Wai M Liu, Angus G Dalgleish
Recent years have seen a rapid increase in the number of reports highlighting a role for LDN in immunological and oncological conditions. These reports present tantalizing glimpses into different ways the drug can be used. Although naltrexone was first employed as a means to support patients with addictive disorders, it was discovered, albeit serendipitously, if used at lower dosages, it could also help with other indications. However, this dose range was very narrow, typically one between 3–5 mg per day for patients. The dosage appeared not to be dependent upon body weight, but more with daily dose, as patients using doses outside of this range commonly reported a loss of activity, which was restored once the dose was re-adjusted to between 3–5 mg/day. More importantly, most of these conditions have a strong inflammatory component and where the effect can be observed directly such as patients with psoriasis, the benefit observed at the commonly used 4.5 mg dose disappears if it is raised to even 6 mg. Reassuringly, however, clinical benefit and activity are quickly restored when the dose is dropped back to 4.5 mg.
The existence of real-world cases describing therapeutic activity by using LDN has led to a number of lab-based studies that have confirmed an immune-modulatory element of LDN. The fact that so many cases have been recorded where adding the agents has improved and/or supported the actions of other treatments highlights the potential of utilizing a drug that is safe and cost-effective. Although there have been a number of randomized trials in some indications showing some benefit, none were large enough to lead to a formal approval. The need for these larger trials would require backing from industry, and understandably, the risks associated with promoting a drug that is generic can be off-putting. Hopefully, the increased understanding of mechanisms of action will present IP and licensing opportunities that will attract the support necessary to deliver a therapeutic product.
Gene analysis of LDN action has identified mechanisms of action, which suggest novel approaches to enhancing its activity. Cancer cells are often resistant to chemotherapy as they possess dysfunctional apoptosis pathways. Studies have shown LDN is capable of altering the balance of proteins that determine cell death in cancer cells, and by swinging apoptosis toward a pro-apoptotic setting, LDN possesses the ability to prime cancer cells to cytotoxic chemotherapy drugs. Studies have also shown that the sequence in which it is given can influence overall activity, and it is the sensitization element of LDN’s activity that is an area of work that is currently being explored in more depth. This is something we and others have highlighted and discussed previously . Hopefully, this will allow for new treatment regimens to be developed that can employ LDN more effectively. Ultimately, these combination approaches mean LDN may be able to partner with a wide range of drugs, and potentially be employed as an ‘universal adjuvant.’
There are a number of conditions for which remarkable activity is hard to explain based upon LDN’s ability to modulate opioid receptors. This led to a search for additional receptors through which LDN could work, and it was discovered naltrexone could inhibit IL-6 production through TLR-7,8 and 9. This effect is also more likely to explain the reported benefits of LDN in Crohn’s Disease and psoriasis, which both over-express TLR-9. The fact that IL-6 is a major promotor of cancer progression and metastatic spread is yet another reason to explore LDN in a range of oncological conditions.