Summary: Fatty acid amide hydrolase (FAAH) inhibitors, a form of medication that boosts endocannabinoids, may be helpful in the treatment of PTSD. FAAH inhibition can improve the recall of fear extinction memories. The drugs could also help treat stress and other psychological disorders.
Source: Linkoping University
A medication that boosts the body’s own cannabis-like substances, endocannabinoids, shows promise to help the brain un-learn fear memories when these are no longer meaningful. These results, obtained in an early-stage, experimental study on healthy volunteers at Linköping University in Sweden, give hope that a new treatment can be developed for post-traumatic stress disorder, PTSD. The study has been published in the scientific journal Biological Psychiatry.
“We have used a medication that blocks the way the body breaks down its own cannabis-like substances, or ‘endocannabinoids’. Our study shows that this class of medications, called FAAH inhibitors, may offer a new way to treat PTSD and perhaps also other stress-related psychiatric conditions. The next important step will be to see if this type of medication works in patients, particularly those with PTSD”, says Leah Mayo, senior post-doctoral fellow and lead investigator on the study, which was carried out in the laboratory of Professor Markus Heilig at the Center for Social and Affective Neuroscience, CSAN, Linköping University.
Post-traumatic stress disorder, PTSD, arises in some – but not all – people who have experienced life-threatening events. A person affected by PTSD avoids reminders of the trauma, even when the danger is long gone. Over time, these patients become tense, withdrawn, and experience sleep difficulties. This condition is particularly common among women, where it is often the result of physical or sexual abuse. It is highly debilitating, and current treatment options are limited.
PTSD is currently best treated using prolonged exposure therapy, PE. In this treatment, patients are repeatedly exposed to their traumatic memory with the help of a therapist. This ultimately allows patients to acquire new learning: that these memories no longer signal imminent danger. Although clinically useful, effects of PE are limited. Many patients do not benefit, and among those who do, fears frequently return over time. The scientists who carried out the current study examined whether fear extinction learning, the principle behind PE therapy, can be boosted by a medication.
The researchers tested a pharmaceutical that affects the endocannabinoid system, which uses the body’s own cannabis-like substances to regulate fear and stress-related behaviors. The experimental medication results in increased levels of anandamide, a key endocannabinoid, in regions of the brain that control fear and anxiety. The medication accomplishes this by blocking an enzyme, FAAH (fatty acid amide hydrolase), that normally breaks down anandamide. The FAAH inhibitor tested by the researchers was originally developed for use as a pain killer, but was not effective enough when tested clinically.
This early-stage experimental study was randomised, placebo-controlled and double-blind, which means that neither the participants nor the scientists knew who was receiving the active drug (16 people) and who was receiving placebo (29 people). Participants were healthy volunteers. After taking the drug for 10 days, they underwent several psychological and physiological tests. In one of these, participants learned to associate a highly unpleasant sound, that of fingernails scraping across a blackboard, with a specific visual cue – an image of a red or blue lamp. Once they had learned to respond with fear to the previously innocuous image of the lamp, they were repeatedly re-exposed to it, but now in the absence of the unpleasant sound. This allowed them to unlearn the fear memory. The following day, the scientists measured how well participants remembered this new learning: that the lamp was no longer a threat signal. This process of un-learning fear is the same principle on which PE therapy for PTSD is based.
“We saw that participants who had received the FAAH inhibitor remembered the fear extinction memory much better. This is very exciting”, say Leah Mayo.
“Numerous promising treatments coming out of basic research on psychiatric disorders have failed when tested in humans. This has created quite a disappointment in the field. This is the first mechanism in a long time where promising results from animal experiments seem to hold up when put to test in people. The next step, of course, is to see whether the treatment works in people with PTSD”, adds professor Markus Heilig.
Funding: Financial support for the study has come from, among other bodies, the Swedish Research Council and the Canadian Institutes of Health Research. Pfizer AB supplied the FAAH inhibitor and placebo for the study free of charge: the company has not influenced the study design, analysis or presentation.
Leah Mayo – Linkoping University
The image is credited to Anna Nilsen/Linkoping University.
Original Research: Open access
“Elevated anandamide, enhanced recall of fear extinction, and attenuated stress responses following inhibition of fatty acid amide hydrolase (FAAH): a randomized, controlled experimental medicine trial”. Leah M. Mayo, Anna Asratian, Johan Lindé, Maria Morena, Roosa Haataja, Valter Hammar, Gaëlle Augier, Matthew N. Hill and Markus Heilig.
Biological Psychiatry. doi:10.1016/j.biopsych.2019.07.034
Elevated anandamide, enhanced recall of fear extinction, and attenuated stress responses following inhibition of fatty acid amide hydrolase (FAAH): a randomized, controlled experimental medicine trial
Post-traumatic stress disorder (PTSD), an area of large unmet medical needs, is characterized by persistence of fear memories and maladaptive stress responses. In rodents, elevation of the endocannabinoid (eCB) anandamide (AEA) due to inhibition of fatty acid amide hydrolase (FAAH) facilitates fear extinction and protects against the anxiogenic effects of stress. We recently reported that elevated AEA levels in people homozygous for a loss-of-function FAAH mutation are associated with a similar phenotype, suggesting a translational validity of the preclinical findings.
in this double-blind, placebo-controlled experimental medicine study, healthy adults were randomized to a FAAH inhibitor (PF-04457845, 4mg q.d.; n=16) or placebo (n=29) for ten days. On days nine and ten, participants completed a task battery assessing psychophysiological indices of fear learning, stress reactivity, and stress-induced affective responses.
FAAH inhibition produced a 10-fold increase in baseline AEA. This was associated with potentiated recall of fear extinction memory when tested 24 hours after extinction training. FAAH inhibition also attenuated autonomic stress reactivity, assessed via electrodermal activity, and protected against stress-induced negative affect, measured via facial electromyography.
Our data provide preliminary human evidence that FAAH inhibition can improve the recall of fear extinction memories and attenuate the anxiogenic effects of stress, in a direct translation of rodent findings. The beneficial effects of FAAH inhibition on fear extinction, as well as stress- and affect-related behaviors, provide a strong rationale for developing this drug class as a treatment for PTSD.