HealthScience & tech How Cannabis Enhances the Effects of Opioids Josh Kaplan March 29, 2018 Red orange Pill bottle spilling out pills onto a black surface

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.

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.

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.

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.

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.

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.

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

4 part series

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