By John Streicher
John Streicher, Ph.D. has built a research program focused on signal transduction cascades, the proteins that sense and respond to drugs, hormones, and similar chemicals and turn that into a response, like pain relief (or addiction!). His work has focused on signaling of the cannabinoid, opioid, adenosine, and related receptors in the context of chronic pain and addiction. By studying how drugs activate these receptors, he works to find new drug types that are more effective in relieving chronic pain without the side effects and burdens of drugs like opioids. Since 2019, this has led him to studying the terpenes found in cannabis and other plants. He has discovered that terpenes like beta-caryophyllene can be highly effective in treating chronic pain and even opioid addiction, without the drawbacks of opioids and cannabinoids. He is currently working to develop terpenes into true therapeutics that can be used in the clinic to treat patients with chronic pain. He is a Professor in the Department of Pharmacology in the College of Medicine at the University of Arizona, where he has worked since 2015. He was previously an Assistant Professor in the Department of Biomedical Sciences at the University of New England from 2012-2015. His education began with a BS in Biology from George Fox University in 1999, and an MS in Neuroendocrinology from Oregon Health and Science University in 2002. He completed his PhD studies with Dr. Yibin Wang of the Department of Anesthesiology at the University of California-Los Angeles in 2009, and his postdoctoral fellowship with Dr. Laura Bohn of The Scripps Research Institute in 2012.
What are terpenes?
Terpenes are small molecules found in Cannabis, and indeed all plants, with a fairly simple chemical structure (Figure 1). Hundreds have been found across thousands of plants. You know about terpenes whether you've heard the name before, because you've smelled and tasted them. The citrusy and fresh scent of a lemon? That's the terpene Limonene. The acrid taste of hops in beer? Humulene. The floral, sleepy scent of lavender? Linalool. And so on. Terpenes have been used for many years, or even many centuries, as food additives, perfumes, essential oils, and more.
More recently, terpenes have been found to have beneficial medicinal properties. Laboratory studies all over the world have found a variety of benefits to different single terpenes or terpene mixtures, including anti-anxiety, anti-inflammatory, anti-bacterial, and pain relief properties in both animal and human studies [1]. In one striking study, inhaling a rose oil (with Geraniol) mixture helped reduce labor pain in women giving birth [2]! These findings are doubly exciting since terpenes are not cannabinoids like Delta-9-THC, and thus are not intoxicating. Nor will they get you in trouble at work!
However, no one has yet taken the leap in developing any terpene product into a true therapeutic for the treatment of disease. That means fully establishing the effectiveness of a terpene in the clinic, but also the side effects, potential toxicities, and the mechanism of action – how they work. While this knowledge remains unknown, the commercial world has leapt ahead, with some terpene products available to purchase as a supplement or additive. This situation motivated my own work to look deeper into terpenes and find their true therapeutic profile and how they work in the body. I hope to use this knowledge to develop terpenes into a true drug that can be prescribed by your doctor to help with chronic pain and other maladies without the side effects and drawbacks of drugs like opioids or cannabinoids.
Terpenes Relieve Chronic Pain by Activating the Adenosine A2a Receptor in the Spinal Cord
Our first terpene study tackled 5 terpenes, Geraniol, Linalool, Beta-Pinene, Alpha-Humulene, and Beta-Caryophyllene (Figure 1). We did the basic work to figure out that terpenes could activate several receptor systems in the body, and that their effect on behavior looked like a cannabinoid, but was not itself a cannabinoid [3]. We also found that terpenes could be combined with a cannabinoid to give stronger pain relief than either alone – a small piece of evidence supporting the "entourage effect" hypothesis, that different chemicals in cannabis can combine to give different effects than any alone.
This first study was exciting and laid the foundation, but we didn't tackle the kind of pain that people really care about. Chronic pain. Pathological pain. Post-surgical, chemotherapy-induced, diabetic neuropathy, nerve trauma-induced, fibromyalgia, and more. People care about treating that kind of pain. We don't need to treat regular pain sensations like when you accidentally stick your hand on a hot stove. We need to treat the kind that grinds you down day after day after day with no end in sight, and for many, the kind of pain that can't be touched by painkillers, not even opioids.
So our following studies all tackled different chronic pain models. So far we've tested the terpenes above in 4 chronic pain models – post-surgical, fibromyalgia, peripheral neuropathy caused by chemotherapy drugs, and inflammatory pain. In all cases, the terpenes produced as much or more pain relief as an opioid drug [4-6]. Interestingly, we even showed that we could combine low doses of terpene with low doses of opioid to produce more pain relief than either alone. This suggests we could make a combined therapeutic with greater pain relief and lower side effects, even opioid addiction.
However, pain relief is only one side of the equation in a good therapy for patients. We also needed to test the side effects. First, and most importantly, we showed the terpenes tested had no addictive properties [6]. They did cause some sedative effects, but this could possibly be turned to our advantage – take them at bedtime, and you have two ways of helping you sleep better, pain relief and direct sleep help from the terpene! The terpenes were also well-tolerated, with no detectable toxic effects. We do have more work to do, but so far, the terpenes we tested seem to have very low side effects.
Lastly, we also wanted to test the mechanism – how were the terpenes causing pain relief in the body? We first tracked at least one site of action to the spinal cord. No surprise, since the spinal cord is a very important part of your body's pain sensing and processing network. However, we were surprised when we found the receptor target, the protein in the body that senses and responds to a drug or hormone. We found it was the Adenosine A2a Receptor. Now, that may not mean much to you, but you know this receptor even if you haven't heard the name. Caffeine is a blocker of this receptor! We found that terpenes activate this receptor in the spinal cord and use it to produce pain relief (Figure 2).
Now, what is next for terpenes and chronic pain? First, we have to finish our analysis of terpenes as potential real pain therapeutics. We have to examine their benefits and side effects in more detail, using additional models to help us understand how these drugs act in the body. We have to use more exacting measurement tools, and test for possible toxic effects. Then, when we're done, we'll start our first clinical trials. We'll take these molecules to real patients suffering from chronic pain like fibromyalgia and find out whether or not terpenes can truly help them.
At the same time, our quest to understand how these molecules relieve pain is ongoing. We've just about nailed down the neuronal circuit in the spinal cord that transmits a drug action into pain relief. That work should be published soon. And we're investigating just how terpenes activate the Adenosine A2a Receptor, since it seems to be a bit different than for a typical drug. These efforts will help us fully understand how terpenes help people, which goes hand-in-hand with our planned clinical testing. Who knows, it could even lead to improved pain therapies beyond even these terpenes!
Terpenes Might Also Treat Drug Addiction
While we were investigating terpenes in pain, we noted that a few other scientists had published just a few papers suggesting that two terpenes could be used to block the addictive effects of cocaine, alcohol, and nicotine [7]. Naturally, this made us curious if the same was true of opioids! While this work is not yet published, we found that Beta-Caryophyllene was excellent in fully blocking the addiction potential of morphine. A little preview of this data can be seen in Figure 3. Now, remember from above when I said that terpenes and opioids could be combined to make a treatment more effective than either at relieving pain? Now think of that along with the addiction-blocking benefits of Beta-Caryophyllene here. That combo therapy would have no addiction potential at all!
Remarkably, we also found that the same molecular target, the Adenosine A2a Receptor, was responsible for the ability of the terpene to block opioid reward. Although in the brain this time, not the spinal cord. The A2a Receptor has a known role in interacting with a specific population of dopamine neurons responsible for regulating reward and addiction called the D2-Medium Spiny Neurons in the Nucleus Accumbens. This gives us a hypothesized mechanism and location in order to figure out and test just how this terpene is blocking opioid addiction potential (Figure 4).
So, again, what's next? First, like with chronic pain, we have to find out if this terpene can be a true treatment for addiction. Using a model of voluntary drug seeking and taking with our collborator Dr. Lauren Slosky at the University of Minnesota, we will find if the terpene can be used to prevent addiction, treat active opioid addiction, or both. We'll find out if the terpene can help with acquiring the addiction, keep it from maintaining, speed up the abstinence period needed to exit from active addictive behavior, or help prevent relapse. Like with pain, we'll also make sure that no side effects are in hiding waiting to cause problems, especially when combined with an opioid use disorder. Then when we know the answers to these questions, we'll take this to a clinical trial and see if we can help people struggling with opioid use. At the same time, we'll be working to find out the mechanism by dissecting the system we propose in Figure 4. We'll figure out what parts of the brain respond to terpenes to prevent opioid reward.
The Future
Terpenes hold a lot of promise as a natural, highly effective, and low side effect treatment for chronic pain and opioid addiction. We're working on all fronts to make that future a reality.
Figure 1: Terpene Chemical Structures
Figure 2: Model of Terpene Action in Chronic Pain.
MOR = Opioid Receptor; A2aR = Adenosine A2a Receptor.
Figure 3. Morphine Activates the Reward System in Your Brain, While Beta-Caryophyllene (BCP) Blocks It!
Brain region is the Ventral Tegmental Area. The green signal shows an increase in the reward system in the brain, which is blocked by BCP.
Figure 4. Model for Beta-Caryophyllene (BCP) Blockade of Opioid Reward.
DA = dopamine. D1/D2 = Dopamine 1 or Dopamine 2 Receptors. MSN = Medium Spiny Neuron. A2aR = Adenosine A2a Receptor.
References
1. Liktor-Busa, E., et al., Analgesic Potential of Terpenes Derived from Cannabis sativa. Pharmacol Rev, 2021. 73(4): p. 98-126.
2. Hamdamian, S., et al., Effects of aromatherapy with Rosa damascena on nulliparous women's pain and anxiety of labor during first stage of labor. J Integr Med, 2018. 16(2): p. 120-125.
3. LaVigne, J.E., et al., Cannabis sativa terpenes are cannabimimetic and selectively enhance cannabinoid activity. Sci Rep, 2021. 11(1): p. 8232.
4. Schwarz, A.M., et al., Terpene blends from Cannabis sativa are cannabimimetic and antinociceptive in a mouse chronic neuropathic pain model via activation of adenosine A(2a) receptors. Neurosci Lett, 2025. 854: p. 138205.
5. Seekins, C.A., et al., Select terpenes from Cannabis sativa are antinociceptive in mouse models of post-operative pain and fibromyalgia via adenosine A(2a) receptors. Pharmacol Rep, 2024.
6. Schwarz, A.M., et al., Terpenes from Cannabis sativa induce antinociception in a mouse model of chronic neuropathic pain via activation of adenosine A 2A receptors. Pain, 2024. 165(11): p. e145-e161.
7. Asth, L., et al., Effects of beta -caryophyllene, A Dietary Cannabinoid, in Animal Models of Drug Addiction. Curr Neuropharmacol, 2023. 21(2): p. 213-218.
