In part one we reviewed the reward system and how opiates/cannabinoids operate through these central pathways. Let’s now learn more about this complex system.
THE OPIOID AND CANNABINOID SYSTEMS IN REWARD
The opioid system consists of three receptors, mu, delta, and kappa, which are activated by endogenous [within the human body] opioid peptides…The endogenous cannabinoid system comprises…endocannabinoids… and cannabinoid receptors CB1 and CB2. These systems play a major role in the control of pain as well as in mood regulation, reward processing and the development of addiction. Both opioid and cannabinoid receptors…are expressed throughout the brain reinforcement circuitry.
Opioid receptors and endogenous opioid peptides are largely expressed throughout the nervous system, noticeably within areas of the neurocircuitry of addiction associated with reward, motivation, or learning and stress (Mansour et al., 1995; Le Merrer et al., 2009; Koob and Volkow, 2010; Erbs et al., 2014).
The endocannabinoid system plays a key role in energy balance, modulation of pain response, with processing of central and peripheral pain signals, learning and memory, reward and emotions…Indeed, CB1 is highly abundant in the central nervous system in areas involved in reward, regulation of appetite and nociception [perception of painful stimuli] while CB2 was initially described as a peripheral receptor…Only few data are therefore available for the CB2 receptor in central function but growing evidence suggest a role in addictive processes, with an implication in cocaine, nicotine, or ethanol effects (Xi et al., 2011; Ignatowska-Jankowska et al., 2013; Navarrete et al., 2013; Ortega-Alvaro et al., 2013) 1.
There exists yet another pathway involving the endocannabinoid system itself. Recent studies have demonstrated that the primary rewarding effects of cannabinoids, nicotine, alcohol and opioids, are through the release of endocannabinoids in the ventral tegmental area (VTA, see above under The Reward System). The VTA is a part of the brain involved in reward signaling.
Not to be outdone, we also know that THC synergizes with morphine and codeine by releasing endogenous opioids 2. The consequences of this relationship have pharmaceutical companies scrambling for THC-like drugs which when added with an opiate may enhance their analgesic properties. This would enable drug companies to offer lower, safer, opiate doses while delivering superior pain relieving performance.
This is particularly cogent now that we understand how toxic acetaminophen (often combined with a narcotic) is to the liver. Percocet, for example, is oxycodone mixed with a measure of Tylenol (acetaminophen). Incredibly, acetaminophen overdose is now the leading cause of acute liver failure in the United States having surpassed alcohol which held first place for the last century. Look for emerging classes of cannabinoid/opioid drugs in the possible near future.
CANNABINOIDS, ETHANOL, NICOTINE, AND PSYCHOSTIMULANTS
The importance of the endocannabinoid system in drug reward varies greatly depending on the drug studied, with a pronounced role for the endocannabinoid system in opioid and ethanol reward and more subtle roles in nicotine and psychostimulant reward…It is also clear that activity of CB1 receptors is important for ethanol to produce maximal reinforcing effects (Mechoulam and Parker, 2003)…CB1 receptors may be critically involved in the rewarding effects of nicotine (Castane et al., 2002; Viveros et al., 2005) 3.
What this tells us is that the cannabinoid system (via CB1) is stimulated by many drugs of abuse (namely opiates, nicotine, and ethanol) which in turn activate the brain’s reward centers; and that the opioid and cannabinoid systems are major players in addictive disorders.
The main receptors: the CB1 and the mu receptor, interact with each other via their parent compounds: cannabis or endocannabinoids, and opiates or endogenous opiates, respectively. Both of these systems share neuroanatomical, neurochemical, and pharmacological characteristics. They have played roles in addictions to ethanol, nicotine, and psychostimulants such as amphetamine 4. That’s because all of these drugs of abuse, by definition, stimulate the same regions of the brain but by completely different mechanisms.
That is not to say that the nature of cannabinoid and opioid interaction might differ in the brain circuits mediating reward and in those mediating other pharmacological properties, such as antinociception (pain perception). 5
Clearly, these drugs also differ markedly in their perceived effects on mentation. In other words the highs from nicotine, marijuana, cocaine and opium are extremely different. However, when it comes to addiction, they all share a similar mechanism, and that’s why cannabis seems to offer help with all of these addictive materials.
In part three we’ll explore the habit forming properties of marijuana itself and how certain extremely enticing foods (yes, we all know what these are), act through the cannabinoid environment.