Words by David Miguel Ojeda
"All drugs aren't created equal."- Lucas Brothers
First thing to have in mind before talking about the potential neuroprotective o damaging properties associated with cannabinoids is that they’re classified as endogenous or exogenous. Consistent with the terminology, endogenous cannabinoids are a biological messenger, more specifically neurotransmitters synthesized by membranous lipids. The two principal endocannabinoids are anandamide and 2-arachidonoylglycerol, which bind to protein receptors of the overall endocannabinoid system (ECS): CB1 and CB2. These receptors are metabotropic, meaning they work by protein signaling and not ions like nicotinic receptors. There are more than 70 exogenous cannabinoids with varying distributions in the Cannabis plant but the mostly understood are: THC (Tetrahydrocannabinol) and CBD (Cannabidiol). The majority of studies conducted have been with these two main cannabinoids aiming to possibly find cellular mechanisms that might simulate the selectivity properties of endocannabinoids. Dr. Vincenzo Di Marzo, leading researcher on cannabinoids, favors the opposite investigative approach emphasizing the need of finding non-selective cannabinoids in order to modulate or “boost” the ECS through other cellular interactions. This change in direction augments studies focused on how different drugs relate with both exogenous and endogenous cannabinoids.
The majority of this cross-research has been on animal models, usually rat and mice. The reason for this is that rodent and human neuronal structures have evolved very similarly. One of those neural similarities is the mesolimbic pathway which is known as the “reward pathway”: the part of the brain that lights up with sex or when eating chocolate. Various neurotransmitters, mainly dopamine, make this pathway the main target for positive and negative reinforcement learning. This is basically what Pavlov used to train his dogs to salivate with a bell or how the educational system tries to get kids to study. The use of “conditioning”, to this date, has also been the main paradigm for studying how drugs influence behaviors.
Cocaine and heroin have been one of the drugs evaluated for their modulatory effects on the endocannabinoid system. The psychostimulant and opiate impact the “reward pathway” where CB1 receptors are highly expressed (Pickel et al.,2004). In a study with cocaine and heroin self-administration (rats press a lever to receive a drug), pre-exposure to THC reduced cocaine injections on a progressive schedule (more work for reinforcement) and remained unchanged on an FR1 schedule (less work for reinforcement) when compared to controls. They also found a reduction in open field locomotion, ultimately hypothesizing that the devaluation of cocaine by THC pre-exposed subjects was due to an increase in “anxiogenic effects” (Panlilio et al., 2016). This kind of conclusion should be critically evaluated since there’s extensive literature on how stress, or “anxiogenic effects”, increase cocaine self-administration, which would oppose the conclusion of the first study and validate THC's stress inhibitory qualities (Brodnik et al., 2007). For heroin there was no change on how fast subject learn to administer the drug but there was a significantly higher amount of intake (Panlilio et al.,2016). The hedonic effects of cannabinoids are pretty well known but their role in other stages of abuse are still obscure. Nonetheless, studies have found that cannabinoids attenuate opiate withdrawal symptoms such as nausea, restlessness and severe flu-like symptoms (Valverde et al.,2001). Opioid withdrawal is characterized by an increase in noradrenergic neuronal activity and pre-treatment with cannabinoid receptor agonist reduced this stress- induced transmission (Reyes et al.,2012). These and other studies provide insight on a new perspective of how cannabinoids are related to opiates.
The various approaches and results of scientific research on drug use are far from being deterministic or absolute. On the contrary, the evident obscurity and convoluted conclusions should function as a catalyst to break with the pre-conceived social notions about the effects of drugs. Terms like “gateway drug” just simply seem inconsistent and biased when there’s evidence of the therapeutic potential of cannabinoids. As individuals who aspire for a critical and better society, there’s an evident need for educating and talking about drugs through a research focus and not sensationalistic terminology.
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