New medication may be able to improve effects of psychological treatment for PTSD
August 29, 2019
Science Daily/Linköping 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 Over time, these patients become tense, withdrawn, and experience sleep difficulties.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.
https://www.sciencedaily.com/releases/2019/08/190829115420.htm
Pre-clinical study suggests path toward non-addictive painkillers
Researchers use a compound with a novel mechanism to treat pain in mice without tolerance or physical dependence
Science Daily/October 25, 2017
Indiana University
A pre-clinical study led by Indiana University scientists reports a promising step forward in the search for pain relief methods without the addictive side effects behind the country's current opioid addiction crisis.
The research, which appears in the journal Biological Psychiatry, finds that the use of compounds called positive allosteric modulators, or PAMs, enhances the effect of pain-relief chemicals naturally produced by the body in response to stress or injury. This study also significantly strengthens preliminary evidence about the effectiveness of these compounds first reported at the 2016 Society for Neuroscience Conference in San Diego, California.
"Our study shows that a PAM enhances the effects of these pain-killing chemicals without producing tolerance or decreased effectiveness over time, both of which contribute to addiction in people who use opioid-based pain medications," said Andrea G. Hohmann, a Linda and Jack Gill Chair of Neuroscience and professor in the IU Bloomington College of Arts and Sciences' Department of Psychological and Brain Sciences, who led the study. "We see this research as an important step forward in the search for new, non-addictive methods to reduce pain."
Over 97 million Americans took prescription painkillers in 2015, with over 2 million reporting problems with the drugs. Drug overdoses are the No. 1 cause of death for Americans under 50, outranking guns and car accidents and outpacing the HIV epidemic at its peak.
Medical researchers are increasingly studying positive allosteric modulators because they target secondary drug receptor sites in the body. By contrast, "orthosteric" drugs -- including cannabinoids such as delta-9-tetrahydrocannabinol (THC) and opioids such as morphine -- influence primary binding sites, which means their effects may "spill over" to other processes in the body, causing dangerous or unwanted side effects. Rather than acting as an on/off switch, PAMs act like an amplifier, enhancing only the effects of the brain's own natural painkillers, thereby selectively altering biological processes in the body that naturally suppress pain.
The PAM used in the IU-led study worked by amplifying two brain compounds -- anandamide and 2-arachidonoylglycerol -- commonly called "endocannabinoids" because they act upon the CB1 receptor in the brain that responds to THC, the major psychoactive ingredient in cannabis.
Although the PAM compound enhanced the effects of the endocannabinoids the study found that it did not cause unwanted side effects associated with cannabis -- such as impaired motor functions or lowered body temperature -- because its effect is highly targeted in the brain. The pain relief was also stronger and longer-lasting than drugs that block an enzyme that breaks down and metabolizes the brain's own cannabis-like compounds. The PAM alone causes the natural painkillers to target only the right part of the brain at the right time, as opposed to drugs that bind to every receptor site throughout the body.
The PAMs also presented strong advantages over the other alternative pain-relief compounds tested in the study: a synthetic cannabinoid and a metabolic inhibitor. The analysis' results suggested these other compounds' remained likely to produce addiction or diminish in effectiveness over time.
While the IU-led research was conducted in mice, Hohmann said it's been shown that endocannabinoids are also released by the human body in response to inflammation or pain due to nerve injury. The compounds may also play a role in the temporary pain relief that occurs after a major injury.
"These results are exciting because you don't need a whole cocktail of other drugs to fully reverse the pathological pain in the animals," Hohmann said. "We also don't see unwanted signs of physical dependence or tolerance found with delta-9-tetrahydrocannabinol or opioid-based drugs. If these effects could be replicated in people, it would be a major step forward in the search for new, non-addictive forms of pain relief."
The PAM used in the study was GAT211, a molecule designed and synthesized by Ganesh Thakur at Northeastern University, who is a co-author on the study. The lead author on the study was Richard A. Slivicki, a graduate student in Hohmann's lab in the IU Program in Neuroscience and Department of Psychological and Brain Sciences. Additional authors on the study are Zhili Xu, an IU research fellow; Ken Mackie, IU professor and director of the Gill Center; Pushkar M. Kulkarni at Northeastern University; and Roger G. Pertwee at the University of Aberdeen, Scotland.
This study was supported in part by the National Institutes of Health.
https://www.sciencedaily.com/releases/2017/10/171025105038.htm
Chili peppers and marijuana calm the gut
The active ingredients in both hot peppers and cannabis calm the gut's immune system
April 24, 2017
Science Daily/University of Connecticut
You wouldn't think chili peppers and marijuana have much in common. But when eaten, both interact with the same receptor in our stomachs, according to a paper by UConn researchers published in the April 24 issue of the journal Proceedings of the National Academy of Sciences. The research could lead to new therapies for diabetes and colitis, and opens up intriguing questions about the relationship between the immune system, the gut and the brain.
Touch a chili pepper to your mouth and you feel heat. And biochemically, you aren't wrong. The capsaicin chemical in the pepper binds to a receptor that triggers a nerve that fires off to your brain: hot! Those same receptors are found throughout the gastrointestinal tract, for reasons that have been mysterious.
Curious, UConn researchers fed capsaicin to mice, and found the mice fed with the spice had less inflammation in their guts. The researchers actually cured mice with Type 1 diabetes by feeding them chili pepper. When they looked carefully at what was happening at a molecular level, the researchers saw that the capsaicin was binding to a receptor called TRPV1, which is found on specialized cells throughout the gastrointestinal tract. When capsaicin binds to it, TRPV1 causes cells to make anandamide. Anandamide is a compound chemically akin to the cannabinoids in marijuana. It was the anandamide that caused the immune system to calm down. And the researchers found they could get the same gut-calming results by feeding the mice anandamide directly.
The brain also has receptors for anandamide. It's these receptors that react with the cannabinoids in marijuana to get people high. Scientists have long wondered why people even have receptors for cannabinoids in their brains. They don't seem to interact with vital bodily functions that way opiate receptors do, for example.
"This allows you to imagine ways the immune system and the brain might talk to each other. They share a common language," says Pramod Srivastava, Professor of Immunology and Medicine at UConn Health School of Medicine. And one word of that common language is anandamide.
Srivastava and his colleagues don't know how or why anandamide might relay messages between the immune system and the brain. But they have found out the details of how it heals the gut. The molecule reacts with both TRPV1 (to produce more anandamide) and another receptor to call in a type of macrophage, immune cells that subdue inflammation. The macrophage population and activity level increases when anandamide levels increase. The effects pervade the entire upper gut, including the esophagus, stomach and pancreas. They are still working with mice to see whether it also affects disorders in the bowels, such as colitis. And there are many other questions yet to be explored: what is the exact molecular pathway? Other receptors also react with anandamide; what do they do? How does ingesting weed affect the gut and the brain?
It's difficult to get federal license to experiment on people with marijuana, but the legalization of pot in certain states means there's a different way to see if regular ingestion of cannabinoids affects gut inflammation in humans.
"I'm hoping to work with the public health authority in Colorado to see if there has been an effect on the severity of colitis among regular users of edible weed," since pot became legal there in 2012, Srivastava says. If the epidemiological data shows a significant change, that would make a testable case that anandamide or other cannabinoids could be used as therapeutic drugs to treat certain disorders of the stomach, pancreas, intestines and colon.
It seems a little ironic that both chili peppers and marijuana could make the gut chill out. But how useful if it's true.
https://www.sciencedaily.com/releases/2017/04/170424152537.htm