Osteoarthritis affects an estimated 500 million people worldwide, causing joint pain, stiffness, swelling, and reduced mobility. The condition is more prevalent in women than in men, with women also experiencing greater osteoarthritis-related pain severity.
Several theories, including hormonal, anatomical, and biochemical factors, have been proposed to explain these differences. A recent study, published in Neurobiology of Pain, explored sex-specific differences in nociceptive behaviour and the amygdala endocannabinoid system in a rat monoiodoacetate-induced model of knee osteoarthritis.
Key Takeaways:
- The condition. Osteoarthritis is one of the most common forms of arthritis, affecting hundreds of millions of people around the world.
- The study. Researchers used a well-established rat model of knee osteoarthritis to compare pain-related behaviour in males and females over about nine weeks.
- Sex differences in pain behaviour. Female rats showed greater pain-related behaviour than males, including more weight taken off the affected leg and more sensitivity in the hind paw.
- The endocannabinoid system. Male, but not female, rats showed raised levels of the body’s own cannabinoid molecules on one side of a brain region called the amygdala. This is the first time this sex difference has been reported in this model.
- What it means. This is early animal research into why osteoarthritis pain may differ between the sexes. It does not tell us how to treat osteoarthritis in people, and it is not evidence that cannabis-based medicines work for it.
What is Osteoarthritis?
Osteoarthritis is the most common form of arthritis, a group of conditions that affect the joints, causing pain, swelling, and stiffness. It happens when the smooth cartilage that cushions the ends of bones gradually breaks down. Over time this can lead to bony growths and, for many people, ongoing pain and reduced mobility.
The cause of osteoarthritis is not fully understood, but several things are known to raise the risk of developing it:
- Joint injury: Putting strain on a joint too soon after an injury or operation.
- Age: The condition becomes more common as people get older.
- Family history: Some evidence suggests osteoarthritis may run in families.
- Obesity: Carrying extra weight puts more strain on joints, particularly the knees and hips.
- Sex: Osteoarthritis is more common in women than in men.
How is osteoarthritis usually treated?
There is currently no cure for osteoarthritis, so treatment focuses on easing symptoms and keeping joints moving. For many people, lifestyle measures such as regular exercise, weight management and suitable footwear can help with pain and mobility. In more severe cases, other treatments including pain relief and, sometimes, joint surgery may be considered. Any treatment plan is decided with a healthcare professional and tailored to the individual.
Why is osteoarthritis more common in women?
Women make up a larger share of people with osteoarthritis, and they tend to report more severe joint pain, especially in the knee. Researchers think this is down to a mix of hormonal, anatomical and biological factors, and there is growing evidence that women and men may also experience osteoarthritis pain differently.
Studies suggest that females can differ from males across several processes linked to osteoarthritis pain, including inflammation, the way the immune and nervous systems interact, and how the nervous system becomes more sensitive to pain over time. Despite this, detailed studies of long-term osteoarthritis pain in both male and female animals have been limited, which is the gap this study set out to help fill.
What is the endocannabinoid system?
The endocannabinoid system is a natural signalling network found throughout the body and brain. It helps to regulate a range of processes, including how we sense and cope with pain. It uses molecules the body makes itself, called endocannabinoids, two of the best known being anandamide (AEA) and 2-arachidonoylglycerol (2-AG), along with the enzymes that build and break them down.
It is worth being clear about the difference between this internal system and cannabis. Cannabis-based medicines contain plant compounds that can act on the same system, but studying the body’s own endocannabinoids, as this research did, is not the same as testing a cannabis medicine. This study did not give the animals any cannabis or cannabinoid product.
What did the study look at?
Researchers at the University of Galway in Ireland used a widely studied rat model of knee osteoarthritis. In this model, a substance called monoiodoacetate (MIA) is injected into one knee to produce joint damage and pain similar to osteoarthritis. Animals in the comparison (sham) group received a harmless saline injection instead.
The team followed male and female rats for about nine weeks (63 days) to track pain-related behaviour over time. They also studied a separate group of female rats to see whether the oestrous cycle, the female hormonal cycle, changed the results. At the end, they measured endocannabinoid levels and related genes in the spinal cord and several brain regions involved in processing pain, including the amygdala.
How did the researchers measure pain in the rats?
Because animals cannot report pain in words, researchers use behaviours that reflect discomfort. In this study they used three main measures:
- Weight-bearing: how much weight an animal puts through the affected leg. Taking weight off a limb suggests it is sore.
- Mechanical sensitivity: how sensitive the hind paw is to gentle pressure, tested with a fine probe.
- Cold sensitivity: the response to a cooling drop applied to the paw.
What were the results of the study?
Female rats showed more pain-related behaviour than males
Across the whole study period, female rats with osteoarthritis showed greater pain-related behaviour than males. They took more weight off the affected leg and showed more sensitivity to pressure in the hind paw. The biggest difference in weight-bearing appeared around day 21. There was no clear sex difference in the response to cold.
This pattern fits with what doctors see in people, where women tend to report more severe osteoarthritis pain than men, although animal findings cannot be read across to humans directly.
The oestrous cycle did not appear to change the results
The researchers checked whether the stage of the female hormonal cycle affected pain-related behaviour. It did not appear to. Female rats showed more pain-related behaviour than males regardless of where they were in the cycle, which suggests the difference was not simply down to hormone levels on a given day.
A sex difference in the endocannabinoid system
When the researchers looked at the amygdala, a brain region involved in pain and emotion, they found a difference between the sexes. Male rats with osteoarthritis had raised levels of the body’s own cannabinoids (2-AG and AEA), and some related molecules, on the left side of the amygdala compared with the right. This left-right pattern was not seen in females, nor in the sham animals. The authors report this as the first time such a sex difference has been shown in this model.
The researchers also found a change in a gene called Mgll, which controls an enzyme that breaks down one of these molecules. Female rats with osteoarthritis showed lower levels of this gene on both sides of the amygdala compared with the sham group. The authors suggest that osteoarthritis pain may involve the endocannabinoid system differently from some other long-term pain conditions.
The table below summarises the main findings.
| What was measured | Finding |
| Weight taken off the affected leg | Greater in females than males |
| Hind paw sensitivity to pressure | Greater in females than males |
| Response to cold | No clear difference between the sexes |
| Influence of the oestrous cycle | No apparent effect on pain behaviour |
| Body’s own cannabinoids in the amygdala | Raised on one side in males, not in females |
| Mgll gene in the amygdala | Reduced on both sides in females |
These are findings in rats. They point to biological differences that may be worth investigating, but they do not, on their own, tell us what causes the sex difference in osteoarthritis pain in people.
What are the limitations of this study?
The researchers are careful about what their work can and cannot show. The main points to keep in mind are:
It is an animal study. Rat models are useful for exploring biology, but they are not the same as human osteoarthritis, and results do not automatically apply to people.
It is early, mechanism-focused research. The study looks at biological differences and signalling, not at treatments or patient outcomes.
It did not test any medicine. It measured the animals’ own endocannabinoid system. It did not test cannabis, cannabinoids or any other drug as a treatment.
The meaning of the brain findings is not yet clear. The authors describe the left-right difference in the amygdala as a new observation whose significance still needs to be worked out.
Group sizes were small. As in much early laboratory work, the number of animals in each group was modest, so the findings need to be confirmed by further research.
What does this study tell us?
This study adds to the evidence that osteoarthritis pain may work differently in females and males. In this model, female rats showed more pain-related behaviour than males, independent of the hormonal cycle, and the two sexes differed in how the endocannabinoid system behaved in the amygdala.
It does not show how to treat osteoarthritis, and it is not evidence that cannabis-based medicines help with it. What it offers is a set of biological clues. As the authors conclude, these findings open up new questions and support the case for more research into why osteoarthritis pain differs between the sexes, and whether sex should be taken into account when developing future treatments.
Frequently Asked Questions
What is osteoarthritis?
Osteoarthritis is the most common type of arthritis. It happens when the protective cartilage around the joints gradually wears away, causing pain, swelling and reduced mobility. It most often affects the knees, hips and hands.
What are the treatments for osteoarthritis?
Osteoarthritis is more common in women, who also tend to report more severe joint pain. Researchers think this reflects a combination of hormonal, anatomical and biological factors, and possibly differences in how pain is processed. The exact reasons are still being studied.
Did this study test cannabis for osteoarthritis?
No. This was an animal study that measured the body’s own endocannabinoid system in rats. It did not give the animals cannabis or any cannabis-based medicine, and it was not designed to test whether such medicines help with osteoarthritis.
Is medical cannabis available for osteoarthritis in the UK?
Cannabis-based medicines have been legal to prescribe in the UK since November 2018, but can only be started by a specialist doctor and only in certain circumstances, usually when licensed treatments have not helped enough. They remain unlicensed for osteoarthritis, and any decision is made by a specialist, sup[ported by a multi-disciplinary team, on a case-by-case basis.
Does this study prove anything about treatment?
No. It is early laboratory research in animals. It points to biological differences that may be worth investigating, but it cannot tell us what will help people with osteoarthritis, and it does not recommend any treatment.
Considering your treatment options?
In the UK, medical cannabis is prescription-only and remains unlicensed for osteoarthritis. It is considered only by a specialist doctor, after a full assessment, and usually only when licensed treatments have not provided enough relief.
If you would like to understand whether a specialist consultation may be appropriate for you, you can complete Curaleaf Clinic’s online eligibility check. Any decision about treatment is made by a specialist doctor on an individual basis.
