Discovery sheds new light on marijuana’s anxiety relief effects

An international group led by Vanderbilt University researchers has found cannabinoid receptors, through which marijuana exerts its effects, in a key emotional hub in the brain involved in regulating anxiety and the flight-or-fight response.

This is the first time cannabinoid receptors have been identified in the central nucleus of the amygdala in a mouse model, they report in the current issue of the journal Neuron.

The discovery may help explain why marijuana users say they take the drug mainly to reduce anxiety, said Sachin Patel, M.D., Ph.D., the paper’s senior author and professor of Psychiatry and of Molecular Physiology and Biophysics.

Led by first author Teniel Ramikie, a graduate student in Patel’s lab, the researchers also showed for the first time how nerve cells in this part of the brain make and release their own natural “endocannabinoids.”

The study “could be highly important for understanding how cannabis exerts its behavioral effects,” Patel said. As the legalization of marijuana spreads across the country, more people — and especially young people whose brains are still developing — are being exposed to the drug.
Previous studies at Vanderbilt and elsewhere, Patel said, have suggested the following:

• The natural endocannabinoid system regulates anxiety and the response to stress by dampening excitatory signals that involve the neurotransmitter glutamate.

• Chronic stress or acute, severe emotional trauma can cause a reduction in both the production of endocannabinoids and the responsiveness of the receptors. Without their “buffering” effect, anxiety goes up.

• While marijuana’s “exogenous” cannabinoids also can reduce anxiety, chronic use of the drug down-regulates the receptors, paradoxically increasing anxiety. This can trigger “a vicious cycle” of increasing marijuana use that in some cases leads to addiction.

In the current study, the researchers used high-affinity antibodies to “label” the cannabinoid receptors so they could be seen using various microscopy techniques, including electron microscopy, which allowed very detailed visualization at individual synapses, or gaps between nerve cells.

“We know where the receptors are, we know their function, we know how these neurons make their own cannabinoids,” Patel said. “Now can we see how that system is affected by … stress and chronic (marijuana) use? It might fundamentally change our understanding of cellular communication in the amygdala.”

(Image: Shutterstock)

Brain-Imaging Study Links Cannabinoid Receptors to Post-Traumatic Stress Disorder—Findings Bring First Pharmaceutical Treatment for Ptsd Within Reach—

In a first-of-its-kind effort to illuminate the biochemical impact of trauma, researchers at NYU Langone Medical Center have discovered a connection between the quantity of cannabinoid receptors in the human brain, known as CB1 receptors, and post-traumatic stress disorder, the chronic, disabling condition that can plague trauma victims with flashbacks, nightmares and emotional instability. Their findings, which appear online today in the journal Molecular Psychiatry, will also be presented this week at the annual meeting of the Society of Biological Psychiatry in San Francisco.

CB1 receptors are part of the endocannabinoid system, a diffuse network of chemicals and signaling pathways in the body that plays a role in memory formation, appetite, pain tolerance and mood. Animal studies have shown that psychoactive chemicals such as cannabis, along with certain neurotransmitters produced naturally in the body, can impair memory and reduce anxiety when they activate CB1 receptors in the brain. Lead author Alexander Neumeister, MD, director of the molecular imaging program in the Departments of Psychiatry and Radiology at NYU School of Medicine, and colleagues are the first to demonstrate through brain imaging that people with PTSD have markedly lower concentrations of at least one of these neurotransmitters —an endocannabinoid known as anandamide—than people without PTSD. Their study, which was supported by three grants from the National Institutes of Health, illuminates an important biological fingerprint of PTSD that could help improve the accuracy of PTSD diagnoses, and points the way to medications designed specifically to treat trauma.

“There’s not a single pharmacological treatment out there that has been developed specifically for PTSD,” says Dr. Neumeister. “That’s a problem. There’s a consensus among clinicians that existing pharmaceutical treatments such as antidepressant simple do not work. In fact, we know very well that people with PTSD who use marijuana—a potent cannabinoid—often experience more relief from their symptoms than they do from antidepressants and other psychiatric medications. Clearly, there’s a very urgent need to develop novel evidence-based treatments for PTSD.”

The study divided 60 participants into three groups: participants with PTSD; participants with a history of trauma but no PTSD; and participants with no history of trauma or PTSD. Participants in all three groups received a harmless radioactive tracer that illuminates CB1 receptors when exposed to positron emissions tomography (PET scans). Results showed that participants with PTSD, especially women, had more CB1 receptors in brain regions associated with fear and anxiety than volunteers without PTSD. The PTSD group also had lower levels of the neurotransmitter anandamide, an endocannabinoid that binds to CB1. If anandamide levels are too low, Dr. Neumeister explains, the brain compensates by increasing the number of CB1 receptors. “This helps the brain utilize the remaining endocannabinoids,” he says.

Much is still unknown about the effects of anandamide in humans but in rats the chemical has been shown to impair memory. “What is PTSD? It’s an illness where people cannot forget what they have experienced,” Dr. Neumeister says. “Our findings offer a possible biological explanation for this phenomenon.”

Current diagnostics for PTSD rely on subjective measures and patient recall, making it difficult to accurately diagnose the condition or discern its symptoms from those of depression and anxiety. Biological markers of PTSD, such as tests for CB1 receptors and anandamide levels, could dramatically improve diagnosis and treatment for trauma victims.

Among the 1.7 million men and women who have served in the wars in Iraq and Afghanistan, an estimated 20% have PTSD. But PTSD is not limited to soldiers. Trauma from sexual abuse, domestic violence, car accidents, natural disaster, violent assault or even a life-threatening medical diagnosis can lead to PTSD. The condition affects nearly 8 million Americans annually.

These findings were made possible through the collaborative efforts of researchers at NYU School of Medicine, Yale School of Medicine, Harvard Medical School, the Department of Veterans Affairs National Center for PTSD and the University of California at Irvine.

(Image caption: Hypothetical cannabinoid receptor CB1 binding to anandamide)