Mindsets, Methotrexate and the Nocebo Effect
Reframing the way we prescribe drugs in chronic disease.
Written By Angharad Bridges
Methotrexate, which is often denoted by MTX, is an antineoplastic, immunosuppressant drug commonly used to manage a wide range of autoimmune conditions, such as rheumatoid arthritis, Crohn’s disease, juvenile idiopathic arthritis (JIA), and psoriasis. Sometimes, it is also used to treat cancers, such as acute lymphoblastic leukaemia (ALL).
MTX works by inhibiting enzymes necessary for DNA replication and can be described as a folic acid (an essential metabolite in this process) antagonist, slowing cell division. It is particularly useful for certain inflammatory diseases because it also causes accumulation of ATP and adenosine, which stimulate adenosine receptors for an anti-inflammatory effect. Its efficacy and low cost make MTX the gold-standard pharmaceutical choice for diseases like rheumatoid arthritis, such that patients with autoinflammatory conditions may be prescribed methotrexate indefinitely. Despite this, many patients experience significant adverse effects.
So what? All drugs have adverse effects, and MTX is no different. Serious, but rare, adverse effects include hepatotoxicity and bone marrow suppression. But here’s the kicker – a large proportion of MTX users experience MTX intolerance symptoms, including feelings of disgust, nausea, and vomiting, which can occur both before and after taking the drug, and these symptoms can last for more than 24 hours.
And research shows that these symptoms cannot possibly be caused by the mechanism of MTX.
Biologically Implausible
In the context of antirheumatic treatment, MTX is prescribed at a low dose of no more than 30mg weekly, either orally or subcutaneously. This almost-insignificant dose actually has little effect on cell replication; additionally, its mechanism of action in rheumatic diseases is barely described by the ATP/adenosine accumulation mechanism. Furthermore, MTX is metabolised quickly; within 24 hours plasma levels of MTX reach less than 5 µmol/L. Therefore, the potent sickness MTX causes is often due to negative experiences and beliefs about the drug, making these symptoms a nocebo effect.
We have established that the MTX nocebo effect experienced by many patients is biologically implausible. Yet, MTX intolerance is experienced by child, adolescent and adult patients with all sorts of chronic inflammatory diseases.
The nocebo effect causes patients to develop associative, anticipatory and behavioural side effects, such as nausea, anxiety and panic attacks. Associative symptoms of MTX intolerance have been described by a classical conditioning mechanism (i.e. Pavlov’s dogs), where patients initially experience drug-caused symptoms after administration, and over time start to experience the same symptoms in response to a neutral stimulus. Neutral stimuli include looking at MTX, thinking about MTX, hearing someone talk about MTX, and smelling something hospital-related (such as disinfectant wipes, which are used to clean the injection site). However, this does not fully explain MTX intolerance because other anti-rheumatic drugs with similar side effects don’t produce the same nocebo symptoms. These symptoms are not transferred across medications, so patients taking MTX alongside another drug don’t experience these symptoms with the other drug. There are several distinguishing features of MTX which have been identified as potentially contributing to physical nocebo manifestations. One such feature is that MTX, in both tablet and injection form, is yellow, which patients may subconsciously interpret as toxic.
Scientific papers quantitatively measure MTX intolerance using the Methotrexate Intolerance Severity Score (MISS) which measures MTX intolerance across four domains: nausea, vomiting, stomach-ache, and behavioural changes. MTX intolerance is confirmed if scoring ≥6 with one associative or behavioural symptom.
A Danish cross-sectional study from 2019 compared MTX intolerance in juvenile idiopathic arthritis (JIA) patients and acute lymphoblastic leukaemia (ALL) patients of similar ages treated with low-dose MTX. Interestingly, they found that significantly more participants in the JIA group were MTX-intolerant compared to the ALL group (p = 0.001). Additionally, only 14% of participants with JIA reported a MISS score of 0 (no adverse effects) compared to 39% of participants in the ALL group. Another significant difference between both groups is that the JIA group had a larger median treatment duration (338 days compared to 115 for the ALL group), which may explain the difference in MISS scores. This makes sense because other studies report that MTX intolerance develops over the first year of treatment, but after the effect develops, it remains at a stable severity. It is interesting to see that the chronicity of treatment may have a role to play in the nocebo effect.
Personal Experiences
Personally, I am very familiar with the MTX nocebo effect. I was diagnosed with JIA before I turned two, and one of my earliest memories is vomiting before being injected with MTX. I still take MTX and experience these symptoms. And even as I put my thoughts on (digital) paper, I feel an uneasiness in my stomach and throat, and I can imagine the disturbing CYTOTOXIC red label on the box - it generates an unnatural sickness which nothing else has ever made me feel.
And it’s not just me. I contacted Jade, Thea and Lucy who are members of Arthritis UK’s Young People’s Panel, which is a national advisory group consisting of young people diagnosed with rheumatic diseases. The accounts I received demonstrate the diversity of experiences of patients taking methotrexate.
Thea, who is diagnosed with psoriatic spondyloarthritis and axial spondyloarthritis, has been taking MTX for the last three years. She also suffers from hair loss, an uncommon side effect of MTX. “I get nausea, headaches and fatigue the following day, and some hair loss which has increased recently. I sometimes find that I get a placebo sort of nausea even before I have taken it, probably due to anxiety caused by the negative things I have heard about it. I would say that my outlook [on MTX] is quite negative, due to the risk and side effects. Also, because it did not have much effect on my arthritis when taken without adalimumab [a monoclonal antibody medication to which MTX is often an adjunct], sometimes I do question if the risks and side effects are worth it.”
Lucy, who is diagnosed with JIA, had been taking MTX for five years before stopping due to side effects. “I took it for 5 years and have just come off it as my side effects outweighed the pros of taking it for me personally. I had a period where it worked so well alongside Abatacept infusions [a biologic that inhibits T-cell activation]. Some of my struggles were mental as once I was hyper-aware of the side effects, I would feel sick just opening the box. It was definitely a bit of a mental battle.”
For the clinician, MTX intolerance produces profound challenges for patient care.
Some studies report MTX intolerance in half of patients with JIA and about 11% of adult patients with rheumatoid arthritis. However, many people who do not have MTX intolerance according to MISS still experience biologically implausible adverse effects.
The nocebo effect is a formidable burden for patients, who suffer from a reduced quality of life, decreased drug adherence and worsened attitudes towards their own care. Over three-quarters of MTX-intolerant patients reluctantly use or totally refuse MTX, which has the potential to cause strain in the doctor-patient relationship if the doctor insists that MTX is the best treatment option. Ultimately, a clinician may have no choice but to prescribe a less effective treatment.
Old Strategies
Doctors, patients, and parents of patients have applied several strategies to reduce these debilitating effects. Doctors may choose to prescribe folic acid, change the route of administration , or prescribe antiemetics, such as ondansetron, as prophylaxis for MTX intolerance. However, these strategies are often based on anecdotal evidence, or no evidence at all.
To demonstrate this, Arthritis UK’s Young People’s Panel members Jade and Thea offered to share their experiences.
Jade, who is diagnosed with JIA, took MTX for three years before stopping it. “I tried different ways to manage it, and the thing that helped me most was eating ginger biscuits. Ginger has natural anti-inflammatory properties and can soothe the digestive system, and although it didn’t completely stop the nausea, it helped me feel like I was actively doing something to support myself. The side effects often left me feeling low and anxious about my next dose, so even that small sense of control made a difference.”
Thea added, “Folic acid helps me a lot - I have also always taken it before bed as I heard from others this prevents noticing side effects as you are sleeping through them. For hair loss I have tried to take better care of my hair by using less heat and using particular shampoos, however I know these won’t address the cause of the hair loss, so they don’t particularly help. I had one period over the summer when I was losing a lot of hair when showering; I did feel quite hopeless about this and anxious.”
These patient accounts reaffirm how important it is for doctors, and even medical students, to recognise that treatments for chronic diseases can negatively impact mental health. Whilst it may not be possible to avoid prescribing MTX, doctors can work with patients to find ways of coping with mental health difficulties, giving patients a greater sense of control over their condition.
In children, behaviours such as crying or refusal to take MTX create significant emotional challenges for parents. So, researchers and dedicated parents have implemented measures to try to reduce the symptoms that their children experience. A study conducted in Germany in 2017 sought to determine if MTX intolerance could be ameliorated in JIA patients with countermeasures, such as antiemetic drugs, covert dosing (secretly giving the child the drug), taste masking (consuming something to distract from the drug’s taste in oral administration) and alternative medicine (e.g. applying acupressure on the Nei Kuan point to reduce nausea). Unfortunately, over six months MTX intolerance measured by MISS did not improve. It is about time that new, evidence-based strategies are integrated into patients’ lives and doctors’ practise.
Dispelling Myths
Overestimation of the devastation of MTX can be propagated by myths surrounding the drug, resulting in anxiety, fear and disdain for the medication.
One complicated issue for patients to navigate is the use of non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, at the same time as MTX. NSAIDs can be prescribed alongside MTX for pain relief in patients with inflammatory arthritis. However, the BNF highlights that “patients should be advised to avoid self-medication with over-the-counter aspirin or ibuprofen” due to potential renal effects. Different healthcare professionals may offer different advice about NSAIDs depending on their training and the context, leaving patients in confusion.
Another common myth about MTX is that it is a brutally toxic chemotherapy drug. Whilst MTX can be used to treat cancers, in the context of autoinflammatory conditions, MTX doses are really quite low. Thea says, “I have heard the myth of methotrexate being chemotherapy, however I did know that this wasn’t actually true and that it is a much smaller dosage of the same drug. However, this has concerned friends and family when they have found out about this - I do feel it would be useful to address this myth when methotrexate is prescribed as I only heard about this online afterwards and it did cause some concern before I looked into it.”
Other circulating myths surrounding MTX include ideas about fertility and pregnancy. MTX is a teratogenic medication, meaning that it can cause birth defects, so it is contraindicated in pregnant individuals. However, some believe that people taking MTX should avoid touching anyone who is pregnant. In fact, a pregnant person has a negligible risk of being exposed to sufficient concentrations of the drug to harm the foetus, even if they are exposed to body fluids from a partner on MTX.
Jade says, “I can see how some of these myths could be misleading and easily believed if you didn’t know where to get reliable information from. I think with areas such as fertility, which is something incredibly sensitive and personal, it’s so damaging for the wrong information and these myths to be out there as there are multiple parties involved and this could deter patients from making the right choice of care for themselves.”
Dispelling myths starts with the first prescription - it is important that healthcare professionals are aware that these myths exist so that they can properly educate patients about what they are taking. This is where developing a rapport with the patient is so crucial, because patients are more likely to feel comfortable asking questions that might seem, in their eyes, stupid or authority-questioning - “Why do I need this - isn’t it a cancer drug? Is my disease that bad?”
Changing Mindsets
In 2024, a randomised control trial conducted in Australia tested a “mindset intervention” on patients who were newly prescribed methotrexate for a range of chronic inflammatory conditions. Participants were randomised to a mindset intervention group and a standard information group. The aim was to see if the wording used when prescribed methotrexate, such as swapping “side effects” for “symptoms” and reframing symptoms as a “sign that the drug is working”, could reduce the nocebo effect of MTX. On the other hand, the standard information group were told things like “the symptoms are just unfortunate side effects”.
After four weeks, participants randomised to the mindset intervention group experienced a reduced symptom burden and fewer general symptoms. All participants experienced an increase in methotrexate-specific symptoms, but this increase was only statistically significant for the standard information group. Additionally, participants in the intervention group were more likely to adhere to MTX, more motivated to take the drug and were less likely to discontinue treatment. There was no significant difference in C-reactive protein (CRP) levels, indicating that the drug had a similar effectiveness in both groups.
However, this study does have some limitations. The study only lasted for four weeks, and, as previously mentioned, MTX intolerance may take a longer period to develop. Additionally, all data (except for CRP levels) were self-reported, which is a source of social desirability bias, where participants may be encouraged to report a higher rate of adherence due to fear of judgement by analysers. So, is this mindset intervention approach actually useful?
An individual diagnosed with Crohn’s disease and ankylosing spondylitis who wishes to remain anonymous says, “When first prescribed methotrexate, my consultant explained it as something that could potentially damage other organs and would need regular blood tests. I was told to expect severe nausea and increased infections. The whole process felt very negative, not like it was something that would help me feel better. I think this contributed to my anticipation of it not working.”
Thea said, “Framing the side effects as something to be somewhat expected as a predicted symptom and to show that it works is helpful and reduces anxiety about side effects. Being better informed on drug safety and that some symptoms are not to be worried about too much would have helped me when I started. I have found that asking my doctor to explain in more detail why it works and how it works has helped me to feel confident in continuing the drug. When I didn’t fully understand the benefit of remaining on [MTX] and how it worked, it seemed much riskier and more questionable, and I did not want to remain on it.”
Lucy shared, “I don’t believe my doctor ever made it seem like a ‘huge’ thing. He just told me I’d need to get regular blood tests to check up on my liver as it’s a stronger drug essentially than the last one I was on. And to take folic acid for side effects too. I think [the mindset intervention] could be effective as I know first-hand how the side effects can affect you mentally and it can definitely feel like a placebo at times. Until I realised how strong it was, I would brush side effects off. Then I started to panic more about it.”
Reframing the way medications are introduced could have a positive effect on patients. It is important for healthcare professionals to understand that chronic diseases and their associated medications become permanent fixtures of our lives. In many cases, they regulate our schedules, dictate the activities we do, and impact relationships with healthcare professionals. It is important that clinicians empathise with us in that we have no ‘light at the end of the tunnel’ – the plan is to take MTX for the rest of the foreseeable future, unless our condition drastically improves or the nocebo burden becomes too much to bear. Nevertheless, there is ample evidence that healthcare professionals and other stakeholders have a large role to play in dispelling myths, changing mindsets, and helping patients to cope with the chronicity of their condition and treatment.
Thanks to Thea, Lucy, Jade and others from Arthritis UK’s Young People’s Panel for sharing their experiences for this article.
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