likely because at this developmental stage the mouse brain is partially impermeant to THC, as shown by the finding that intraperitoneal injections of THC (5 mg/kg) produced brain concentrations and a brain-to-plasma ratio of the drug that were 40–60% lower in adolescent relative to adult animals [49,55]. This may be at least partly due to the fact that the brains of adolescent mice contain higher mRNA levels of the multidrug transporter breast cancer resistance protein, which may extrude THC from the brain, and higher mRNA levels of claudin-5, a protein that contributes to blood-brain barrier integrity [49].

Immediately after the end of adolescent THC treatment, when the drug was cleared from brain tissue but was still present in fat depots, the mice expended more energy than did vehicle-treated controls. Even more notably, as they reached young adulthood (PND70) and completely eliminated the drug, THC-treated animals transitioned to an abnormal metabolic state whose features included decreased fat mass and white adipocyte area, increased lean mass, partial resistance to diet-induced obesity and dyslipidemia, enhanced thermogenesis, and blunted lipolysis. The latter two effects are especially noteworthy because they are suggestive of a pervasive impact on the body’s capacity to manage energy and nutrients. In THC-exposed mice, baseline body temperature was higher and the thermogenic response to cold or pharmacological adrenergic stimulation was all but suppressed. Lipolysis was similarly impaired, which raises the intriguing possibility that adolescent THC exposure might deprive the adult brain of critical adipose-derived nutrients which are mobilized by sympathetic activation under conditions of social or environmental stress.

The emergence of this distinctive phenotype depends on CB1 receptor activation in differentiated adipocytes of adolescent mice. Three sets of experiments support this conclusion [52]. First, when young-adult animals (PND 70-83) received the same THC treatment given to adolescents, their body-weight trajectory remained unchanged, and the limited transcriptional modifications observed in their adipose organ did not include expression of muscle-related genes. Second, the change in body-weight gain induced by THC was prevented by co-administration of a global CB1 receptor inverse agonist (AM251) or a peripheral CB1 neutral antagonist (AM6545), but not by the CB2 inverse agonist AM630. Lastly, and importantly, no such change occurred in adolescent mice lacking CB1 receptors in adipocytes that express the protein hormone adiponectin, which are thought to be fully differentiated [56,57].

Collectively, the findings outlined above suggest that daily exposure to THC in adolescence promotes—through a developmentally regulated mechanism that requires CB1 activation in differentiated adipocytes—a lasting state that resembles healthy leanness but results in fact from a dysregulation of stimulus-induced lipolysis and thermogenesis, two basic functions of the mature adipose organ. We refer to such a state as ‘pseudo-lean’.