Efficacy of Δ9 -Tetrahydrocannabinol (THC) Alone or in Combination With a 1:1 Ratio of Cannabidiol (CBD) in Reversing the Spatial Learning Deficits in Old Mice

Abstract

Decline in cognitive performance, an aspect of the normal aging process, is influenced by the endocannabinoid system (ECS). Cannabinoid receptor 1 (CB1) signaling diminishes with advancing age in specific brain regions that regulate learning and memory and abolishing CB1 receptor signaling accelerates cognitive aging in mice. We recently demonstrated that prolonged exposure to low dose (3 mg/kg/day) Δ9-tetrahydrocannabinol (THC) improved the cognitive performances in old mice on par with young untreated mice. Here we investigated the potential influence of cannabidiol (CBD) on this THC effect, because preclinical and clinical studies indicate that the combination of THC and CBD often exhibits an enhanced therapeutic effect compared to THC alone. We first tested the effectiveness of a lower dose (1 mg/kg/day) THC, and then the efficacy of the combination of THC and CBD in 1:1 ratio, same as in the clinically approved medicine Sativex®. Our findings reveal that a 1 mg/kg/day THC dose still effectively improved spatial learning in aged mice. However, a 1:1 combination of THC and CBD failed to do so. The presence of CBD induced temporal changes in THC metabolism ensuing in a transient elevation of blood THC levels. However, as CBD metabolizes, the inhibitory effect on THC metabolism was alleviated, causing a rapid clearance of THC. Thus, the beneficial effects of THC seemed to wane off more swiftly in the presence of CBD, due to these metabolic effects. The findings indicate that THC-treatment alone is more efficient to improve spatial learning in aged mice than the 1:1 combination of THC and CBD.

Low-Dose Delta-9-Tetrahydrocannabinol as Beneficial Treatment for Aged APP/PS1 Mice

“…In this regard, the THC doses used in this study were much lower than the dose that could induce the anxiety-like behavior in mice. Contrary to common belief, a handful of preclinical studies have revealed the beneficial effect of in vivo THC treatment at doses ranging of 0.002 and 3 mg/kg against the age-related decline in cognitive performance of aged mice [ 25 , 26 , 27 ]. Unlike the documented in vivo studies [ 25 , 26 , 27 ], the present study was carried out on aged APP/PS1 mice, and the animals were treated with 0.02 and 0.2 mg/kg of THC once every other day, which were lower than the doses of 1 and 3 mg/kg/d reported by Zimmer’s group [ 25 , 26 ].…”

“…Contrary to common belief, a handful of preclinical studies have revealed the beneficial effect of in vivo THC treatment at doses ranging of 0.002 and 3 mg/kg against the age-related decline in cognitive performance of aged mice [ 25 , 26 , 27 ]. Unlike the documented in vivo studies [ 25 , 26 , 27 ], the present study was carried out on aged APP/PS1 mice, and the animals were treated with 0.02 and 0.2 mg/kg of THC once every other day, which were lower than the doses of 1 and 3 mg/kg/d reported by Zimmer’s group [ 25 , 26 ]. Results of our study confirmed that aged APP/PS1 mice exhibited significantly elevated Aβ production and impaired spatial memory that recapitulated the early-stage AD in humans ( Figure 3 , Figure 4 and Figure 5 and Figure 6 C–G), suggesting that aged APP/PS1 mice are a better model than aged wild-type mice for evaluating the potential of THC in the treatment of AD.…”

“…In the previous in vitro study using N2a-variant Aβ protein precursor cells, we observed that THC treatment inhibited the production and aggregation of Aβ40, the production of phosphorylated tau protein, decreased the intracellular phospho-GSK3β expression level, and enhanced mitochondrial function [ 24 ]. Two recent in vivo studies by Zimmer’s group demonstrated that treatment with 1 and 3 mg/kg/d of THC through osmotic minipumps for 28 consecutive days significantly improved the special learning performance of male C57BL6/J mice at the ages of 12 and 18 months [ 25 , 26 ] whereas a 1:1 combination of THC and CBD (1 mg/kg/d for each) failed to achieve the same effect as THC monotherapy [ 26 ]. Another study showed that single-dose intraperitoneal (IP) administration of THC at 0.002 mg/kg restored the cognitive function in 24-month-old female wild-type mice [ 27 ].…”

Dos(e)Age: Role of Dose and Age in the Long-Term Effect of Cannabinoids on Cognition

“…Low doses of THC have been employed to reach this goal, i.e., to improve the cognitive performance of aged mice. Interestingly, while Bilkei-Gorzo [62] and Nidadavolu [63] obtained this result after chronic treatment, Sarne [64] demonstrated the positive effect of a single ultralow dose of THC (0.002 mg/kg) in aged female mice that lasted at least 7 weeks. They suggested that a single dose of THC was able to induce long-lasting structural alterations, likely through the involvement of Sirtuin-1, a protein deacetylase that was shown to be involved in synaptic plasticity, memory formation, learning capability, neuronal development, and neuroprotection, and that was found decreased in old mice [64].…”

“…According to this hypothesis, the paucity of papers investigating the effect of modulation of the endocannabinoid system in aged rodents seems to suggest that replenishing the lost endocannabinoid signaling would be beneficial to slowing down the physiological aging process (Table 4) [62][63][64]. Low doses of THC have been employed to reach this goal, i.e., to improve the cognitive performance of aged mice.…”