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In the past, we’ve discussed the wonderfully complex relationship between cannabis and various neurological disorders. As more and more research comes to light, it’s become alarmingly clear that the endocannabinoid system that regulates the human body’s response to cannabis is also inextricably involved in healthy brain functioning. Whether they’re keeping the brain’s immune system from attacking healthy cells or simply altering brain wave patterns, cannabinoid receptors are involved in the day to day of neuronal “management”.
In the state of California, one of the approved reasons a doctor can prescribe a medical cannabis recommendation is for “social anxiety”. This term is somewhat purposefully vague and seems to cover a lot of conditions. However, the impetus behind the inclusion is real: many cannabis patients specifically consume cannabis to combat anxiety about social situations that can be otherwise absolutely crippling. Something about consuming cannabis gives them the relaxation or edge to feel comfortable enough in social settings to function properly. Of course, it might be easy to chalk this up as an effect of absolutely any social drug; one could say the same about alcohol. However, there is an important differentiation here, being that cannabis, unlike alcohol, is not generally an inhibition lowering substance. Drunk drivers tend to drive too fast. Stoned drivers tend to observe the speed limit or drive too slowly. Regardless, without much legitimate research on the topic, we’ve been curious about this association between cannabis and social functioning. Thankfully, researchers from UC Irvine have released a new study that might shed some light on the answer. However, in this case, it comes in a study of the extreme social impairment that appears as a side effect of Autism.
Individuals suffering from Autism Spectrum Disorder “restrict themselves to repetitive behaviors” and illustrate “deficits in social reciprocity” and ability to communicate with others. The biological reason this happens is truly unknown. For a while, one research theory has been that oxytocin, a hormone and signaling molecule in the brain, is disregulated. This theory has gained more traction in recent years due to studies that indicate early treatment with oxytocin can decrease the likelihood of development of extreme social disorder. In an effort to understand why, scientists have begun to look at the systems that interact with oxytocin. As it turns out, *surprise* the endocannabinoid system directly interacts with oxytocin! In the case of this current study, researchers therefore decided to directly ask how manipulating the endocannabinoid system could affect Autism in mice.
To accomplish this, researchers selected two common models of Autism in mice: BTBR mice and fmr1 knockout mice. BTBR mice are mice that were bred specially to have pronounced deficits in social interaction. FMR1 knockout mice were genetically modified to be without the FMR1 gene, which creates Fragile X Syndrome, one of the most common causes of Autism Spectrum Disorder in humans. As we’ve explored in previous posts, cannabinoid receptors can be manipulated in multiple ways. Although we generally think of adding THC or another cannabinoid to trigger these receptors, we can also block the enzyme that takes up our body’s own version of THC, thereby allowing more to reach the receptors or stay bonded longer. In this case, the FAAH enzyme breaks down anandamide, the primary molecule our body produces that bonds to CB1 cannabinoid receptors. Researchers therefore decided to apply an FAAH inhibitor to see how this could affect social behavior (by increasing available anandamide), and in reverse, also tested an inverse agonist that would produce the opposite reaction. After applying these substances, researchers then submitted the mice to two tests. In the first, the social approach test, mice were allowed to habituate to a chamber with two chambers on either side. In one of these chambers, another mouse of the same age, sex, and weight was held, and in the other chamber, a previously unfamiliar object (in this study, a pencil cup) was presented. With this test, researchers measured the time spent in each chamber and could therefore make statements about each mouse’s preference for interest in new social activity. In the second test, the common elevated maze test, mice were placed at the center of a Plexiglas maze and allowed to freely explore. By comparing the time spent in open arms of the maze (two entrances) vs. closed arms of the maze (only one entrance), researchers could then establish the relative confidence of each mouse in exploring new areas, although not necessarily social confidence.
First as a control, researchers tested normally developing mice with and without the FAAH inhibitor (in this case URB597) and with and without the inverse agonist (in this case, AM251). Researchers found that neither substance significantly altered the outcomes of the social approach test. In contrast, when BTBR non-social mice were given the FAAH enzyme inhibitor, they spent significantly more time in the social chamber than before, effectively eliminating the deficit for social preference they had previously showed when compared to normally developing mice. Not surprisingly, after applying AM251, the inverse agonist which effectively shuts off the CB1 receptor, this beneficial change once again disappeared, indicating that the effect is in fact occurring through the CB1 cannabinoid receptor, which is activated by both anandamide and THC. Interestingly enough, the elevated plus maze results were mostly unaffected, indicating that the effect of the CB1 receptor is more social in effect than merely inhibition lowering. Proving that these results are not specific to BTBR mice, the same trends were all then confirmed once again in the fmr1 knockout mice model. Although these mice did not illustrate reduced social behavior in the social approach test when compared to normally developing mice, application of FAAH inhibitor never the less increased the amount of time the mice spent in the social chamber.
What does this mean for humans? Technically these are animal tests with imperfect models of human diseases. However, due to the robust nature of the data, in multiple mouse models and the confirmation of CB1’s involvement, we have a hunch that this is the start of a real break though in Autism Spectrum Disorder treatment and research. We also finally have some sort of basis for evaluating how cannabis is being used to treat social anxiety. If these results are accurate, perhaps it has to do with oxytocin signaling. Regardless, we look forward to keeping you updated as more research continues to define the relationship between the endocannabinoid system and social functioning.
Don Wei, Drake Dinh, DaYeon Lee, et al. Enhancement of Anandamide-Mediated Endocananbinoid Signaling Corrects Autism-Related Social Impairment. Cannabis and Cannabinoid Research (2016) 1:1. DOI: 10.1089/can.2015.0008.