April 20, 2012 (Arlington, Virginia) — New brain imaging research showing increased cannabinoid receptors in the brains of patients with posttraumatic stress disorder (PTSD) suggests a potential treatment target for the disorder.
Using positron emission tomography (PET), investigators from New York University Langone Medical Center in New York City found that expression of the CB1 cannabinoid receptor was increased in both the amygdala and the anterior cingulate of patients with PTSD vs healthy control participants.
“Believe it or not, at least to my knowledge there has not been a single pharmacologic treatment developed [for PTSD] to this day that is really based on neuroscience evidence,” principal investigator Alexander Neumeister, MD, from New York University Langone Medical Center, told delegates attending the Anxiety Disorders of America 32nd Annual Conference.
“We know from clinical practice that PTSD patients take everything that’s illegal for the [likely] reason that everything that’s illegal is better in terms of treatment effects than what is legal,” he added.
But whereas exogenous cannabinoids such as marijuana have been “highly and very successfully used” in the short term by many PTSD patients, their long-term use results in “very profound” changes in the endocannabinoid (eCB) system, which takes about 1 year to normalize after cessation.
“So while this is highly successful in the short run, it’s a misguided path as a PTSD treatment because the downstream effects are not what we want to see,” he said.
Instead, he and his colleagues are working toward the first clinical trials of a drug that they believe can block eCB metabolism, thereby normalizing the upregulation of cannabinoid receptors seen on imaging.
The imaging study showed that compared with healthy control participants (n = 15), PTSD patients’ (n =15) expression of the CB1 cannabinoid receptor was increased in both the amygdala and the anterior cingulate.
In addition to increased expression of the CB1 cannabinoid receptor, the investigators also found “very interesting” sex effects in which CB1 expression was higher in women than in men in the PTSD group and in the healthy control group.
Increased CB1 expression also correlated to some degree with increased anxiety and stress sensitivity, but not depression.
“That’s also interesting because when we look at depression studies, the evidence seems to be much stronger for CB1 receptor dysfunction in anxiety disorders than in depression.”
Higher expression of CB1 was also correlated with lower plasma levels of cortisol and anandamide, an eCB.
“We believe, and the basic pharmacological model would suggest this, that higher CB1 binding is occurring in response to compromised endocannabinoid function. So lower endocannabinoids leads to an upregulation of the receptor.”
To address this, Dr. Neumeister and colleagues are working on developing a medication that blocks fatty acid amide hydrolase (FAAH), an enzyme that is known to break down the endocannabinoid, anandamide.
“If you block this enzyme, you increase endocannabinoid production,” which in turn downregulates CB1 receptor expression, he explained.
A Lead Worth Following
Commenting on the study for Medscape Medical News, Charles B. Nemeroff, MD, PhD, from Leonard M. Miller School of Medicine, University of Miami, in Florida, said the study’s finding of eCB receptor upregulation in PTSD “is indeed a lead worth following up on in terms of the development of novel treatments for this devastating disorder.”
“The key here will of course be the development of cannabinoid receptor agonists without any abuse liability — not an easy task, as we have learned in studying agonists at other receptors, including opiates,” he said.
“Dr. Neumeister’s strategy to increase endocannabinoid availability by the use of anandamide obviates this problem and is a viable and testable research approach. Only by elucidating the pathophysiology of PTSD will we be able to develop novel and effective treatments for this devastating disorder.”
Dr. Nemeroff reports owning stock, stock options, and equity with CeNeRx, NovaDel Pharma Inc, PharmaNeuroBoost, Revaax Pharma, and Concept Therapeutics. He is on the Board of Directors of the American Foundation for Suicide Prevention (AFSP) and NovaDel Pharma Inc. He is on the Scientific Advisory Boards for CeNeRx, NovaDel Pharma Inc, PharmaNeuroBoost, AFSP, the National Alliance for Research on Schizophrenia and Depression, and Takeda. He holds patents on a device for the transdermal delivery of lithium and on a method for assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay. Dr. Neumeister has disclosed no relevant financial relationships.
Anxiety Disorders Association of America (ADAA) 32nd Annual Conference. Session 316R, presented April 13, 2012.