The most reliable data therefore suggest that, if LDN has therapeutic effects, it is likely modest, inconsistent and patient specific.
There is more discussion about why the anecdotes and lower quality trial results don't hold when good trials are done.
Several factors likely contribute to the gap between anecdotal reports and controlled findings.
They also rely heavily on subjective patient-reported outcomes, which are particularly vulnerable to placebo effects in conditions with fluctuating symptoms or strong patient expectations.
It's fantastic to see published literature mentioning this issue, and applying it to their analysis of the evidence-base. (Unfortunately, lots of people think the placebo effect is some useful magical effect, where the body fixes itself through belief alone, so that reason is not as convincing as it should be.)
Other problems mentioned are negative results not being published, small sample sizes, short durations, poor participant characterisation, and co-administration with other medications.
Although case reports are susceptible to selective reporting, they do document genuine individual responses. These accounts indicate that LDN may offer meaningful benefit to some individuals, even when this is not consistently replicated in RCTs. This raises the possibility that LDN functions as an individualised therapy with variable and unpredictable responses rather than a uniformly effective treatment. Despite being considered the highest-quality study design, conventional parallel-group RCTs may therefore be poorly suited to detecting benefit in small responder subgroups.
In this context, N-of-1 RCTs offer a promising alternative, preserving randomisation and blinding, while directly quantifying within-patient treatment effects [123, 124]. Aggregation of data from a series of N-of-1 trials is possible with appropriate statistical techniques. Such designs are particularly suited to identifying which individual patients may benefit from LDN and therefore warrant consideration in future research to determine genuine therapeutic value beyond population-level averages.
Damn, the paper was going extremely well, until they got to this bit. "Although case reports are susceptible to selective reporting, they do document genuine individual responses."
No!! Case reports without relevant biomarker data and sound knowledge of the therapeutic mechanism are, at best, evidence of a 'genuine improvement', not a 'genuine response'. The authors of this review have already acknowledged the problems with conditions with fluctuating symptoms, short duration evaluation periods and the impact of patient expectations that make case reports unreliable. But, crucially, a case report with only subjective outcomes is not enough to know that a reported improvement is caused by the treatment.
The authors call for N-of-1 RCTs, where an individual is given the treatment or a placebo without them knowing which. And, they suggest that these N-of-1 RCTs can be combined to give some useful data. But, surely, the aggregation of N-of-1 RCTs is pretty much a normal RCT?
I think what they should have been calling for here, is detailed characterisation of participants and sufficient sample sizes, so that post-trial stratification studies can be done to identify possible responder groups (that can be investigated in later studies).
Future research should focus on adequately powered, placebo-controlled trials with objective endpoints in the most promising indications, alongside N-of-1 methodologies to identify which patients derive benefit and refine treatment selection.
Perhaps I'm wrong, but I think the authors sort of lost the plot at the end here with their support for N=1 evidence. Perhaps if you have the patient cycling on and off a treatment multiple times, you could get to some certainty about whether something works for an individual, but even a couple of cycles of treatment and placebo won't produce proof that a treatment works, certainly not with the marginal benefits that most of these therapies are reported to produce.
It's like some clinician (a reviewer or supervisor?) came along at the end and said 'but, we can't take away people's hope. These therapies don't work for everyone, but I'm convinced they do work for some people', and got the author team to water down their conclusions.
Until such evidence emerges, LDN should be considered a low-risk experimental therapy with insufficiently validated clinical benefit. Nonetheless, the use of LDN may be a genuinely reasonable option in treatment-resistant cases.
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