Acetaminophen (Tylenol) is a common over-the-counter medication that’s long been used as a pain reliever. The mechanism of action by which acetaminophen relieves pain has not been fully appreciated—until now. Emerging evidence indicates that acetaminophen exerts its pain-relieving effects through the endocannabinoid system (ECS),1 a system in the body involved in pain control. We’ve written a lot about the ECS and how it affects many aspects of health. Acetaminophen’s effects on pain indicate the ECS is at work again!
In this article, we’ll address the role of acetaminophen in the ECS as well as discuss the possible advantages of using cannabidiol (CBD) together with acetaminophen to relieve pain.
Getting Reacquainted with the ECS
An abundance of research indicates that phytocannabinoids—substances such as cannabidiol (CBD) are known to act on receptors in the ECS. Your body produces endocannabinoids, including anandamide and 2-arachidonylglycerol (2-AG), activating ECS receptors. Two important receptors in this system that are involved in pain management are CB1 and CB2.2
Acetaminophen, CBD, and the ECS
The cannabinoid system plays a role in acetaminophen analgesia against acute pain but also against inflammatory pain, working through CB1 receptors.1
Both acetaminophen and CBD work through the ECS system. However, they work in different ways. Acetaminophen increases endocannabinoid levels, but it does so indirectly.1 This common pain reliever blocks the reuptake of the endocannabinoid anandamide, increasing CB1 activity in the brainstem.1 The desired result is reduced pain.
CBD acts most directly on CB2 receptor.3 It prevents the breakdown of anandamide, leading to longer-lasting effects.3 It also directly interacts with receptors that regulate inflammation and pain sensitivity. The ability of CBD to act on CB2 receptors blocks activation of the brain cells known as microglia, thereby preventing the development of neuropathic pain.4 In addition, CBD interacts with serotonin receptors, leading to anxiety-reducing and analgesic effects.5
Table: How Acetaminophen and CBD Work in the Body
| Feature | Acetaminophen | CBD (Cannabidiol) |
| Primary Action | Analgesic, Antipyretic | Analgesic, Anti-inflammatory, Anxiolytic |
| Mechanism of Action | Metabolized into AM 404, which enhances endocannabinoid signaling and activates CB1 receptors in the rostral ventromedial medulla (RVM) | Modulates CB1 and CB2 receptors indirectly increase anandamide (AEA) levels by inhibiting FAAH, and interacting with TRPV1 and serotonin receptors |
| Pain Relief Pathway | Enhances endogenous cannabinoid signaling (CB1 activation) | Reduces inflammation (CB2 activation) and modulates pain perception (TRPV1 activation) |
| Anti-Inflammatory Effects | Minimal | Significant |
| Liver Toxicity | High in overdose | Low |
Can Acetaminophen and CBD Work Together to Control Pain?
Acetaminophen is known to cause liver toxicity, increasing as the dose increases. Acetaminophen overdose is the most common cause of acute liver injury in the US.6 It would, therefore, be advantageous to reduce the dose to a point less likely to cause liver damage while still inhibiting pain. CBD’s ability to impact the ECS and elicit an anti-inflammatory response may allow lower doses of acetaminophen to be used, potentially reducing the adverse effects of the over-the-counter pain reliever.
One caution: CBD suppresses liver enzymes (the CYP450 family),7 of which are involved in metabolizing acetaminophen and other medications. This slowed metabolism of acetaminophen could increase blood levels. This is why it’s critical to reduce the acetaminophen dosage while taking CBD to protect liver health. People who are taking acetaminophen or who have liver conditions should consult a healthcare provider before combining it with CBD.
Optimizing Absorption of CBD
In clinical practice, I prefer CBD formulated with the VESISorb® technology delivery system, which helps the body absorb CBD and is even more effective.8 In a study of human subjects, this technology is used to increase bioavailability upwards 6X more via multiple PK studies measured in human subjects.8
Additional information on VESISorb® can be obtained at www.TruGen3.com. Dr. Meletis is an independent educator for TruGen3.
References
1. Klinger-Gratz PP, Ralvenius WT, Neumann E, et al. Acetaminophen Relieves Inflammatory Pain through CB(1) Cannabinoid Receptors in the Rostral Ventromedial Medulla. J Neurosci. 2018;38(2):322-334.
2. Miller RJ, Miller RE. Is cannabis an effective treatment for joint pain? Clin Exp Rheumatol. 2017;35 Suppl 107(5):59-67.
3. Leweke FM, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2012;2(3):e94.
4. Toth CC, Jedrzejewski NM, Ellis CL, Frey WH, 2nd. Cannabinoid-mediated modulation of neuropathic pain and microglial accumulation in a model of murine type I diabetic peripheral neuropathic pain. Mol Pain. 2010;6:16.
5. Han K, Wang JY, Wang PY, Peng YC. Therapeutic potential of cannabidiol (CBD) in anxiety disorders: A systematic review and meta-analysis. Psychiatry Res. 2024;339:116049.
6. Chao X, Wang H, Jaeschke H, Ding WX. Role and mechanisms of autophagy in acetaminophen-induced liver injury. Liver Int. 2018;38(8):1363-1374.
7. Herdegen T, Cascorbi I. Drug Interactions of Tetrahydrocannabinol and Cannabidiol in Cannabinoid Drugs. Dtsch Arztebl Int. 2023;120(49):833-840.
8. Knaub K, Sartorius T, Dharsono T, Wacker R, Wilhelm M, Schön C. A Novel Self-Emulsifying Drug Delivery System (SEDDS) Based on VESIsorb(®) Formulation Technology Improving the Oral Bioavailability of Cannabidiol in Healthy Subjects. Molecules. 2019;24(16).
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