CNR1

The CNR1 gene codes for cannabinoid receptor 1 (CB1). CB1 is one of the receptors responsible for stimulating the brain’s endocannabinoid system [R, R].

CB1 has many benefits. For example, CB1 activation may:

• Reduce stress and anxiety [R, R]
• Improve mood [R, R]
• Induce sleep [R]
• Promote brain development [R, R]
• Prevent brain cell damage [R, R]
• Relieve inflammation and pain [R, R, R, R]
• Lower blood pressure [R, R]

However, excessive CB1 activity may lead to negative outcomes. These include:

• Impaired memory, executive function, decision-making, and attention [R, R, R]
• Psychotic symptoms (delusions, hallucinations, paranoia, or disorganized thinking) [R]
• Increased food intake and insulin resistance [R, R]

Read: The Lectin Sensitive Gene

About The CB1 Receptor

The cannabinoid system plays an important role in neural plasticity, stress response, and learning and memory (R).

CB1 receptors are found in particularly high density in the hippocampus and amygdala, regions are known to play a role in emotional regulation and memory, and regions suggested playing a role in ADHD, emotional regulation, and other psychiatric disorders (e.g., bipolar, mood, anxiety disorders) (R).

The cannabinoid system is also important in dampening intestinal inflammation in humans.  It increases intestinal flow/motility (R).

CB1 receptors are found primarily in the brain and appear to impact predominately the GABA and Glutamate systems (R), but also affects the dopamine and serotonin systems.

As far as brain regions, the anti-anxiety effects of Cannabinoids seem to be from its effects on activating prefrontal cortex (PFC) and shutting down the amygdala, two structures commonly involved in anxiety.  Anxiety is typically associated with reduced activity in the Prefrontal and enhanced activity in the amygdala (R).

Cannabinoids in the prefrontal can enhance neuronal activity through a suppression of GABA release while suppressing glutamate release and excitability within the amygdala (dendrites) (R).

Psychological stress decreases anandamide (internal cannabinoid) levels in multiple limbic brain regions (involved with emotion, cognition), but more robustly in the amygdala -and the reduction lasts at least 24 hours (R).

It's believed that the reduced anandamide is responsible for at least some of the cortisol release from psychological stress (R).

Acute disruption of CB1 receptor reliably increases anxiety, impairs our ability to handle stress and activates the HPA axis (R).

Prolonged exposure to elevated glucocorticoids (cortisol, aldosterone), such as those induced by chronic stress conditions, significantly reduces hippocampal CB1 receptor binding site density (R), leading to lower cannabinoid function.

In fact, a recent study suggests that CB1 receptor deficiency may mimic the effects of chronic stress on emotional behavior (R).

Cannabinoids are also known to increase CCK release (R).

CB1 receptor activation decreases bone density (R).

CB1 receptor activation increases PPAR gamma (R).

Animal Studies on the CB1 Receptor

In rats, cannabinoids impair memory, increase slow wave sleep and rapid eye movement sleep at the expense of wakefulness and impair recognition memory  (R).

Mice without CB1 receptors appear more anxious (less GABA and higher glutamate function) and have an enlarged amygdala. Overall, strong converging genetic studies indicate that CB1 receptors are important for reducing anxiety, particularly during times of high stress periods (R).

In animals, increasing our natural internal cannabinoids (anandamide) also results in anti-anxiety benefits.  There are studies on cannabinoid activation and fear extinction (which is useful in PTSD).

However, unexpectedly, in some cases (such as alcohol withdrawal), activation of the CB1 receptor can contribute to anxiety (R).

In certain neurons and in the short term, CB1 can contribute to depression.  However, chronic CB1 blocking causes depression and actually decreases neurotransmitter and BDNF levels

Mice without CB1 receptors have reduced hippocampal (memory center) BDNF (R).

Mice without CB1 receptors reduce sugar intake more during stress than normal mice (R).

Chronic stress in mice without CB1 receptors show an enlarged fear center or amygdala (dendrites) (R).

Animal data indicate that CB1 activation has other weight gaining mechanisms besides increased food intake. CB1 activation prevents the breakdown and burning of fat cells for energy. In white fat, the activation of CB1 inhibits the secretion of adiponectin, and in brown fat CB1 activation decreases the thermogenic factor, UCP-1 (R).

Human Studies and The CB1 Receptor

Clinical studies with CB1 receptor activators have shown therapeutic benefit in the treatment of both generalized anxiety conditions and post-traumatic stress disorder (PTSD) (R).

In humans, regular cannabis use can effectively dampen activation of the amygdala in response to stressful conditions (R).

In humans, blocking the CB1 receptor helps people lose weight and also alleviates metabolic abnormalities associated with obesity; however, drugs tested for this were removed because people developed anxiety and depression (R).

There was approximately a threefold increase in anxiety symptoms compared to the placebo with one anti-cannabinoid drug, and these studies were all performed on individuals who had no history of psychiatric illness (R).

One case report discusses a severe bout of depression, which subsided following cessation of the drug (R).

The CB1 blocking drug made people more negative and pessimistic activated the HPA axis and blunted pleasure to things (anhedonia) (R).

Individuals who did not mount a 2-AG (internal cannabinoid and CB1 activator) response to stress exposure exhibited dramatically higher levels of cortisol (R).

Women with lower 2-AG had higher rates of depression (R).

People with more anandamide (internal cannabinoid and CB1 activator) after a stressful event had less cortisol (R).

Interestingly, people with higher Anandamide and 2-AG were found to be at higher risk for minor depression.  Researchers believe that these CB1 activators may curb the development of major depression (R).

It has also been found that individuals who had post-surgical depression also had low levels of Anandamide and 2-AG (R).

The lower anandamide levels in people, the higher the anxiety scores, both in a healthy population and in those with major depression (R).

A recent report found anandamide and 2-AG  are significantly lower in individuals with PTSD, compared to both healthy controls and those exposed to trauma who did not develop PTSD (R).

• Lectin Avoidance Diet
• Stress reduction – Prolonged exposure to elevated glucocorticoids (cortisol, aldosterone), such as those induced by chronic stress conditions, significantly reduces hippocampal CB1 receptor binding site density (R)
• Exercise -increases anandamide (which is our natural CB1 activator) (R),
• Nicotine or Galantamine (Activation of nicotinic receptors leads to increased cellular levels of calcium (Dani et al., 2001), which is known to stimulate release of endogenous cannabinoids such as anandamide (Piomelli, 2003) (R)
• Fish oil/DHA -increases cannabinoid synthesis and CB1 and CB2 receptors (R).