Responses to COVID
THE SCIENCE UNDERLYING ADOLESCENTS’ INCREASED RISK FROM CANNABIS Timmen Cermak, MD The onset of puberty introduces a period of rapid neurological development characterized by an explosion of synaptic connections, followed by over a decade of pruning, and an increase in axonal efficiency through myelinization. The THC in cannabis interferes with these neurodevelopmental processes by over-activating the brain’s endogenous cannabinoid system (ECS). The ECS is our largest neurotransmitter system. It consists of THC-like neurotransmitters such as anandamide and 2-AG, which are synthesized on demand from postsynaptic cell membrane fatty acids, and cannabinoid receptors (CB1R) that are located presynaptically. The ECS is activated by arrival of a wide variety of neurotransmitters at their postsynaptic receptors. Endocannabinoid neurotransmitters are synthesized in response and then diffuse back across the synaptic space to activate CB1R on the presynaptic neuron. Activation of CB1R produces negative feedback on the presynaptic neuron, decreasing the amount of neurotransmitter released by each axonal firing. This process of tonic negative feedback provides homeostatic regulation of brain chemistry.1 THC activates the brain’s cannabinoid receptors more strongly and longer than anandamide or 2-AG. As a result, CB1R downregulate with the first dose of THC, with CB1R upregulation to normal levels taking sufficient time that too frequent repetition of THC use leads to an accumulation of CB1R downregulation. Two weeks of daily THC downregulates CB1R in rats between 20-60% depending on the brain area.2 MRI demonstrates a 20% reduction in CB1R in the frontal lobes of humans using cannabis regularly that takes a month of abstinence to upregulate to normal levels.3 Chronic use leads to 44% reduction in hippocampal synapses.4 Diffusion Tensor Imaging (DTI) reveals increased anisotropy in the anterior commissure connecting the two hemisphere’s frontal lobes5 as well as in axons within each frontal lobe6, demonstrating disturbances in the flow of intracellular fluid from cell body toward synaptic terminals. These impacts of THC on frontal lobe structure and function are of special relevance to adolescence since the frontal lobes are the last brain region to fully mature. The earlier cannabis use begins, the more profound the impact. This fact is especially well illustrated by the often misinterpreted Dunedin Study.7 A 25-year longitudinal study of 1037 citizens of Dunedin, New Zealand born in 1972/1973 analyzed the long-term cognitive impacts of cannabis. Neurocognitive testing at age 13 established each individual’s baseline frontal lobe functioning, including overall IQ. The level of cannabis use was evaluated at ages 18, 21, 26, 32 and 38, when neurocognitive testing was 32
SAN FRANCISCO MARIN MEDICINE
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repeated. Careful reading of the article reporting this study reveals the following points about reductions in IQ caused by, or associated with, cannabis use: • The more persistently adolescent onset users continue using cannabis during adulthood, the greater is their reduction in IQ at 38.
• Those who began cannabis use earliest and continued throughout adulthood lost an average of 8 IQ points, which is sufficient to alter academic success and job opportunities. •
Stopping cannabis use did not fully restore neuropsychological functioning among adolescent onset former persistent cannabis users. Impairment was still evident for one year or more after cessation of use.
• The only individuals at age 38 who showed a reduction in IQ were those who were using marijuana at least once a week during adolescence. Heavy use during adulthood only did not reduce IQ. Tests measuring IQ are comprised of an aggregate of several subtests. Analysis of the Dunedin data reveals that impairments in early onset persistent users are detected across five areas: Executive Functioning, Processing Speed, Memory, Perceptual Reasoning, and Verbal Comprehension, with the most robust findings being decreased processing speed and impaired executive functions, confirming previous reports.8,9 More specifically, digit symbol testing reveals reduced processing speed, Wisconsin Card Sort reveals increased perseveration and reduced mental flexibility, and Stroop testing reveals increased impulsivity and difficulty ignoring distractions. Participants in the study also identified informants who “knew them well.” These informants reported significantly more everyday life problems with attention and memory among individuals with the most persistent cannabis dependence. This confirms that cognitive deficits caused by cannabis are of more than academic interest. Presenting this data is not intended to demonize cannabis, but rather to establish the inconvenient truth that frequent use is riskier for adolescents than for adults. The Dunedin study also documented that individuals with early onset cannabis use are more likely to be persistent users during adulthood. This finding is consistent with data showing that Cannabis Use Disorder (CUD) occurs more frequently and more quickly in early onset users.10 For example, an 11-year-old who starts using cannabis has over a 17% chance of being addicted by age 13. Starting at 12 has over a 16% chance of addiction by age 14. Starting at 16 runs almost a 13% risk of addiction by 18. Waiting until 18 to WWW.SFMMS.ORG
