One study in healthy humans linked CB1 polymorphisms (small variations in a gene that are not directly linked to any particular deficit) to variations in the time people spent looking at happy faces (Chakrabarti and Baron-Cohen, 2011). As this ‘gaze duration’ is a measure for autism, the endocannabinoid system may be implicated in autistic behavior.
Similarly, CB2-mediated signaling was significantly upregulated in peripheral blood mononuclear cells obtained from autistic children (Siniscalco et al., 2013).
In addition, the endocannabinoid synthesizing enzyme NAPE-PLD was upregulated and the endocannabinoid degrading enzyme FAAH was downregulated in autistic children (Siniscalco et al., 2014), suggesting raised levels of endocannabinoids.
Treatment with GcMAF normalized NAPE-PLD and FAAH levels and reduced macrophage activation (Siniscalco et al., 2014) further underlining the involvement of the endocannabinoid system in autism.
In a mouse model of autism (BTBR T+tf/J mice), THC was found to alleviate aberrant locomotor behavior associated to autism (Onaivi et al., 2011).
Interestingly, in another genetic mouse model of mental retardation and autism (FMR1 knockout), blockade of CB1 normalized cognitive defects (Busquets-Garcia et al., 2013), suggesting CB1 may be a therapeutic target for autism treatment.
In another mouse model the human autism-associated R451C mutation of the neuroligin-3 gene was studied.
Neuroligin-3 was found to be specifically required for tonic- but not phasic endocannabinoid signaling (Földy et al., 2013), strengthening the association between autism and the endocannabinoid system.
In a rat model of autism (Valproic Acid model), GPR55, PPARα and PPARγ were reduced in several brain regions involved in higher cognitive functions (frontal cortex and hippocampus). Also, hippocampal Anandamide, OEA and PEA were increased after social exposure (Kerr et al., 2013) once more stipulating the involvement of the endocannabinoid system in autism.
It should be noted however, that no good rodent models exist for autism, and thus that these results should be treated with care.
Some descriptive studies have linked Measles, Mumps and Rubella vaccination with increased risk of developing autism.
Although epidemiological studies do not support this link, acetaminophen/paracetamol which is often given to suppress mild fever after vaccination, might precipitate autism through abnormal activation of the endocannabinoid system.
The abnormal endocannabinoid system in turn may cause autism through immune dysregulation (Schultz, 2010).
Busquets-Garcia, A., Gomis-González, M., Guegan, T., Agustín-Pavón, C., Pastor, A., Mato, S., Pérez-Samartín, A., Matute, C., de la Torre, R., Dierssen, M., et al. (2013). Targeting the endocannabinoid system in the treatment of fragile X syndrome. Nat. Med. 19, 603–607.
Chakrabarti, B., and Baron-Cohen, S. (2011). Variation in the human cannabinoid receptor CNR1 gene modulates gaze duration for happy faces. Mol. autism 2, 10.
Földy, C., Malenka, R.C., and Südhof, T.C. (2013). autism-Associated Neuroligin-3 Mutations Commonly Disrupt Tonic endocannabinoid Signaling. Neuron 78, 498–509.
Kerr, D.M., Downey, L., Conboy, M., Finn, D.P., and Roche, M. (2013). Alterations in the endocannabinoid system in the rat valproic acid model of autism. Behav. Brain Res. 249, 124–132.
Onaivi, E.S., Benno, R., Halpern, T., Mehanovic, M., Schanz, N., Sanders, C., Yan, X., Ishiguro, H., Liu, Q.-R., Berzal, A.L., et al. (2011). Consequences of cannabinoid and monoaminergic system disruption in a mouse model of autism spectrum disorders. Curr. Neuropharmacol. 9, 209–214.
Schultz, S.T. (2010). Can autism be triggered by acetaminophen activation of the endocannabinoid system? Acta Neurobiol. Exp. (Warsz.) 70, 227–231.
Siniscalco, D., Sapone, A., Giordano, C., Cirillo, A., de Magistris, L., Rossi, F., Fasano, A., Bradstreet, J.J., Maione, S., and Antonucci, N. (2013). cannabinoid receptor type 2, but not type 1, is up-regulated in peripheral blood mononuclear cells of children affected by autistic disorders. J. autism Dev. Disord. 43, 2686–2695.
Siniscalco, D., Bradstreet, J.J., Cirillo, A., and Antonucci, N. (2014). The in vitro GcMAF effects on endocannabinoid system transcriptionomics, receptor formation, and cell activity of autism-derived macrophages. J. Neuroinflammation 11, 78.