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How Cannabis Enhances the Effects of Opioids

March 29, 2018
Pain is the number one reason people seek medical care—and quite possibly medical cannabis—and it affects more people than diabetes, heart disease, and cancer combined. In the clinic, pain is often treated with opioid drugs like OxyContin, Percocet, Vicodin, and Fentanyl. This has traditionally been a first-line treatment approach because they work—at first.

On their own, low doses of cannabis or opioids do not relieve pain, but in combination, they do.

But opioid use has spiraled out of control and we find ourselves amidst an opioid epidemic that cost the U.S. $504 billion in 2015 alone, claims the lives of over 30,000 annually, and damages the quality of life of countless others. Clearly, we must do something to curb the growing opioid epidemic, but unfortunately, it appears that the federal government is ignoring one of its strongest solutions: cannabis.

Related

This Medical Cannabis Researcher Explains How Marijuana Can Combat the Opioid Epidemic

We know that cannabis is effective in treating chronic pain. We understand its ability to effectively substitute for opioid medication, and that CBD can combat opioid abuse by reducing its rewarding effects. Here, we’ll take a look at how cannabis enhances the effects of opioids—an interaction worth exploring in an era plagued by opioid dependence and overdose.

CB1 Receptors Are Important for the Effects of Opioids

The original natural painkiller, opium, dates back to 3,400 B.C. in Southwestern Asia. Cannabis followed a half a century later. It’s unclear if they were ever used together to treat pain, but consumers would have found profound pain relief from low doses of both drugs when used together.

Science is revealing that the cannabinoid and opioid systems can work synergistically to achieve greater pain relief. This interaction becomes clear when you consume super low-doses of THC or opioids; on their own, these low doses do not relieve pain, but in combination, they do.

When THC and prescription opioids are co-administered, the same level of pain relief is achieved with lower opioid dosage. This can prevent some of the negative side effects of opioid treatment and allow patients to reduce opioid use. (Photo credit: Amy Phung/Leafly)

For instance, a recent double-blinded, placebo-controlled study (the gold-standard in clinical research) investigated the effects of low-dose cannabis (5.6% THC) and the opioid drug, oxycodone (2.5 mg) on pain thresholds in human subjects. Neither THC nor oxycodone independently affected pain, but when used in combination, participants were able to withstand higher levels of painful stimuli consistent with substantial pain reductions.

To achieve these pain-relieving effects, could THC’s primary target, cannabinoid type I (CB1) receptors, and opioid receptors be working together? There’s evidence that they do.

Take mice that have been genetically engineered to not express CB1 receptors (that’s right, you can create mice without CB1 receptors!). These mice enjoy nicotine, amphetamines, cocaine, and they’ll eagerly press a lever to self-administer these drugs. But they won’t do it for the opioid drug, heroin. Normal mice do, but not the mice without CB1 receptors. This tells us that CB1 receptors are important in the euphoric effects of heroin. Extending these findings to pain, blocking the activity of CB1 receptors weakens morphine’s ability to reduce pain.

Related

America’s Opioid Crisis: Can High-CBD Cannabis Combat Pain and Reduce Addiction Rates?

So CB1 receptors are important in opioid drugs’ ability to make you feel good and reduce pain.

These are two critical elements driving the opioid epidemic and an integral component of the pain experience. After all, pain is subjective. The severity of pain is determined by numerous factors including:

  • Incoming signals from an injured area (e.g., knee inflammation)
  • Cognitive factors (e.g., attention to injury)
  • Contextual factors (e.g., do you expect it to be painful?)
  • Mood factors (e.g., are you already depressed or anxious?)
  • Chemical factors (e.g., endocannabinoid or opioid system function)
  • Genetics (e.g., are you predisposed to have low opioid levels?).

Opioid medications predominately target two of these factors. First, they weaken the strength of the pain signals from the site of injury to your brain, and second, they improve your mood by boosting levels of the pleasurable dopamine chemical.

Related

Cannabis as an Opioid Exit: 5 Real-Life Stories

These dual effects make stopping opioid use difficult, especially when repeated opioid use leads to long-term brain changes that reduce the number of opioid receptors in the brain and body. Lower numbers of opioid receptors enable stronger pain signals to enter your brain and reduces the levels of mood-boosting dopamine. This is the phenomenon of tolerance, which leads to increased opioid consumption, the transition to stronger drugs, and increased risk for overdose and death.

CB1 and Opioid Receptors Interact

Pain signals begin at the site of injury, then make their way into the spinal cord and travel up to the brain. After exiting the spinal cord, they activate brain cells in critical pain processing regions including the periaqueductal gray, thalamus, and cortex. If you were to design a pain medication, you’d try to (a) weaken pain signals as they enter and exit the spinal cord and (b) dampen their effect in the brain.

CB1 receptors and opioid receptors, specifically the µ-opioid receptors that modulate pain, are found expressed together in the spinal cord, the periaqueductal gray, and the brain’s reward centers. That is, you find these two receptors together in all the places that are important in pain relief.

Related

The Biology of Cannabis vs. Opioids for Pain Relief

Once activated by either opioids or cannabinoids, they share many common downstream signaling features. In fact, if you activate one receptor, it affects how the other one responds. This has led many to believe that the CB1 and µ-opioid receptors physically interact. The consequence of this interaction depends on where in the brain they’re found, but in some cases, it means that their co-activation by low amounts of drug leads to a stronger effect than what would be predicted by activating either CB1 or opioid receptors on their own.

While the physical interaction between CB1 and opioid receptors is likely important for the pain-relieving effects of cannabis and opioids, cannabis can enhance the effect of opioids by also increasing the body’s endogenous opioid levels, themselves. The effect is reciprocal; THC can increase opioid levels to help relieve pain, and using drugs to boost the body’s own opioid levels enhances THC’s pain-relieving effects.

Related

Is Cannabis Better for Chronic Pain Than Opioids?

So, taken together, cannabis can increase opioid’s pain-relieving effects by modulating opioid-receptor signaling directly through physical interaction between CB1 and opioid receptors, and by increasing the body’s own opioid levels.

What About CB2 Receptors?

THC’s other primary target, the CB2 receptor, can also interact with the opioid system but these effects are less well-studied. The greatest evidence for CB2’s effects on opioid signaling occurs at the site of injury, where activating CB2 receptors stimulates the release of endogenous opioids to help dampen the pain where it starts. As discussed in part one of this series, CB2 receptors play a large role in regulating inflammation.

 

Lead image: gcsherman1/iStock

Josh Kaplan's Bio Image

Josh Kaplan

Josh Kaplan, Ph.D., is an Assistant Professor of Behavioral Neuroscience at Western Washington University. He is a passionate science writer, educator, and runs a laboratory that researches cannabis' developmental and therapeutic effects.

View Josh Kaplan's articles

4 part series

  • Kris Shaw

    Thats great n all i love pot but people forget a great deal of people cant handle marijuania ever and they never well alot of people take even a hit of any strain well freak out get panic attacks so marijuania as a pain medicine may work for some with opiates but not all so that still leaves millions needing opiates alone

    • Jon holmes

      It sounds to me like you are creating a convenient excuse to not stop abusing opioids the anxiety can be easily regulated

      • William

        Figure out what your anxiety is about without opioids. opioids are for serious pain; Papaver somniferum is a very beautiful and potentially dangerous flower. Pain starts with the first bicycle wreck you got in. The human body was not meant to go as fast as our machines now allow us. And when you get older, such can be a problem. There are many situations that opioid can address very well, but, and it can be very dangerous. Use wisely, under a doctor’s care…oh, wait, the doctors are all freaked out,having been terrorized, and doctors are to be reported by all pharmacists. Seig Heil, a little more than I care for. Papaver Somniferum is the oldest medicinal plant used; opioid has been used by hundreds of millions, quite successfully and well. Problems happened when those bright, pesky German chemist/doctors figured out how not only to separate morphine, the primary alkaloid among about 40, but, and make them stronger “synthetics”. Then diacetyl morphine, then the fentanyls… the race was on to “synthesize”. Simple opium must be delightful. I am rather practiced in the withdrawal syndrome, so I am, as well. Opium withdrawal, if gone that far (probably a week; if you make the decision to go there), you will be at least dependent quickly. Withdrawal varies for substance amount, ingestion route, and substance. Withdrawal: Opium, (I can only imagine) is like a cold, or bad flu at worst. Morphine is brutal, depending on how far you go. Don’t, you won’t like it. But, and only if you must, serious. Withdrawal from fentanyl will be brutal without assistance. The problem is that these chemicals have gotten so out of control; the suppression of legal opioids has only benefitted the heroin dealers, and I don’t want to even know their names. I can only get out loud staying honest with all. Always (my bona fides are at the top, and I am no longer naive. Read it yourself. I know.) I know. I apologize to Josh, but and I rarely am motivated by such a well written article; researched with great truths. Thank you, Josh Kaplan

    • lovingc

      I have seen people not want to use cannabis due to allergy but not because of anxiety. Of course I have only used for the past 45 years.

    • Open Minds

      The author pointed out that the study only used 5.6% THC in combination with 2.5 mg of oxycodone. 5.6% THC won’t freak people out. And for those that do, black pepper can minimize it.

    • Molly Swipas

      ”alot of people take even a hit of any strain well freak out get panic attacks”

      Besides your ”my parents are brother & sister” grammar this simply isn’t true.

      You need to lay off the pot and go back to 2nd grade.

      • Rachel Schooff

        It’s “a lot”…Alot is not a word
        Will freak out or well freak out?
        You just need to go to school.

    • Niels Andrews

      I have seen that if you balance CBD to THC there is no anxiety. I have stopped my own and others panic attacks with straight CBD. I keep CBD on hand for such times. High THC with low CBD trips me every time.

      • 360dunk

        And dispensaries carry a nice product assortment of CBD/THC at a 1:1 ratio, which eliminates most of the euphoria that some people want to avoid. There’s really no need to ever get started on opiates.

    • Willdorf

      There is a risk of anxiety with any psychoactive drugs, be it THC, opiates, benzodiazepines, SSRIs… it depends on the individual’s particular brain chemistry and mindset. Any drug won’t work for everyone but may work work for the majority and should be taken seriously. The best thing about Marijuana is that it doesn’t have a serious withdrawl like opiates, or worse, benzos or alcohol. Although those also have their place (not alcohol lol unless you’re just partying) as THC doesn’t usually treat severe pain or anxiety.

  • 360dunk

    Well written and obviously not from an Abbott Lab or Pfizer lobbyist. If you’re on opiates, ask your doctor to help you ween yourself off of them. Try edibles, shatter, hashish….anything to get you away from Vicodin or Oxycontin. HeII, move away from your backwards state that has no medicinal dispensaries, if you must. Just don’t let Big Pharma take over your life.

    • Dug Friedrich

      Thanks, you’re spot on, on big pharma. Profit based medical care is a huge problem. Health care is right not a privilege.😎

    • William

      And how do I deal with a broken spine, and major neuropathy? Please don’t tell me to just smoke pot; I am near 70 yoa, and first smoked in 1967. Thai weed is perfect, I must say; it is dipped in opium. And I don’t see it anywhere near here. Papaver somniferum was put here for a purpose; it is probably the oldest medicinal plant and has been used by hundreds of millions, if not billions of people for at least six thousand years (fossilizing poppy plant material has been found in Switzerland, at an ancient Neanderthal camp, of all places, if I remember correctly). It is currently popular mind think to demonize opiate; I sadly see the pro cannabis users are attacking this plant to bolster their argument. Just like the old boss, who drank talked about pot. Sad, folks. I am in favor of both plants, and both should be used wisely. “Make tea, mon.” (Quote from movie “Rockers”). The Sanskrit is clear that Ganja is the herb of Lord Shiva, and that when you smoke it, you are toying with death. Perhaps death should be toyed with, as it is inevitable, and frightening to most Europeans. Smoke on, keep fighting and be kind to each other. And pray you don’t need the relief of the opiates one day; to die slowly from pain is not something you want to experience. And, yes, the heroin cartel is succeeding in demonizing big pharma; it was easy to do. Oxycontin was pushed by the Sackler family, on a small letter by Porter and Jick, telling the world opiates, if made right, are not addicting. It was a lie. Another lie is the opioid “crisis”. FDA and CDC stats are compiled by calling any death with any opioid at autopsy, is labeled an opioid related death. Sam Quinones, author of “Dreamland” and perhaps the most middle line voice out there, says 16,000 death from actual opioid overdose is likely. Johann Hari has the answers if you are looking. “Chasing the Scream” is his tome, and that book is astounding. Therapeutic and rage reducing if you are interested in such. A fascinating read altogether. Harry Anslinger, who had Billie Holiday murdered, mentored Joe Arapaio. But, and I digress. Fear is the soup du jour, and nearly all of you have bought into it. After 9/11, freedom in this country ceased to exist as we once knew it. Hell, you could buy an ounce of diacetyl morphine, heroin, over the counter in 1910. Heroin, the first extracted molecule from opium/morphine base must be an amazing pain reliever. They called it “calming powder”. The personal problems people have with opiates is their restriction, not their availability. In more enlightened countries (blasphemy, America is the most enlightened because we have the most shit), well, heroin addicts, supplied their drug of choice (yours may be beer and pot; good for you- the beer not so much), enjoy productive lives. If you are looking, and can see, many captains of industry and the military are high dosed, pin eyed, focused people moving through the world. Today. Yes; look and you will see; they are some of the most focused and productive members of society. Opiates can be of great value and beauty. And who has the power to suppress legal opioids, while flooding the world with cheap, potent heroin? The world had no problem with drugs until the Anslingers (a racist sadist) and Nixons made it a problem. And the drug war is not about drugs. It is about YOU, and social control.
      (Josh, pardon my story, and thank you for allowing me to write on your site. You keep up the good work, young brother; your article is great)

    • William

      Yeah, the Stackler family of Purdue Pharma really screwed the pooch. They used a short note by Porter and Jick that said perhaps opioids weren’t addicting. And they ran with it. 35 Billion dollars later, the Stacklers are in no position to be brought to accountability. They are the makers of Oxy. They have tried re-arranging the formula so that if water is added, it turns to a gel. I don’t know what’s with big pharm now, much, as there are changes being considered behind closed doors, about how the government is going to deal with legal opioids in the face of diacetylmorphine (the first synthesis of the morphine molecule)-heroin. Opioidica is serious business kids. Stay away unless you are sure, would be my recommendation. There are tens, if not hundreds of thousands of people suffering unnecessarily. Our bodies have not adapted in the hundred or so years we can move at very fast speeds. Such is where the damage to your skeletal frame can begin to show Be careful out there, and hope you never get into a situation where opioids could make your life livable. (from bikes as a kid to car wrecks later, to illnesses; eech). They do. Be careful the biology of the opioid molecules. An ancient and blessed medicine. As is cannabis. Make Tea.

  • Debbie Cerasani Ricigliano Pic

    Can people be allergic to cannabis?

  • William

    All that is happening re: opioids is yes: there is a problem. The stats are piled up; if someone has died with opioid in their system, they had an “opioid related death. That’s the stats. The solution is in models all over the world. Switzerland, to Portugal, and other kindsmart people’s countries. The solution to the drug war is simple, and not so easy. help with your opioid is probably efficacious to both. And could be dangerous. Nice article, I could not find much inaccuracy, if any. Well written; I just quit about 18 years at 1,o10; one thousand and ten milligrams of morphine per day. 3 years of fentanyl, and with the help of my pain doctor, not now. No mas para me, pero, comprendo. Totalamente

    • Rainey

      “… if someone has died with (one or more) opioids in their system, they had an “opioid related death.”
      Yep, just so. Most people are unaware of how the “opioid-related” stats are collected and used — and slanted to prove a claim that can’t be verified by a closer look at those figures!

      • William

        Rainey; sister, brother ? You understand…I wish people would stop demonizing one plant for another. Papaver somniferum is wondrous, and a serious medicine for those in serious pain. And Opioidica, Sister Morphine, Dilaudica, Fentica; all are serious sisters who , if you visit, and want to stay there, you better have the wherewithal ,and funds to stay there. I don’t recommend it, unless, and until you have the aforementioned situation/s. They are beautiful. And seriously jealous if you try to leave. I just left 21 years there. Life there is real, it’s just not real life. And anger attached to pain can be very motivating. Rainey; nice to see someone knows, and is not taken in by the illusion of “the opioid crisis”. All the suppression of legal pain medication is doing, is boosting heroin sales, coming at the world from the two wars we have going. The war for the Greater Middle East, and the drug war. And there is a great exodus called immigration. It’s Biblical, they just don’t know it yet. What would Jesus say. What would Jesus do. (cont: That sounded a little preachy; sorry. I have examined closely; I have just gotten off of 1,010 mgs/day Morphine, and up to 100mics/hr Sister Fentina. I have left the land of Opioidica. If you have visited there, you know. If you haven’t, and I don’t recommend , in most cases, you do, you don’t. Know. Sam Quinones author: “Dreamland” is a very down the middle of the road, trying not to be biased, I’m so angry, not after writing this book, Mr. Quinones. A great read. He says 16,000 is the number. That sounds high, but, and 64,000 it ain’t. The very light at the top of the argument, is Johann Hari’s “Chasing the Scream”; CTS is rage reducing; it is therapeutic; a beauty of a book. Definitive for any argument, about the drug war. The one to the south of us, and in our cities, called the drug war, and the drug and oil war now in Afghanistan/ the entire Middle East, creating an exodus, from the horror of war. For oil. 40 years ago, when we intervened in the Middle East, we thought the sea passages must become a part of our national interest. And we have created war in Beautiful Mexico, Central America. Life was simple in Medillin until it got, what? What happened to…I gotta get a blog. Thanks gang for letting me write on here; I gotta getta blog, and stop shouting in a room full of dear people. I saw a quote a few days ago, I am not sure who said it, it’s great: “How can you shine in a digital world?”

    • Alex

      Hi William. Do you have experience working within the healthcare system in Switzerland as a patient or otherwise know of experiences there? I am currently faced with the possibility of having to relocate away from long time doctors and specialists for a period of 18-24 months and I’m curious as to how disabling chronic pain is handled there. I currently take a large daily does of Oxycodone for a variety of problems all of which are well documented but I’m really concerned with the potential that I may run into issues with doctors not being too eager to fill my Rxs for pain medicine like my doctor here has been doing properly for the last 8 years. Any info would be greatly appreciated as this is really a stress point in trying to prepare for this temporary move.

  • The right doses of THC:CBD can be huge in helping people either use fewer opioids or avoid them altogether. We’ve seen firsthand how cannabis (especially CBD) can increase the efficacy of an opioid medication. This could be instrumental in allowing folks to ease off without feeling as much of a withdrawal. Opioid tolerance is the main reason use gets out of hand so quickly. Cannabis can help with this. Use of a low-THC/high-CBD strain (or caplet) can make the same dose feel like more (without doing the damage of more.)

  • John Antonellis

    Thanks Josh, the more scientific perspectives that are applied to the possible use of medicinal marijuana will ultimately help to legitimize this alternative. I’m a five year pancreatic cancer survivor, whipple, chemo and radiation. In addition to the challenges and effects of this disease I also suffer chronic pain. I fractured 3 vertebrae in the cervical area and dislocated a shoulder from a mountain biking accident and add another half dozen surgeries from an active lifestyle I use MM effectively to manage my issues. The only time I take pain relief medicine (tramadol hcl 50mg x 2) is to play golf, otherwise I couldn’t swing a club. When doing this I combine with a high cbd strain. The routine I use has helped me manage these issues while remaining very active and productive.

    • darren r

      Hi John great message I was so happy you living well into 5 years I was T3N1 in October 2013 poorly differentiated late stage 3 adenocarcinoma pancreatic cancer as well.
      Keep the faith John – I never would have made it this far without Jesus xxx cheers from Australia.

  • Rainey

    How do we KNOW that 64,000 deaths in 2016 were opioid-related? The Substance Abuse and Mental Health Services Administration (SAMSA) requires medical facilities to report results from emergency room visits and hospital deaths. Those reports include substances found in patients’ blood. Each substance is counted separately, but not identified as to source, amount or legality. SAMSA reporting forms do not distinguish between an addict who injects heroin and an individual who has taken a prescription medication for pain — and make no mention of how much they took prior to death.
    If I have a root canal and take a dentist-prescribed percoset, and then am hit by a car in the parking lot and taken to the hospital with a broken leg, blood tests will show opiates in my system. There is NO record of the fact that the opiates I took were legal.
    Now, the important part: If I am killed by that car, my death will be recorded as “opioid-related” by SAMSA.
    If an addict dies at the hospital after injecting heroin and ingesting morphine and oxycontin tablets, each opiate is reported separately by SAMSA. Now, there is a record of THREE opioid-”related” deaths instead of one death involving three separate substances.
    The forms do not report the actual cause of death, but do include patients suffering from a wide variety of illnesses, including COPD, high blood pressure, cancer, heart disease, accident, gunshot wound and even old age. All the SAMSA reports show is that those individuals consumed opioids within a specific time frame.
    Addicts, who are the most likely to overdose and die, are also the most likely to ingest multiple opiates. Non-addicted individuals rarely take more than one type of opiate at a time. The 64,000 figure is wildly inflated, but is used incorrectly to show that America is undergoing a severe opioid crisis.

  • Bryan Rowley

    I always find cannabis as my best buddy in health. Cannabis is the best medicine. For inquiries and medical purchase i recommend ANNCANNMED.

  • Sandra
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  • Alex

    Does anyone have any advice for someone relocating on a temporary basis to Zurich while on a high dose daily regiment of Oxycodone as well as some specialty medicines due to various diagnosed medical conditions and a nasty autoimmune disease. I’m concerned about the potential for not being able to find a good medical provider, running into a treatment wall and having to make regular 16 hour excruciating flights home for medicine every couple months because I’m unable to get the proper relief away from my regular doctors. Please, any help/info/anything would help. Thanks!

  • Ramon Rosa

    Do pain management doctor’s still test for weed

    • Melissa Merrill Snyder

      In Ohio they do….

  • Donald Junior

    Getting pain medications certain times proves difficult especially with doctors a times not wanting to do scripts or a times the crazy prices charged by some pharmacies out there . I was badly in need of pain medication until a friend of mine recommended me to use this pharmacy site try them out they got pain medications which work greatly
    Their web address is http://www.authenticmeds(dot)com
    Good luck!!!

  • Phoenix

    Hi. I’ve been smoking hemp before bed. The next morning I my tolerance to codeine has lowered. When I don’t smoke hemp my tolerance rises quickly again. I’m very sure of this.

    Consuming hemp or cannabis before bed could be a very effective way of tapering off the opiate.

    Hemp has low amounts of THC but high amounts of CBD. Can anyone tell me if they notice a tolerance drop when consuming hemp before bed or at any time? It’s quite fascinating.

  • Kat Kandel

    Is it illegal in Florida for a pain management doc to prescribe oxycodone or tramadol to a patient who uses medical marijuana? One doc tells me yes. Another doc and a pharmacist tell me no. I haven’t been able to find an answer online.