Indented sections in grey are written by a trained and published biochemist - Chad Sallaberry.

Researchers and scientists have been studying addiction for a long time now and have made great progress. However, there still remains a lot of unknowns in science around addiction and how it affects our overall motivation and behaviors. 

In the first article we spoke about dopamine, the chemical we produce inside our bodies, that is known by scientists as the molecule of “more”. We learned that dopamine is the driver molecule that motivates us and gives us the energy and fuel we need to accomplish things in life. 

We all naturally produce the molecule of more “dopamine'' inside our bodies. This is an amazing feat of evolution and is one of the primary drivers that has allowed humans to advance as a species. It has driven us to find shelter, food, plan ahead, and is what drives us to accomplish great things in life. It's also the source of our creativity, loves novelty, and is driven by our deepest beliefs about ourselves. 

Certain substances such as meth and cocaine have tremendous effects on our dopamine system causing HUGE spikes followed by huge crashes, leaving us with the feeling that we want more to satisfy our urges. 

The problem with dopamine is that it does not produce a feeling of fulfillment and is only concerned with driving us for MORE, whether that be through drugs, work, or even in our love life. 

For example, we are all familiar with the honey-moon phase of love and the feelings we have when we first meet a person at the beginning of a relationship. Dopamine is the main driving force for this feeling and we find ourselves going through a great deal of effort to be with this person. We all know how this love drunk feeling doesn’t last forever, and eventually it fades away. When this feeling fades, a lot of us decide that this is not the relationship for us and decide that there must be another person out there for us, who can make us feel that way again.

The truth is this feeling is just our biochemistry, specifically dopamine, that is excited about the novelty of new relationships, and what possibilities it may bring to us. Whenever this novelty fades, so does the feeling, and this is the reason why we begin to question our relationships. In order for us to change this pattern in our lives, we must begin shifting our biochemistry from dopamine to the “here and now” molecules like serotonin, oxytocin, and even endocannabinoids. Here and now molecules are the part of our biochemistry that allow us to enjoy the “here and now”. They are responsible for our feelings of connectedness, bliss, and enjoyment of the present moment.

It is important for us to understand the role of dopamine and how it motivates our behavior so we can harness its power towards the goals and things we want to achieve in life. Since dopamine is the molecule of more it means that it is never satisfied and will continue driving us back towards actions that it feels are the most important to us. If our dopamine is wired incorrectly towards drugs and substances that artificially boost our dopamine, then these will become the dominant forces that drive our behavior.

We believe that one of the biggest secrets, to the massive problem of addiction, is through our endocannabinoid system. Our ECS is the balancing system that influences and modulates all of the other systems inside the body. Once we understand the connection between our ECS and our dopamine system then we can begin to solve the problem of how to balance it, correct it, and point our motivation towards our goals and the things we want to achieve in life.  

In order for us to better understand what we can do to overcome our addictions we first must understand the mechanisms of how addiction interacts with the biochemistry inside our bodies.

The ECS has been shown to be able to manipulate dopamine signaling on the mesolimbic pathway¹. This is relevant as the mesolimbic pathway has been identified as one of the most notable areas in the brain that influences addictive tendencies. The reason for this is the amount of dopaminergic receptors present there². Dopamine is a neurotransmitter that belongs to the class of catecholamines³. It is notable for being the neurotransmitter responsible for “reward” behaviors in the brain. More specifically, it is responsible for both the craving and acceptance of these rewards. For example; when you anticipate having a bite of chocolate, finishing a project at work, or getting a raise, the feelings of both anticipation and subsequent euphoria is due to dopamine release from the synaptic cleft and subsequent binding to dopamine receptors⁴. These receptors can be classified as D1,D2,D3,D4,D5, based on genetic location and function⁵⁻⁶. For the purpose of addiction, D5 is not relevant. D2 and D1 on the other hand is especially relevant due to its impact on the learning process⁷. 

The dopamine system inside our bodies that science currently uses to measure the impact on our addictive behaviors on, is called the “mesolimbic dopamine system”. We know this because we have the most dopaminergic receptors inside this system. We release dopamine for both the “anticipation” of what we will get from a behavior as well as for the “reward” we get from that behavior. We also know that the ECS also has receptor sites located within this mesolimbic dopamine system, which can play a role in modulating and affecting this system.

To better understand the role dopamine plays in addiction, it is good to understand the pathway where the majority of addiction-based dopamine binding occurs. The mesolimbic system stems from the ventral tegmental area (VTA) to mainly the nucleus accumbens (NA)⁸. In the mesolimbic system, there are a plethora of interactions between dopamine and its receptors, with a notable amount of interactions involving the D2 receptor. A study has shown that the degree of D2 receptors in the mesolimbic pathway was positively correlated with the amount of value placed by an individual on a dopamine stimulating task⁹. So just based on receptor quantity, it will impact how value and reward are perceived by an individual. Another study showed how cocaine, morphine, and certain amphetamines can cause sensitization of dopaminergic neurons through this system. Administration of these drugs resulted in an increase of available dopamine in the cleft ¹⁰. As they are highly addictive substances, it makes sense that they would impact these neurons rich with dopamine. Another study showed that in chronic cocaine abusers, when they are not taking the drug, there is markedly less dopamine activity in areas rich with D2 receptors¹¹. Illustrating how long term abuse can negatively impact this system. Finally, one more thing to consider is dopamine’s role not just in reward and pleasure, but pain. We talked about how the mesolimbic pathway runs mainly from the VTA to the NA. However, another part of this pathway involves starting in the substantia nigra (SN) and going to the NA¹². This tract has been closely associated with dopamine’s regulation of pain, showing a second side to dopamine’s impact in reward in addiction¹³.

Scientists have located specific dopamine receptors known as D1 and D2 receptors that greatly influence our behavior and drive towards certain actions. The degree that our behavior affects our dopamine pathway is the degree to which our motivation or pull to this behavior will be. When studies have been conducted around users of meth, cocaine, and  morphine we see a SIGNIFICANT impact on our D2(dopamine) receptors which explains why these substances can be so ADDICTIVE and why it’s so hard for people to change this behavior. When users of these types of drugs stop using the substances, not only is there an intense pull back towards them but also the user will experience physical pain and withdrawal symptoms as well. This makes it even harder on the addicted user to overcome the destructive behavior in their life and is why so many people who are addicted to these substances have difficulties kicking them for good.

So in breaking down all of these studies, what exactly can we learn about dopamine’s role in addiction? First off, we can see its role in addiction by it being impacted both in the short term and long term by addictive substances. Its ability to fire and create “euphoric cravings” upon anticipation of a substance can draw an individual to an addictive substance, whether it be food, drugs, or even work. As well, the additional feeling of joy from accomplishing the task is similarly the result of mass dopamine firing. However, this fleeting pleasure is one of diminishing returns when abused. As we saw in long term cocaine users, the resting levels of dopamine actually decreased, instead of the increase seen with short term use. Last but not least, dopamine’s role in pain regulation. We hear of addicted individuals having a physical response from not having said addictive substance, and this makes sense because dopamine also plays a role in the regulation of pain.

Our tolerance to a specific behavior and drug can build over time. Tolerance is partly driven off of dopamine levels. When we repeat certain behaviors over time we begin to see less overall dopamine levels from the result of our behavior. We then seek more of that behavior to achieve the same rush and feeling we had the first time we engaged with it. The more we seek, the more our tolerance grows, and the more we engage in this behavior to achieve the same dopamine rush. If the addictive behaviors we have are also toxic for us, like drugs such as cocaine, then we are therefore collecting higher amounts of toxicity from our addictive behaviors inside the body. Obviously some addictive behaviors carry more consequences and have more adverse effects than others do. 

Now that we have an understanding of biochemistry and the different aspects that form and create our addictions. How can we go about resetting this biochemistry? How can we reduce our tolerance? And the strong pulls and urges we have back to our old patterns?

The ECS’s homeostatic nature is key to realizing how it can help repair some of the damage done to our native neural pathways caused by addiction to anything from work, to harmful drugs such as heroin. The ECS not only has receptors directly on the mesolimbic pathway, including the VTA and NAc, but on areas that directly influence activity in these regions, such as the prefrontal cortex (PFC), basolateral amygdala (BLA), hippocampus (HIPP), ventral pallidum (VP), globus pallidus (GP), dorsolateral striatum (DLSTr), bed nucleus of the stria terminalis (BNST) and central nucleus of the amygdala (CeA)i. This not only allows the ECS to modulate dopamine receptor expression via dopamine release, but also through impacting both glutamate (the main excitatory neurotransmitter) and GABA (the main inhibitory neurotransmitter).

We stated earlier that our endocannabinoid systems primary role is to create homeostasis and balance inside our bodies. Our endocannabinoid system has receptor sites in every system inside our body. These ECS receptor sites communicate together to maintain homeostasis and correct imbalances in our body, including helping maintain a healthy balance in our dopamine systems. Scientists and researchers have found endocannabinoid receptor sites directly in the regions of our brain that are responsible for addiction and our motivations. Given the nature of the ECS, we can conclude that the ECS plays an important role in balancing this system and restoring it back to baseline.

With this known, it is most useful to think of the ECS effect on addiction on three fronts; the ability to alter motivation towards a drug, the ability to restructure receptors at the synapse/alter synaptic plasticity, and finally to alleviate the urge to relapse with said substances. In terms of motivation, this is important because as we mentioned this is the key to how dopamine draws one towards a drug. It was shown that by either agonizing or antagonizing the CB1 receptor, there was an increase or decrease of drive reported in the model organism for ethanol (representative of alcohol), opiates, and nicotine¹⁴⁻¹⁵. In cocaine, both agonism and antagonism of the CB1 receptor resulted in a decreased motivation for drug administration¹⁶. This shows that manipulating CB1 can possibly remove the urge addicted individuals feel to use addictive substances. The second feature is the ability to restructure the synapse and alter synaptic plasticity. The ECS is responsible for regulating normal signaling in dopaminergic neurons. This signaling has been shown to be disrupted when cocaine and other drugs, such as opiates, are present. This disruption is considered a large reason why there is an increase of dopaminergic signaling following cocaine introduction, due to the interferences of the ECS to promote GABAergic (inhibitory) signaling. This shows how the ECS is responsible for maintaining the proper amount of dopamine in the synaptic cleft, which can directly influence synaptic plasticity¹⁷⁻¹⁸.  Finally, the ECS is implicated with preventing the urge to relapse. This is a theory based on two mechanisms. The first was mentioned above, how antagonizing the CB1 receptor can decrease motivation for drug use. The second is how averse or traumatic memories are often associated with drug use and abuse. The ECS plays a large role in formation and retaining memories, and it has been shown that by inhibiting CB1 signaling, you can reduce these aversive memories, helping prevent drug relapse¹⁹. Through understanding addiction and the different ways the ECS can interact with these dopaminergic neurons, it is evident to see the massive role the ECS plays in addition, and how manipulating it can help repair the damage caused by the neuronal re-wiring caused by addictive substances.

So how exactly can our endocannabinoid system affect our addictions? There are 3 primary methods that have been studied and observed by scientists.

Altering Motivation Towards the Addiction:

The draw, urge, and motivation towards a drug is caused by the chemical Dopamine. Research has shown that when our CB1 receptors are stimulated this affects Dopamine levels and our motivation back towards that behavior. Cannabinoids found in the Cannabis plant, such as THC and CBD, can either Antagonize, interfere with dopamine signaling, or can be an Agonist, stimulate dopamine signaling. This is the reason why Cannabis has been studied for both a potential addictive substance and also for its ability to HELP with addictions. In the next article we will be going into more depth on the specific cannabinoids and terpenes that interfere or stimulate our dopamine response.

Regulate the Firing of Dopaminergic Neurons:

When someone ingests cocaine, alcohol, or meets a new potential partner, dopamine is fired at an increased rate between one neuron to another. Although this can be exciting at the beginning, we must understand that this firing is also driving our motivation and behavior. When our dopamine systems are firing quickly towards behaviors that are not in our highest good this can be problematic in our lives. Our ECS helps regulate this rate of neuronal firing by a process that scientists call “retrograde signaling”. Dopamine is fired from synapse(one neuron) to postsynapse(another neuron) when it is released inside our body. The ECS uses “Retrograde Signaling” which means it can fire in the opposite direction from post-synapse to the synapse and therefore will modulate the rate of this dopamine firing.