Concept: Mechanisms Underlying Analgesic Properties of Terpenes and Minor Cannabinoids

Council Date: October 5, 2018

Program Director: Inna Belfer, M.D., Ph.D. 

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Background 

Chronic pain impacts over one-third of the U.S. population, consumes substantial health care resources, and significantly reduces work productivity. Long-term management of chronic pain has largely relied on opioid-based pharmacologic interventions, which not only lack long-term efficacy but also carry risks for adverse events and contribute to the national epidemic of opioid misuse. The development and identification of novel pain management strategies is a high priority and unmet need. Natural products have historically been a source of novel analgesic compounds developed into pharmaceuticals (e.g., willow bark to aspirin). A growing literature suggests that the cannabis plant has analgesic properties; however, research into cannabis’s potential analgesic properties has been slow. One major challenge is whether the potential analgesic properties of cannabis can be separated from its psychoactive properties. In order to address this question more research is needed into the basic biology of the plant’s diverse phytochemicals, specifically the cannabinoids and terpenes. 

Cannabis contains approximately 110 different cannabinoids and 120 different terpenes. Very few of these phytochemicals have been extensively studied. The cannabinoid, Δ9-tetrahydrocannabinol (THC), is one of the most abundant and studied of all the cannabinoids. This cannabinoid has demonstrated analgesic properties, however its psychoactive effects on cognition, emotion, and behavior limit its desirability for analgesia. Other cannabinoids (e.g., cannabidiol [CBD], Cannabigerol [CBG], and Cannabichromene [CBC]) have also been shown to have analgesic properties and are not thought to be psychedelic or addictive; however, these cannabinoids are not as potent as THC. Terpenes comprise a smaller percentage of the phytochemicals in cannabis but give the plant its strain-specific properties such as aroma and taste. Terpenes can be found in other plants (e.g., fruits, vegetables, and edible herbs), and unlike cannabinoids they are not controlled substances. There is evidence to suggest that specific terpenes (e.g., Myrcene, β-caryophyllene, Limonene, α-terpineol, Linalool, α-phellandrene, α-pinene, β-pinene, γ-terpinene, and α-humulene) have analgesic properties; however, a lot more research is needed to understand the underlying mechanisms of action. One of the putative mechanisms of action is that terpenes can influence the activity of cannabinoids or signaling from the cannabinoid receptors, but conclusive evidence to support this hypothesis is lacking. It is also unknown how minor cannabinoids and terpenes, either alone or in conjunction with each other, may modulate the biological and neural systems associated with pain perception and analgesia.

Limited basic and clinical evidence indicates that cannabis can enhance the potency of opioids in relieving pain; and the synergy from using these products together can result in more effective pain relief with lower doses of opioids. Yet, it is unclear which components of cannabis may have these properties. Especially, whether terpenes and minor cannabinoids may interact with the opioid system remain understudied. More specific research is therefore needed to uncover the mechanisms of action for terpenes and minor cannabinoids, as well as whether these molecules, alone or in combinations, can be used to treat pain, opioid use disorder, and other pain-related comorbidities.

Purpose of Proposed Initiative

This proposed initiative aims to encourage research on terpenes and minor cannabinoids as it relates to pain, nociception, and analgesia. Terpenes and cannabinoids of interest include: Myrcene, β-caryophyllene, Limonene, α-terpineol, Linalool, α-phellandrene, α-pinene, β-pinene, γ-terpinene, α-humulene, Cannabidiol (CBD), Cannabigerol (CBG), Cannabinol (CBN), and Cannabichromene (CBC). This initiative intends to support highly innovative basic and/or mechanistic studies in appropriate model organisms and/or human subjects aiming to identify, demonstrate, and predict if terpenes and minor cannabinoids can help treat pain. The mechanisms and processes underlying potential contribution of terpenes and minor cannabinoids to pain relief and functional restoration in patients with different pain conditions may be very broad. This initiative encourages interdisciplinary collaborations by experts from multiple fields—pharmacologists, chemists, physicists, physiologists, neuroscientists, psychologists, endocrinologists, immunologists, geneticists, behavioral scientists, clinicians, caregivers, and others in relevant fields of inquiry. 

Objectives

Examples of research topics of interest include, but are not restricted to:

• Investigate the potential analgesic properties and adverse effects of terpenes, alone or in combination with each other or cannabinoids 
• Investigate the mechanisms by which terpenes and minor cannabinoids may affect pain signaling pathways
• Explore the impact of sex, age, and ethnicity on potential analgesic properties of terpenes and minor cannabinoids
• Explore the analgesic potential of terpenes and minor cannabinoids for different pain types (e.g., acute vs chronic pain, inflammatory pain, neuropathic pain)
• Investigate the pharmacology (pharmacokinetic and pharmacodynamic profiles) of terpenes and minor cannabinoids
• Explore binding abilities of terpenes and minor cannabinoids to cannabinoid and opioid receptors
• Investigate the impact of dose and/or route of administration on potential analgesic effects of terpenes and minor cannabinoids
• Characterize if/how specific terpenes may influence potential analgesic properties of cannabinoids
• Explore potential opioid sparing effects of terpenes and minor cannabinoids
• Explore the interaction between the microbiome and terpenes or minor cannabinoids
• Improve methods to quantify systemic levels of terpenes and minor cannabinoids.