How CB1 and CB2 Receptors Regulate Impulsive Behaviors

by , in CBD (Cannabidiol)

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Let’s face it: we’ve all gotten a little impulsive at some point in our lives. Acting without forethought or without regard for consequences is what’s known as impulsiveness or impulsivity and it’s a behavior that plays an important role in our lives.

Sometimes it works out great. A person might try a new cuisine and end up loving it. Or they might act on a whim and make a romantic connection with someone. When an impulsive action results in a positive outcome, it is known as functional impulsivity. In these cases, the behavior can help us adapt to uncertainty, complexity and rapidly changing environments. It may also allow us to act swiftly and seize an opportunity that might otherwise pass us by. When such actions have positive outcomes, they tend not to be seen as signs of impulsivity, but as indicators of boldness, quickness, spontaneity, courageousness, or unconventionality.

Yet on the other hand, impulsiveness can result in terrible consequences. Acting on a whim can sometimes cause us to say something inappropriate, or do something that we would later regret. This is what’s known as dysfunctional impulsivity which is a tendency to engage in behaviors that are premature, risky, and/or poorly thought-out, resulting in unwanted or negative outcomes. Impulsive behavior can negatively affect all facets of your life including relationships, finances, work, and health and make you appear out of control, erratic, or reckless. But on the bright side, negative outcomes may also teach us some of our most valuable lessons in life.

 

Impulsivity in Psychiatric Disorders and Drug Treatment Options

Not surprisingly, impulsivity is present in many psychiatric disorders such as bipolar disorder, personality disorders, attention-deficit hyperactivity disorder (ADHD) and substance use disorders. Clinical and neuroscience research has demonstrated that impulsivity cuts across many psychiatric disorders and therefore may represent a useful target for treatment. Individuals who struggle with impulse control may have deficient impulse control functioning and require pharmaceutical treatment. Some psychopharmacological options include the use of:

Selective serotonin reuptake inhibitors or SSRIs. These antidepressants are likely most effective in treating impulse aggression.

Serotonin–norepinephrine reuptake inhibitors or SNRIs. Another antidepressant, these drugs are typically prescribed for ADHD and could help with binge eating disorder.

Opioid Antagonists. These drugs may be helpful for alcohol use disorder, gambling disorder, and kleptomania.

Glutamatergic Agents. These may be helpful for certain substance use disorders, and trichotillomania (hair pulling disorder).

Atypical Antipsychotics. Prescribed for conduct disorder and shows promise for trichotillomania.

Lithium. Prescribed for conduct disorder and shows promise for gambling disorder.

Unfortunately, many of the conditions mentioned previously are notoriously difficult to treat. In many cases these drugs are highly ineffective in treating impulsivity related to gambling and substance addictions and are known to produce numerous side effects.

That’s why researchers have expanded their search to other pharmacotherapeutic targets like the endocannabinoid system (ECS).

 

The endocannabinoid system has garnered widespread attention for its role in moderating impulsive behaviors.

The “classic” ECS includes the cannabinoid receptors CB1 and CB2, the endocannabinoid ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes. It has garnered much interest in the regulation of impulsivity in recent years.

In an article for the 2015 publication Cannabinoids in Neurologic and Mental Disease, co-authors Joost Wiskerke from Princeton University and Tommy Pattij from the VU University Medical Center in Amsterdam wrote, “evidence suggests that particularly CB1 receptor activity in the prefrontal cortex and/or the ventral tegmental area may be relevant for the regulation of impulsive action. In these brain areas, cannabinoid signaling can modulate the activity of other neurotransmitter systems, including the dopamine, glutamate, and GABA neurotransmitter systems.”

Studies also point to the presence of functional CB2 receptors in the brain, which play a role in motivated behavior and dopamine transmission in the ventral striatum (part of the brain involved in reward processing). Also, because CB2 receptors found in the medial prefrontal cortex were found to control neuronal excitability and because activity in the frontocorticostriatal region of the brain is linked to impulsivity, CB2 receptors could play a functional role in modulating impulsive behavior. This evidence points to the need for new pharmacological experiments with CB2 receptor ligands to further unravel the involvement of CB2 receptors in different modes of impulsivity.

Finally, the authors concluded that considering the evidence, the ECS has emerged as an interesting pharmacotherapeutic target to improve impulsivity in psychopathology and neurological disorders.

 

Could CBD be the answer to impulsivity?

CBD is the second most common compound found in cannabis and is non-psychoactive compared to THC. This exogenous cannabinoid has been targeted as a potential treatment for a variety of conditions.

But if the ECS is a prime target for pharmacotherapies for impulsive-like behaviors, then does CBD have the potential to be a novel treatment?

Unlike THC, CBD doesn’t activate CB1 and CB2 receptors which likely explains its lack of psychotropic activity. However, in spite of its low affinity to these receptors, researchers have discovered that CBD can interact with these receptors at reasonably low concentrations and is actually capable of antagonizing CB1 and CB2 receptor agonists in the mouse brain.

Why is that important?

First, consider Rimonabant. This drug was an appetite suppressant and anti-obesity drug that worked as an inverse agonist for the cannabinoid receptor CB1. Although it was eventually banned worldwide for its serious side effects, this CB1 inverse agonist was effective in controlling impulsive behaviors related to overeating.

Meanwhile, CBD produces none of Rimonabant’s side effects but research has shown that it exhibits particularly high inverse agonist efficacy at the CB1 receptor.

Second, researchers have investigated the CB2 receptor’s role in impulsive behaviors such as motor hyperactivity, increased exploration, novelty seeking behavior, attention deficit and greater delay discounting and behavioral disinhibition in mice and found that treatment with the CB2 receptor antagonist AM630 produced a significant improvement in attention deficit, and reduced novelty seeking behavior.

Meanwhile, CBD has also been found to be a potent CB2 receptor antagonist as well. CBD’s ability to interact with the CB1 and CB2 receptors could help explain why researchers are finding success with using CBD to treat impulsive behaviors.

For example, impaired impulse control is a major risk factor for relapse which impedes recovery from addiction. However, in a presentation at the Neuroscience 2013 convention in San Diego, a team of researchers found that CBD may have significant potential to prevent drug seeking associated with various risk factors for relapse.

After treating male Wistar rats with a history of ethanol (alcohol) or cocaine self-administration, they found that CBD lowered cue- and stress-induced reinstatement of both ethanol – and cocaine-seeking over the 7-day treatment phase. In fact, these effects lasted for as long as 5 months after CBD treatment was terminated. The researchers also observed that CBD reduced anxiety-like behavior without producing motor impairment and reversed the high impulsivity profile of rats with a dependence history.

The researchers concluded that, “these observations suggest that cannabidiol restores normal function to neural mechanisms regulating incentive motivation, stress and anxiety and, thus, may have unique treatment drug potential beyond mere transient pharmacotherapeutic amelioration of vulnerability states. Additionally, since cocaine and alcohol addiction often go hand in hand, cannabidiol may provide a particularly effective strategy for the treatment of these substance use disorders.”

In another study published in the Journal of Psychopharmacology in 2012, researchers from Australia investigated CBD’s effects on rats treated with the N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801. MK-801 has been shown to stimulate motor activity (hyperactivity) and induce significant inhibition of social interactions in rats. These are just some of the signs of Hyperactive-Impulsive ADHD.

The researchers found that pretreatment with CBD not only normalized social investigative behavior but increased it beyond control levels. It also inhibited hyperactivity in MK-801 treated rats as well – showing that CBD had the ability to reverse MK-801 induced deficits in social interaction and hyperactivity.

Finally, in a study published in European Neuropsychopharmacology in 2016, U.K. researchers conducted a randomized-controlled trial using the oromuscal spray Sativex (1:1 ratio of CBD and THC) for patients with ADHD. The researchers found that Sativex improved hyperactivity/impulsivity, improved inattention, improved activity and cognitive performance, and emotional liability. They concluded that the data represented preliminary evidence that ADHD may represent a subgroup of individuals that gain cognitive enhancement and reduction of ADHD symptoms from the use of cannabinoids.

Although there is a need for further research, these studies clearly show that CBD could have a significant impact on impulsive behaviors and may be an interesting option for future drug development.

 

https://www.leafly.com/news/science-tech/cannabis-and-impulsive-behavior-how-cb1-and-cb2-receptors-regulat

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3252982/

http://www.hemplandusa.com

https://en.wikipedia.org/wiki/Impulsivity

http://sfn2013.conferencespot.org/55321-sn6-1.225941/t-001-1.227231/119-06-1.227270/119-06-1.227271

https://www.ncbi.nlm.nih.gov/pubmed/22495620

http://www.europeanneuropsychopharmacology.com/article/S0924-977X(16)30912-9/pdf

https://www.psychologytoday.com/blog/teen-angst/201510/the-blessings-and-curses-impulsiveness

http://www.psychiatrictimes.com/cme/psychopharmacological-options-treating-impulsivity/page/0/2

https://books.google.com.hk/books?id=utKcBAAAQBAJ&pg=PA343&lpg=PA343&dq=%22The+cannabinoid+system+and+impulsive+behavior%22&source=bl&ots=IsjbqhpOxA&sig=FNoD4wskEVLi24wNTEZzLNZgPV0&hl=en&sa=X&redir_esc=y#v=onepage&q=%22The%20cannabinoid%20system%20and%20impulsive%20behavior%22&f=false

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2219532/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2189767/

https://www.ncbi.nlm.nih.gov/pubmed/28576350

 

 

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Tags: Cannabidiol, CBD, CBD research, Endocannabinoid System

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