Your Body's Cannabis-Like Chemicals Respond to Knee Surgery and Pain | Research

The takeaway

Patients undergoing knee replacement had higher endocannabinoid levels than healthy controls, and those with more pain had lower anandamide in spinal fluid — suggesting the body's cannabis system actively responds to surgical pain.

People facing joint surgery, pain management researchers, and anyone interested in the body's natural cannabis-like pain system.

What the researchers found

Knee replacement patients had higher CSF and plasma concentrations of anandamide and related N-acylethanolamines compared to controls. Patients with higher pain scores had lower CSF anandamide levels before and after surgery, and higher 2-AG levels before (but not after) surgery.

Why it matters

The endocannabinoid system may be a target for non-opioid pain management after surgery. Understanding how natural cannabinoids respond to surgical pain could lead to new treatments that work with the body's own pain-relief system.

The numbers in context

40 patients enrolled. 3 sampling timepoints. Higher CSF and plasma N-acylethanolamines vs. controls. Higher pain = lower CSF anandamide. Higher 2-AG pre-surgery in high-pain patients. Pain measured by Defense and Veterans Pain Rating Scale.

How the study worked

Prospective observational cohort study of 40 adults with osteoarthritis undergoing total knee arthroplasty. Cerebrospinal fluid and blood samples collected at 3 timepoints (pre-surgery, post-acetaminophen, 24h post-op). Endocannabinoids quantified by validated LC/MS assay. Linear regression with sex, age, BMI covariates.

What this study cannot tell us

Small sample (40 patients). Observational — cannot determine if endocannabinoid changes cause or result from pain. CSF collection is invasive, limiting broader application. No cannabis-based intervention was tested.

How to read the evidence

Small prospective cohort (n=40) measuring biomarkers — informative but not sufficient to guide treatment decisions.

When this study was published

Published in 2026, reflecting growing interest in endocannabinoid-based pain management.

The bigger picture

The opioid crisis has driven urgent interest in non-opioid pain strategies. This study suggests that chronic pain from osteoarthritis alters the body's endocannabinoid tone, and that these natural compounds could be leveraged for targeted post-surgical pain relief.

Questions still open

Could cannabinoid-based treatments improve post-surgical pain outcomes? Would supplementing anandamide reduce pain after knee replacement? How do endocannabinoid levels change across different types of surgery?

Common questions

What are endocannabinoids?

Endocannabinoids are cannabis-like chemicals your body naturally produces. Anandamide and 2-AG are the two main ones. They help regulate pain, inflammation, and other functions through the same receptors that THC and CBD interact with.

Could this lead to new pain treatments after surgery?

Potentially. The finding that lower anandamide correlates with more pain suggests that boosting endocannabinoid levels could help. However, this study only observed the pattern — no cannabinoid-based intervention was actually tested.

Read the original research

Endocannabinoids, perioperative pain, and acetaminophen in patients undergoing total knee arthroplasty: a prospective cohort study.

Pain reports, 11(2), e1369

View on PubMed ↗Publisher’s paper ↗

Citation

Clendenen, Nathan; Clendenen, Anna; McClain, Robert; Wheeler, Garret; Klawitter, Jost; Christians, Uwe; Clendenen, Steven R; Klawitter, Jelena. (2026). Endocannabinoids, perioperative pain, and acetaminophen in patients undergoing total knee arthroplasty: a prospective cohort study.. Pain reports, 11(2), e1369. https://doi.org/10.1097/PR9.0000000000001369