Boosting the endocannabinoid 2-AG in the brain can counteract opioid addiction while preserving their pain relief, a Weill Cornell Medicine study finds. This approach, tested in mice using the chemical JZL184, may lead to safer treatments for pain management.
The natural enhancement of chemicals produced by the body, known as endocannabinoids, may mitigate the addictive properties of opioids like morphine and oxycodone while preserving their pain-relieving effects, according to researchers from Weill Cornell Medicine in collaboration with The Center for Youth Mental Health at NewYork-Presbyterian. Endocannabinoids interact with cannabinoid receptors found throughout the body, which play a role in regulating functions such as learning and memory, emotions, sleep, immune response, and appetite.
Opioids prescribed to control pain can become addictive because they not only dull pain, but also produce a sense of euphoria. The preclinical study, published recently in the journal Science Advances, may lead to a new type of therapeutic that could be taken with an opioid regimen to only reduce the reward aspect of opioids.
In 2023, opioid abuse or overuse was responsible for more than 80,000 deaths, fueling a national crisis, according to the U.S. Centers for Disease Control and Prevention. Illegally obtained drugs were ultimately responsible for many deaths, but not all of them. “When someone has surgery and is taking opioids for pain management, there’s always a risk of developing a dependence on these drugs,” said senior author Dr. Francis Lee, chair of the Department of Psychiatry at Weill Cornell Medicine and psychiatrist-in-chief at New York-Presbyterian/Weill Cornell Medical Center.
The co-senior author is Dr. Anjali Rajadhyaksha, adjunct professor of neuroscience research in pediatrics at Weill Cornell Medicine and director of the Center for Substance Abuse Research at Lewis Katz School of Medicine at Temple University. The first author, Dr. Arlene Martinez-Rivera, was an instructor in Dr. Rajadhyaksha’s lab at the time of the study and is now an assistant professor at the Katz School of Medicine.
A Different Perspective
None of the researchers were studying opioids when they started this project. Dr. Lee was investigating the role of endocannabinoids in fear and anxiety. Next door, Dr. Rajadhyaksha was studying mouse models of cocaine addiction. They decided to work together when reports in the literature suggested that the opioid system could potentially interact with the endocannabinoid system’s complex network of chemicals and receptors.
Just as opioids stimulate the brain’s reward system to release dopamine, so do the naturally occurring endocannabinoids and related drugs, such as tetrahydrocannabinol (THC), the substance in marijuana that produces a “high.” Although they have similar effects, endocannabinoids and THC both act through cannabinoid receptors and opioids interact with different receptors.
Surprisingly, the findings also upend the central dogma in the opioid field that combining endocannabinoids and opioids should exacerbate addictive behaviors in a synergistic way. “By both of us not being members of the opioid field, we came up with the counterintuitive idea that one system might actually block the other system from having effects on reward,” said Dr. Lee, who is also a professor of neuroscience at the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine.
Surprising Interaction of Reward Systems
Running with that idea, Dr. Martinez-Rivera tested elevating the two main endocannabinoids— first, anandamide (AEA) and then 2-AG—in mice. “We got lots of negative results initially while studying AEA, and we were actually going to give up on the project,” she said. “But then we switched to 2-AG and got positive findings.” Increasing the levels of 2-AG counteracts the rewarding properties of opioids, dampening behaviors associated with opioid addiction, yet still controlling pain in a mouse model.
The researchers used a chemical called JZL184 that prevents 2-AG from breaking down thereby increasing the level of this endocannabinoid in the brain. In separate assays, the team found less addiction-associated behavior when mice were treated with a low dose of JZL184 before being given morphine or oxycodone.
In pain assays, mice treated with JZL184 still appeared to experience the pain-relieving effects of morphine and oxycodone. “This suggests that endocannabinoids and opioids may not act together in areas of the brain and spinal cord involved in analgesia,” Dr. Rajadhyaksha said. “In contrast, their interaction in brain regions is involved in decreasing reward and dependence.”
Additional experiments showed that 2-AG exerts its effect through the CB1 cannabinoid receptor in the ventral tegmental area, a group of neurons in the midbrain that plays a key role in reward and motivation. Elevating 2-AG levels also reduced dopamine signaling, a key element of the reward system.
“This is one of the first examples showing that engaging the endocannabinoid system can have an antagonistic effect on another reward system—in this case, the opioid system,” Dr. Rajadhyaksha said.
Potential drugs like JZL184 are currently being tested in clinical trials as possible treatments for anxiety disorders, so Dr. Lee is optimistic about the timeline for testing them in combination with opioids for pain management in humans. “We’re thinking about this methodically and working toward translating these preclinical findings to help patients,” Dr. Lee said.
Reference: “Elevating levels of the endocannabinoid 2-arachidonoylglycerol blunts opioid reward but not analgesia” by Arlene Martínez-Rivera, Robert N. Fetcho, Lizzie Birmingham, Jin Xu, Ruirong Yang, Careen Foord, Diego Scala-Chávez, Narmin Mekawy, Kristen Pleil, Virginia M. Pickel, Conor Liston, Carlos M. Castorena, Joshua Levitz, Ying-Xian Pan, Lisa A. Briand, Anjali M. Rajadhyaksha and Francis S. Lee, 29 November 2024, Science Advances.
DOI: 10.1126/sciadv.adq4779
This work was supported by the National Institutes of Health through grant numbers DA054368, MH123154, DA029122, R01 DA053261, R01 MH125006, R01 MH118934, R01 DA050454, DA042888, DA051529, DA042943, DA048635, DA047851, MH109685, MH118451, DA047265, DA049837, 5F30MH115622, and by The Center for Youth Mental Health at NewYork-Presbyterian, the Gelband Family Foundation, The Paul Fund, the Pritzker Neuropsychiatric Disorders Research Consortium, a Rohr Family Research Scholar Award, an Irma T. Hirschl/Monique Weill-Caulier Research Award, the Hope for Depression Research Foundation, the Rita Allen Foundation and the National Science Foundation through grant number GRFP #2139291.
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22 Comments
Even with all we know today about addiction, addicts are still seen by many (supposedly) sober people as simply being products of weak willpower and/or moral crime. At the same time, pharmaceutical corporations have intentionally pushed their own very addictive and profitable opiate resulting in immense suffering and overdose death numbers — the real moral crime — and got off relatively lightly and only through civil litigation.
Although always sympathetic, decades ago I’d also look down on those who had ‘allowed’ themselves to become heavily addicted to hard drugs or alcohol; yet, I myself have suffered enough unrelenting PTSD symptoms to have known, enjoyed and appreciated the great release upon consuming alcohol or THC.
The unfortunate fact is: the greater the induced euphoria or escape one attains from the self-medicated experience, the more one wants to repeat the experience; and the more intolerable one finds their non-self-medicating reality, the more pleasurable that escape will likely be perceived. In other words: the greater one’s mental pain or trauma while not self-medicating, the greater the need for escape from one’s reality, thus the more addictive the euphoric escape-form will likely be.
Especially when the substance abuse is due to past formidable mental trauma, the lasting solitarily-suffered turmoil can readily make each day an ordeal unless the traumatized mind is medicated. Not surprising, many chronically addicted people won’t miss this world if they never wake up.
Nevertheless, societally neglecting, rejecting and therefore failing people struggling with crippling addiction should never be an acceptable or preferable political, economic or religious/morality option.
They definitely should not be consciously or subconsciously perceived by sober society as somehow being disposable. Too often the worth(lessness) of the substance abuser is measured basically by their ‘productivity’ or lack thereof. They may then begin perceiving themselves as worthless and accordingly live and self-medicate their daily lives more haphazardly.
Meanwhile, most people, including me, self-medicate in some form or another (besides caffeine), albeit it’s more or less ‘under control’. And there are various forms of self-medicating, from the relatively mild to the dangerously extreme, that include non-intoxicant-consumption habits, like chronic shopping/buying, gambling, or over-eating.
If they’re anything like drug-intoxication self-medicating or addiction, it should follow that: the greater the induced euphoria or escape one attains from it, the more one wants to repeat the experience; and the more intolerable one finds their non-self-medicating reality, the more pleasurable that escape will likely be perceived. In other words: the greater one’s mental pain or trauma while not self-medicating, the greater the need for escape from one’s reality, thus the more addictive the euphoric escape-form will likely be.
With food, the vast majority of obese people who considerably over-eat likely do so to mask mental pain or even PTSD symptoms. I utilized that method myself during much of my pre-teen years, and even later in life after ceasing my (ab)use of cannabis or alcohol. Though I don’t take it lightly, it’s possible that someday I could instead return to over-eating.
You have some great points however I smoked for over 30 yrs started at age 9yrs old I hated the smell and hated smoking and tried for years to quit had nothing to do with escaping reality I was full blown addicted to the chemicals and would have LOVED not being addicted. After over 100 agonizing attempts I finally am 18yrs a non smoker. Total hell I still crave them from time to time. Sucks.
As been a recovering opiate addict, pills turned to heroin.. snorting to shooting. I became addicted at 40. Endured domestic violence from 15 to age 40. I live with chronic pain, I strived to go to college and obtain a good job to be placed on SSD. Which is a traumatic experience in and of itself. It would be awesome to get pain relief and not have an addiction receptors set off. I truely hope scientists are able to bring this to forefront. In Alabama we are still waiting on the approval of medical weed. Our physical system still has it tied up in court.
The one downside that I see is the body would still be physically addicted to the medication.
Well the reward system is needed with pain.. This just turns people back to fentanyl. We’re not getting away from nature
.try as we may
Also until we legalize heroin but triple down fentanyl possession, making it. 3x worse legal The drug Lords will send heroin in
Be too scared to bring in fentanyl
The heroin would become cheap
Fentanyl can become a thing of the past.
Increasing punishment for bringing or using drugs will deter nothing! Finding a way to block the opioid response will only send those looking for a high to other drugs. I’ve taken opioids for 38 yrs without problems other than tolerance. I don’t feel anything different, no high, no euphoria no reward. Other than my severe symptoms relieved giving me some quality of life. Most people who take opiates do because they are truly helping them and they do not become addicted. Most drug problems did not start with prescriptions overdoses were not due to prescriptions but mixing drugs
The lozenges themselves should be outlawed. I was prescribed those for years, and to me, the taste of the “candy” was better than I’ve ever experienced. I don’t feel a typical high when I take any opioids. My high is the relief of pain, itself.
But I will 100% guarantee that if a child finds an Actiq (fentanyl lozenge), they will consume the entire substance. It’s a lollipop from hell to children.
I don’t have the bitter tasting genes, so I wouldn’t know if it was bitter, but it has a taste that is much better than common lollipops. They would make millions if they just opened a candy store and sold those without containing drugs.
But with the fentanyl additive, it will kill a child. I often suspect a child finding the Actiq version, when I hear or read about childhood death of fentanyl.
It really should be stopped.
Good for you! You did it! I am so proud of anyone that kicks any kind of activity that makes them ashamed of themselves. I became an alcoholic after my first drink at 17 and tried many times to quit. I didn’t quit “for good” until I was 61. Part of me is still ashamed that it took so long but I did it! And I know “for good” only lasts as long as my vigilance to not take sobriety for granted lasts.
I’m 65 and finally quit smoking 5 years ago. I started when I was 11. My dad always smoked and I watched him die a terrible death of emphysema almost 23 years ago. Even after watching him die it was still so hard to stop. Unfortunately I have COPD and it’s not fun. Every time I get a cold, it goes right to my lungs. I have to use an inhaler in an nebuliser everyday. I’ve been very blessed though with 10 grandchildren and 8 great-grandchildren and the ones that are old enough. I beg them every day to never, Ever smoke, To this day, so far, none of them do, thank God. Congratulations on eighteen years off the cigarettes that is amazing.
Synthetic opioids re-wire the brain. It has nothing to do with euphoria or escaping ones life.
And this website censors comments by prohibiting one to post.
Scitech daily can go pound sand!
I am on methadone and oxycodone and the dosage that I take doesn’t have an effect on my chronic pain. I have had 2 surgeries on my back and I am scheduled to have another surgery on my back but I also have to have a surgery on my neck. I am not addicted to any medication or any other substance with the exception of marijauna . I have come to a point in my life where I no longer can smoke anymore and I also quit smoking cigarettes because of my breathing problems so I have to injest the herbal supplement by eating it. I live in Alabama and we have medical cannabis but the government has said that we will be able to get it from big pharmacy and I don’t think it is worth the risk of having side effects. So I have to grow a couple of plants each year to get what I need to take to control my pain and I have to keep my plants in a controlled environment so that I don’t get arrested. I am praying that Donald Trump will legalize cannabis on the federal level and we will be able to have it for free. I am 73 years old and I have been smoking cannabis since 1961 and yes I did it for a different reason I have found that it was worth it for the fact that I was able to get things done and it was very helpful to me
Well said. Thank you
I really appreciate your thoughts on addiction. I have always felt that in many cases the etiology can very often be traced back to one or another societal ills. Happy, fulfilled people rarely feel the need to seek out a daily psychological numbing agent just to get through it without being in misery. It’s a much deeper problem and it isn’t one of individual character flaws or personal weakness.
I am ” addicted ” to the Totally Reaction – free, Problem- free PAIN RELIEF I’ve experienced for 20 years with powerful Opioid medication. That I’ve been on Fentanyl Transdermal, Oxycodone or Hydromorphone ( and Meloxicam and Lyrica ) with absolutely No breathing problems, euphoria or somnalence ,having gotten no relief from 12 injections, TENS, or acupuncture. This puts me in a precarious position due Primarily, if not Exclusively because of Criminal Manufacturing and patients who somehow didn’t understand that they Can’t CHEW TRANSDERMAL PATCHES, Take More Pain Medication than prescribed, or divert Anything to Anybody Ever. Now, because of 80,000 Opioid- related deaths, many, if not most, pain management physicians have refused to prescribe effective, safe medication to Responsible Patients. They have ” thrown out the baby with the bathwater “.
Amen
The problem was never the pain meds, it was the abuse. Many had to turn to illegal street versions after suddenly being branded addicts.
I am going through the same situation!!
I am 63 years old. I am definitely in need of pain medications. I have life long pain and it’s one thing or another. The Drs. have to pull teeth to even be able to provide their patients with medication. I have been and am still looking to the government for an answer. In the meantime patients have their life tossed and turned not to see the light at any point. The quality of my life for the past 7 years have been absolutely miserable. I don’t know where to turn to start living life again.
Yes, the patients are left to suffer and the cost to lives has been extreme! Some of this comes to the trend nobody is responsible for their own actions, its always someone else’s fault. Its the Dr, pharmacy, drug company’s fault. Not theirs for misuse of medication. Now we patients are who got cut off for it. Its destroyed so many patients lives.
I take methadone for my pain management. My doctor had been trying to get me to take it for a long time but I didn’t like the idea of being lumped into the same group of addicts taking it to get off heroin,etc. But now I wish I had taken it when he first asked me about it. Its amazing. I’m allergic to steroids and most anti inflammatory meds and most muscle relaxers don’t do any good. Dr won’t prescribe Soma which is the only one that works. I have COPD so THC can’t be taken.
There are edibles and liquid forms of THC you can consume. They have drinks, food, topicals that you rub on. Even capsules. If interested look into it, no one should suffer everyday when there is solutions available.
Have you tried drops under the tongue? They can contain THC. I take it for motion sickness, and just one drop gives me several hours of relief.
I was on methadone years ago and it made me nauseous and caused headaches. It made me very tired. But I don’t feel the high with opioids. My high is in pain relief, however, I do get withdrawals when I go too long without it. Still, if it wasn’t for pain itself, I wouldn’t have any desire for opioids.
But back when I was on low dose methadone, the pharmacists treated me like a drug addict. I hated the ostracization. I hated picking up my scripts. If I could find a medication that doesn’t rot out my bowels, cause side effects or have a bad connotation, but relieves pain, I would love to try it.
I don’t believe these people who claim that pain is our friend, and we can control it with our minds. People who believe that obviously have a high pain tolerance. Mine has been very low all my life. I shouldn’t have to suffer in pain because some other dude was blessed with pain tolerance.
That would be like me saying, “Just psych yourself out of addiction! I did!”, when I apparently have a very low or no risk of addiction.
But you may want to consider trying CBD Full Spectrum drops. Do not buy off the internet! I tried that, and they all had additives. Try to get a medical marajuana card and go to a medical dispensary. They have pharmacists inside who can help you find the right formula for you; since there are so many species of plants that result in a variety of effects. Sativa, for instance is more about energy, while indica is about rest and relaxation (“In da couch”) 🙂. But if you explain your purpose for THC, they can help you find what you need.
I also don’t like how a large amount of THC makes me feel. With dementia throughout my family, it seems to give me a preview of what I may one day face. So I don’t like it. One drop has no side effects for me, thankfully.
Good luck!