LDN - Educational material

In 1963, scientists developed naItrexone as a drug that blocks opioid receptors in the brain. Like naIoxone, another opioid blocker, naItrexone is more effective when taken orally and lasts longer in the body.

The FDA approved naItrexone in 1984 for the treatment of opioid dependence. People typically take between 50 and 100 mg per day, with 50 mg tablets commonly available. The idea of low-dose naItrexone (LDN) emerged in the 1980s when researchers noticed that lower doses of naItrexone, about one-tenth of the dose used to treat opioid dependence, had a unique effect.

At these low doses, around 4.5 mg per day, naItrexone provided pain relief and reduced inflammation, which was not observed at higher doses. These benefits were associated with an increase in the body's natural opioids.

Doctors began using LDN in the mid-1980s, but detailed scientific research into its effects on various conditions did not begin until the late 1980s. The first human study of LDN was published in 2007 and since then scientists have been slowly investigating its potential benefits for chronic diseases.

Key points on low doses of naItrexone

- Dosage and administration: Most LDN studies use a dose of 4.5 mg taken approximately one hour before bedtime. If this causes insomnia, it can be taken in the morning. If side effects occur, it may be helpful to reduce the dose to 3.0 mg.

Commercial availability: naItrexone is only available on the market in 50 mg tablets. As there is no ready-made LDN, people get it from specialised pharmacies that prepare it.

Safety and side effects: LDN has few reported side effects. The most common is vivid dreams, experienced by around 37% users, but these usually subside over time. Some people may also experience headaches or anxiety. There is no need for frequent liver function tests unless one has severe liver disease, as naItrexone does not significantly affect liver enzymes even at higher doses.

Abuse potential: naItrexone is used for the treatment of addiction and has no abuse or dependence potential. It does not cause a high or addiction. When treatment is discontinued, symptoms gradually return to previous levels.

Health benefits of low doses of naItrexone

Originally developed for the treatment of opioid dependence, naItrexone has shown potential in the treatment of a variety of conditions when used at low doses. Recent studies suggest that low-dose naItrexone (LDN) may offer therapeutic benefits for conditions such as fibromyalgia, chronic pain, inflammation, autoimmune diseases and other conditions, making it a versatile option for treating complex medical problems.

Low-dose NaItrexone in the treatment of fibromyalgia

Fibromyalgia is a chronic condition characterised by widespread musculoskeletal pain, fatigue and tenderness in localised areas. It is often accompanied by other symptoms such as sleep disturbances and cognitive difficulties.

Researchers have investigated the potential of low doses of naItrexone to effectively treat these symptoms. A study by Younger et al (2013) examined the effect of low doses of naItrexone (4.5 mg/day) on the severity of fibromyalgia compared to placebo. The study included 31 women with fibromyalgia.

Results showed a significant reduction in baseline pain (28.8% reduction) compared to placebo (18.0% reduction), with statistical significance (P = 0.016). In addition, participants reported improvements in overall life satisfaction and mood with low-dose naItrexone, although there were no significant changes in fatigue or sleep quality [1].

In another study, Bruun-Plesner et al (2020) aimed to identify the optimal dose of low-dose naItrexone for the treatment of fibromyalgia by examining the dose-response relationship. The study included women aged 18-60 years diagnosed with fibromyalgia. A top-down approach was used to determine the most effective doses for 50% (ED50) and 95% (ED95) participants.

The results showed effective doses of 3.88 mg for ED50 and 5.40 mg for ED95. The study also reported an improvement in fibromyalgia symptoms. This study supports the use of 4.5 mg as a test dose in future studies [2]. Furthermore, Paula et al (2023) evaluated the combined effects of low doses of naItrexone and transcranial direct current stimulation (tDCS) in patients with fibromyalgia. This study involved 86 women with fibromyalgia who were divided into four groups: LDN + tDCS, LDN + tDCS Sham, placebo + tDCS and placebo + tDCS Sham.

The results showed significant reductions in VAS pain scores in the LDN + tDCS, LDN + tDCS Sham and placebo + tDCS Sham groups. In particular, the LDN + tDCS group showed reduced pain frequency and intensity, as well as a reduced impact of pain on activity and emotion. Interestingly, the participant reported an improvement in depressive symptoms.

These findings suggest that the combination of LDN with tDCS may offer synergistic benefits in the treatment of pain in fibromyalgia [3]. In addition, Younger and Mackey (2009) conducted a pilot study to investigate the efficacy of low doses of naItrexone in relieving fibromyalgia symptoms. The study showed a significant reduction in fibromyalgia symptoms in women using LDN, with over 30% improvement over placebo.

NaItrexone, known for its opioid receptor antagonism, also inhibits microglia activity in the central nervous system, potentially reducing inflammation. These findings highlight low-dose naItrexone as an effective, well-tolerated and inexpensive treatment option for fibromyalgia [4].

Low-dose naItrexone and drug use in rheumatic disease

Interestingly, a study by Raknes and Småbrekke (2019) examined the effect of low-dose naItrexone on medication use in patients with rheumatic diseases. They used data from the Norwegian Prescription Database and compared prescriptions one year before and one year after starting LDN use. The results showed a 13% relative reduction in cumulative defined daily doses (DDD) of all drugs studied, with significant reductions in analgesics, NSAIDs, opioids, DMARDs and TNF-α antagonists among regular LDN users. These findings suggest that LDN may reduce the need for other drugs in the treatment of rheumatic conditions and may ultimately reduce the risk of potential side effects [5].

Low-dose NaItrexone in the treatment of psoriasis

Psoriasis is a chronic autoimmune disease characterised by itchy, scaly and red lesions on the skin. Traditional treatments vary in efficacy and can have significant side effects.

Low-dose naItrexone (LDN) has shown significant results in the treatment of psoriasis. Many patients experienced brighter skin and less discomfort, making LDN a valuable option in the treatment of this chronic skin disease. A study by Khan et al (2020) evaluated the efficacy of low-dose naItrexone (6 mg daily) in the treatment of psoriasis. Patients aged 13 years and older were included in the study.

The results showed significant improvements: the mean Psoriasis Area and Severity Index score decreased from 18.47 to 13.51, the mean body surface area from 11.97 to 8.07 and the mean Dermatology Quality of Life Index from 22.63 to 16.31. They concluded that low-dose naItrexone is effective, cost-effective and well tolerated in the treatment of psoriasis [6]. In addition, Weinstock et al (2020) presented a series of case reports involving 15 patients treated with 4.5 mg of oral naItrexone daily. Patients self-assessed improvement in their psoriasis. The results showed that 53% patients reported significant improvement, 13% slight improvement and 33% no change. The positive results were attributed to the potential of low doses of naItrexone in regulating lymphocyte responses and reducing cytokine production [7].

Furthermore, Muller et al (2018) described a 75-year-old man with plaque psoriasis treated with low-dose combination naItrexone. The patient experienced significant symptom relief with minimal side effects, in particular dry skin near the lesions [8]. Furthermore, in another case report by Beltran Monasterio (2019), a patient with severe erythrodermic psoriasis was treated with 4.5 mg LDN daily. Within six months, the patient showed significant improvement, achieving remission after three months of treatment. The treatment was well tolerated with no significant side effects [9]. Also Bridgman and Kirchhof (2018) documented a 60-year-old woman with moderate plaque psoriasis. She started taking 4.5 mg LDN daily after other treatments had failed. After six months, her affected body surface area decreased from 10% to 1% and her Psoriasis Area and Severity Index score decreased from 7.2 to 0.9.

The patient reported no side effects. LDN appears to reduce pro-inflammatory markers and increase endogenous opioids, effectively controlling pain and itching [10]. In terms of mechanisms, low-dose naItrexone is thought to act by regulating the immune response and reducing inflammation. It temporarily blocks opioid receptors, leading to an increase in endogenous opioids, which may help modulate pain and immune function.

Additionally, LDN can inhibit microglia activity, reducing central and peripheral inflammation. These studies and case reports indicate that low-dose naItrexone can reduce psoriasis symptoms and improve quality of life with minimal side effects.

low-dose naItrexone used in other skin diseases

low-dose naItrexone (LDN) is being investigated for its potential benefits in the treatment of various dermatological conditions.

Acne excoriée and prurigo excoriée

In a case study, Timoney and Bunker (2021) described a 53-year-old woman with a 25-year history of acne vulgaris and pruritus, characterised by severe pruritus and significant scarring. Previous treatment included multiple topical agents, phototherapy and systemic agents such as isotretinoin, antibiotics, anti-anxiety agents and neuromodulators, all of which proved ineffective.

Treatment with 3 mg LDN per night resulted in the patient no longer experiencing itching within a few weeks. She experienced a significant improvement in quality of life and reported no side effects from LDN. This case demonstrated the remarkable efficacy of LDN in the treatment of refractory pruritus associated with these conditions [11].

Hailey-Hailey disease

Furthermore, Ibrahim et al (2017) conducted a case series involving three patients with recurrent Hailey-Hailey disease (HHD). This rare genetic dermatosis is characterised by chronic, recurrent vesicles, erosions and maceration in the volar areas.

Each patient received LDN at a daily dose of 1.5 to 3.0 mg. Clinical response was monitored at 2- to 3-month intervals, focusing on erosion healing, erythema improvement and pain relief. All patients showed at least 80% improvement in disease and one patient achieved 90% resolution of disease. Quality of life improved significantly and no adverse effects were reported.

These findings suggest that LDN may be a low-cost and low-risk alternative for the treatment of recurrent HHD [12]. In another case study, Albers et al (2017) treated three patients with severe Hailey-Hailey disease with a dose of 3 mg LDN per night, with the dose increased to 4.5 mg in two patients. Significant healing of erosions and plaques was observed within one to two weeks, with complete resolution of clinical symptoms within two months. Symptoms were exacerbated when LDN was discontinued, but resolved rapidly when treatment was resumed. These results highlight the potential of LDN in the treatment of severe Hailey-Hailey disease [13].

Lichen planus

In another case report, Strazzulla et al (2017) reviewed the medical records of four patients with lichen planus (LPP), a scarring alopecia involving the scalp. They were treated with 3 mg LDN daily. All patients reported a reduction in pruritic symptoms, and clinical evidence indicated a reduction in scalp inflammation and disease progression. Treatment was well tolerated with no adverse events. These results suggest that LDN is beneficial and cost-effective in the treatment of LPP [14].

Darier's disease

In addition, Costa et al (2023) presented a case report of a 34-year-old woman with severe Darier's disease, an autosomal dominantly inherited genetic skin disorder. She was treated with 4.5 mg LDN daily. She had previously undergone multiple ineffective therapies, including oral isotretinoin, cyclosporine, doxycycline, methotrexate, azitretinoin and subcutaneous adalimumab.

After three months of LDN treatment, she experienced almost complete resolution of her lesions with no reported side effects. LDN can alter intracellular calcium transport and reduce levels of pro-inflammatory cytokines, benefiting conditions such as Darier's disease. This case supports LDN as a promising treatment for refractory Darier's disease [15].

Epidermolysis Bullosa Pruriginosa

LaMonica et al (2023) described a patient with severe pruritus due to epidermolysis bullosa pruriginosa, a rare subtype of dystrophic bullous epidermolysis. The patient was treated with LDN. Previous treatments, including topical corticosteroids, tacrolimus, cyclosporine, antihistamines, thalidomide, dupilumab and oral JAK inhibitors, were ineffective or caused unacceptable side effects.

After starting LDN, the patient experienced a significant reduction in itching and burning in the lower extremities. Clinical examination after 3 and 5 months showed thinning of the discoloured, lichenised plaques with fewer diffuse vesicles. The positive patient response suggests that LDN is a valuable treatment option for pruritus associated with EBP [16].

Sarcoidosis

For sarcoidosis, a chronic inflammatory disease, Weinstock et al (2017) described a patient treated with LDN at a dose of 1 mg/day, which was gradually increased to 4.5 mg/day. The patient experienced severe fatigue, a sarcoid rash and significant gastrointestinal involvement. Within two months, she reported a reduction in fatigue and dyspnoea and was able to discontinue inhalers and minocycline without recurrence of the rash.

After twelve months of continuous LDN treatment, she maintained improved energy levels and experienced no recurrence of the skin rash. A follow-up CT scan showed complete resolution of the spleen and liver lesions. The results suggest that LDN's ability to regulate endogenous opioids and suppress T- and B-lymphocyte responses likely contributes to these results. This case highlights the potential of LDN in reducing sarcoidosis symptoms and inflammation [17].

Systemic sclerosis

Frech et al (2011) conducted a case series involving three patients with systemic scleroderma (SSc), an autoimmune disease causing fibrosis and vasculopathy in the skin, lungs and gastrointestinal tract. They were treated with LDN.

Results showed significant improvement in pruritus and gastrointestinal symptoms, particularly in the subscales of constipation and flatulence. The treatment was well tolerated and no significant adverse effects were reported, except for two nights of insomnia in one patient.

This case series suggests that LDN may be an effective treatment for pruritus and gastrointestinal symptoms in systemic scleroderma [18]. These studies and case reports demonstrate that low-dose naItrexone offers significant benefits in the treatment of various dermatological conditions. It can reduce symptoms and improve quality of life with minimal side effects.

Low-dose NaItrexone in autoimmune diseases

Low-dose naItrexone (LDN) is being investigated for its potential benefits in the treatment of various autoimmune diseases, such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and others. A study by Lie et al (2018) investigated the efficacy of LDN in treating 47 patients with IBD who were not in remission and unresponsive to conventional therapies. Significant clinical improvement was found in 74.5% patients, with 25.5% achieving remission. LDN significantly improved wound healing and reduced endoplasmic reticulum (ER) stress in intestinal epithelial cells and human IBD intestinal organoids.

These findings suggest that LDN improves epithelial barrier function by promoting wound healing and reducing ER stress, providing a promising alternative for the treatment of refractory IBD [19].

In another study, Kariv et al (2006) evaluated the efficacy and safety of PTI-901, a low-dose naItrexone preparation, in 42 patients with irritable bowel syndrome. This open-label study involved a daily dose of 0.5 mg PTI-901 for 4 weeks. The researchers found improvement in 76% patients, with a significant increase in the number of pain-free days (from 0.5±1 to 1.25±2.14, P=0.011). Patients also did not experience any significant adverse effects.

These findings suggest that low-dose naItrexone is effective in relieving pain and general symptoms in patients with irritable bowel syndrome [20]. In addition, Raknes et al (2018) conducted a before-and-after study using data from the Norwegian Prescription Database (NorPD) to assess the effect of LDN on medication use in patients with inflammatory bowel disease. The study included 582 patients who received LDN. Significant reductions in several drugs were found: overall drug use decreased by 12%, intestinal anti-inflammatory agents by 17%, other immunosuppressants by 29%, intestinal corticosteroids by 32% and aminosalicylates by 17%. Interestingly, patients with Crohn's disease showed a 44% reduction in intestinal corticosteroid use, while patients with ulcerative colitis showed a 53% reduction in intestinal corticosteroid use and a 24% reduction in systemic corticosteroid use.

These findings suggest that LDN may help reduce the need for other drugs in the treatment of inflammatory bowel disease [21]. In a pilot clinical trial, Smith et al (2013) investigated the potential of low-dose naItrexone in 14 children aged 8 to 17 years with moderate to severe Crohn's disease. Participants received placebo or naItrexone (0.1 mg/kg) for eight weeks, followed by an open-label extension of naItrexone treatment. naItrexone was well tolerated, with no serious adverse events. At the end of the study, 25% children achieved remission and 67% showed improvement. In addition, systemic and social quality of life improved significantly.

These results indicate that naItrexone is safe and potentially effective in children with moderate to severe Crohn's disease [22]. In addition, Smith et al (2007) conducted an open pilot study in 17 patients with active Crohn's disease. Participants received 4.5 mg naItrexone daily for 12 weeks.

The researchers found a significant reduction in Crohn's disease activity index scores (P=0.01) and improved quality of life. 89% patients responded to treatment and 67% patients achieved remission (P<0.001). No laboratory abnormalities were reported and the most common adverse effect was sleep disturbance. These results suggest that LDN is an effective and safe treatment for active Crohn's disease, warranting further study [23].

Low-dose NaItrexone in the treatment of opioid dependence and detoxification

Treating opioid dependence and opioid withdrawal is difficult, and current treatments often result in significant side effects and incomplete symptom relief. Research points to low-dose naItrexone (LDN) as a potential therapy to improve detoxification outcomes and support long-term recovery.

A study by Mannelli et al (2012) examined the effects of combining very low doses of naItrexone (VLNTX) with clonidine in the treatment of opioid withdrawal. In a double-blind, randomised trial involving 127 people undergoing 6-day methadone withdrawal, participants received VLNTX (.125 or .25 mg/day) with clonidine (.1-.2 mg every 6 hours) or placebo. The combination of VLNTX and clonidine significantly reduced withdrawal symptoms and improved treatment completion rates compared with placebo or clonidine alone.

Patients reported an alleviation of subjective withdrawal symptoms and showed higher rates of detoxification completion, with no significant adverse events. These results suggest that VLNTX in combination with clonidine may improve withdrawal treatment in opioid-dependent patients [24]. In addition, Mannelli et al (2003) conducted a pilot study on five methadone-treated patients. As the methadone dose was reduced, they received very low doses of naItrexone, starting at 0.125 mg and increasing daily for six days. The detoxification process was completed smoothly and all patients transitioned to naItrexone maintenance treatment without significant incident or discomfort.

Treatment was well tolerated and patients did not experience intense withdrawal symptoms. This study suggests that very low doses of naItrexone may facilitate a smoother and more comfortable detoxification process, reducing the intensity and duration of withdrawal [25]. In addition, Mannelli et al (2011) also examined the effect of very low doses of naItrexone on detoxification outcomes in opioid-dependent patients who also consumed alcohol. In a double-blind, randomised trial involving 174 patients undergoing 6-day methadone detoxification, very low doses of naItrexone (0.125 or 0.250 mg/day) or placebo were administered.

Problem drinkers treated with very low doses of naItrexone showed a significant reduction in withdrawal symptoms and lower discontinuation rates compared to placebo. In addition, fewer patients resumed alcohol consumption immediately after hospital discharge. Low-dose naItrexone also reduced symptoms such as anxiety, sweating, tremor, nausea, stomach cramps and alcohol craving. These findings suggest that very low doses of naItrexone may improve detoxification outcomes in patients with concomitant alcohol and opioid dependence [26]. In addition, Mannelli et al (2009) conducted a randomised double-blind study involving 96 patients undergoing inpatient detoxification.

Patients received either very low doses of naItrexone (0.125 or 0.250 mg daily) or placebo along with a reduction in methadone dose. The very low-dose naItrexone intervention reduced withdrawal symptoms and reduced drug use in the first 24 hours after hospital discharge compared with placebo. In addition, the very low-dose naItrexone group had a higher rate of negative opioid and cannabis tests and greater engagement in outpatient treatment after one week [27]. In another study, Mannelli et al (2007) assessed whether extending post-detoxification treatment with low-dose naItrexone could improve patient outcomes. In an open-label study with 435 patients, two outpatient treatment options were offered: clonidine extended treatment (CET) or enhanced extended treatment (EET) combining NTX (1-10 mg / day) with CET. EET patients showed significantly better outcomes, including longer retention in the programme, lower drop-out rates, lower opioid use and better adherence to long-term outpatient treatment.

These findings suggest that low-dose naItrexone can significantly improve post-detoxification outcomes in opioid-dependent patients [28]. These findings indicate the potential of low-dose naItrexone to treat opioid dependence and improve detoxification outcomes. Clinical studies and case reports indicate that it can reduce withdrawal symptoms, improve treatment completion rates and improve recovery from detoxification with minimal side effects.

Low-dose NaItrexone in smoking and alcohol cessation

Overcoming addiction to psychoactive substances and quitting smoking are major health challenges, especially for heavy smokers and drug addicts.

Recent studies have looked at the use of low-dose naItrexone (LDN) with other therapies to improve efficacy. In a study, Ray et al (2014) tested whether the use of varenicline (VAR) with low-dose naItrexone (L-NTX) helps reduce cigarette cravings and alcohol cravings in compulsive smokers. After a 9-day adjustment period to the drug and a 12-hour break from nicotine, 130 participants were tested. The group taking both VAR and L-NTX had less craving for cigarettes and alcohol and consumed less of both substances compared to the other groups.

This suggests that the addition of low-dose naItrexone may help heavy smokers to quit smoking more effectively [29]. Furthermore, Roche et al (2015) examined how varenicline, low-dose naItrexone, a combination of both drugs and placebo affected smoking behaviour in 120 compulsive smokers. After a 9-day medication adjustment period, they smoked their first cigarette of the day under observation. The group using both VAR and L-NTX showed different smoking patterns, such as slower enlistment and less intense enlistment, which are associated with higher odds of quitting.

These findings suggest that the combination of VAR and L-NTX may alter smoking habits, facilitating smoking cessation [30]. Furthermore, Sushchyk et al (2016) investigated the effects of combining levo-tetrahydropalmatine (l-THP) with low-dose naItrexone (LDN) to prevent relapse to cocaine dependence. Using rats, they found that the combination reduced the desire to seek cocaine more effectively than l-THP alone. In addition, the combination reduced the sedative effects of l-THP and increased levels of certain chemicals in the brain.

These findings suggest that this combination may help to reduce relapse to cocaine dependence by affecting multiple systems in the brain [31]. These findings suggest that low-dose naItrexone likely works by regulating opioid receptors, increasing the body's natural opioid production and reducing withdrawal symptoms. When combined with other therapies, such as varenicline or levothyrohydropalmatine, LDN may target multiple pathways involved in addiction and withdrawal, enhancing the overall treatment effect.

Low-dose NaItrexone and multiple sclerosis (quality of life)

Studies have shown that low-dose naItrexone (LDN) can significantly improve quality of life and mood in patients with multiple sclerosis (MS) and other conditions. Cree et al (2010) looked at the effect of taking 4.5 mg of LDN each night on quality of life in patients with multiple sclerosis.

They conducted a study with 80 patients in which neither the patients nor the researchers knew who was receiving LDN and who was receiving placebo. The study showed that LDN was well tolerated without serious side effects. Among the 60 patients who completed the study, there were significant improvements in mental health and quality of life.

These findings suggest that LDN may improve mental health quality of life in patients with multiple sclerosis [32]. In another study, McLaughlin et al (2022) investigated whether LDN could help manage anxiety and depression in multiple sclerosis patients during the early months of the COVID-19 pandemic.

They surveyed a small group of multiple sclerosis patients in central Pennsylvania about their anxiety and depression. The results showed that patients taking LDN had significantly lower anxiety and depression scores compared to those taking only standard disease-modifying therapy. This indicates that LDN may help to reduce anxiety and depression. These findings suggest that LDN may be a beneficial and safe option for improving mental health in patients with multiple sclerosis, especially during stressful times such as the COVID-19 pandemic [33]. Furthermore, Gironi et al (2008) conducted a six-month pilot study to evaluate the safety and efficacy of LDN in patients with primary progressive multiple sclerosis (PPMS).

The study showed that LDN was generally safe and well tolerated. In particular, significant improvements in spasticity were observed, with an increase in beta-endorphin levels by the end of the study. Although improvements in pain, fatigue, depression and quality of life were also noted, they were not statistically detailed.

These findings suggest that LDN may help manage the symptoms of primary progressive multiple sclerosis [35]. In a case study, a 62-year-old woman with multiple sclerosis who experienced chronic migraines was treated with LDN. The dose was gradually increased to 4.5 mg per night and the Wahls protocol, a dietary plan designed to reduce inflammation and improve health.

After one month, she reported a significant reduction in the frequency, severity and duration of migraines, as well as improvements in sleep quality, fatigue, mood and physical mobility. These benefits persisted for 11 months of continuous LDN use and adherence to the Wahls protocol, except for a short break. The patient described the treatment as "life-changing".

This case suggests that the combination of LDN and the Wahls Protocol can significantly improve chronic migraine symptoms and overall quality of life in patients with multiple sclerosis [36]. These findings highlight the potential of LDN to improve quality of life and mood in patients with multiple sclerosis and other conditions.

NaItrexone at low doses and major depressive disorder

NaItrexone at low doses can help reduce depressive symptoms in patients with major depressive disorder who do not respond fully to dopaminergic antidepressants.

In a study, Mischoulon et al (2017) investigated whether LDN could help patients (12 adults) with major depressive disorder who were not responding fully to current antidepressants. They conducted a study with subjects who were randomly assigned to receive one of these drugs or a placebo for three weeks.

The results showed that patients taking naItrexone (1 mg twice daily) had significant improvements in depression scores compared to those taking placebo. These results suggest that LDN may help reduce depressive symptoms in patients with major depressive disorder who do not respond fully to dopaminergic antidepressants [34].

NaItrexone in low doses for chronic fatigue

Chronic fatigue syndrome (CFS) is a debilitating condition characterised by severe fatigue, pain and cognitive impairment. Research suggests that low-dose naItrexone (LDN) may be a promising treatment for CFS and similar conditions.

In a series of case reports, three patients with long-standing CFS were treated with LDN at doses ranging from 4 to 12 mg daily. Results varied from patient to patient. One patient experienced a significant improvement in general health, including a significant reduction in fatigue and pain. Another patient experienced moderate improvement in some symptoms, while a third patient had minimal improvement.

These case reports highlight that LDN can significantly help some patients with CFS, although others may see less benefit [37]. In addition, a retrospective cohort study investigated the efficacy of LDN in the treatment of post-COVID-19 symptoms, comparing LDN with other treatments, such as amitriptyline and physical therapy, with 108 patients from a post-COVID-19 clinic.

The study showed that patients taking LDN were significantly more likely to improve their fatigue and pain compared to those receiving physical therapy alone. This suggests that LDN may be a valuable treatment option for symptoms after COVID-19 [38]. Additionally, a pilot study evaluated a combination of LDN (4.5 mg/day) and NAD+ supplementation in 36 patients with persistent fatigue after COVID-19. At 12 weeks, participants showed significant improvements in quality of life and reduced fatigue.

About half of the participants were classified as responders, showing at least 20% improvement in fatigue scores. Treatment was generally safe, with only mild adverse effects reported. These results suggest that LDN in combination with NAD+ may be an effective treatment for fatigue after COVID-19 [39]. The results of the study and case reports indicate the potential of low-dose naItrexone in the treatment of chronic fatigue and related conditions, including post-COVID-19 syndrome.

Low-dose NaItrexone in pain relief

Research shows the potential of low-dose naItrexone (LDN) in relieving various types of chronic pain. In a study, Dieckmann et al (2021) conducted a retrospective study to evaluate the effects of LDN in 59 patients with refractory neuropathic corneal pain.

They were treated with 4.5 mg LDN before bed for at least four weeks. The results were promising. Patients reported a significant decrease in pain scores, with the mean pain score dropping by 49.22% from 6.13 to 3.23 (p < 0.001). Of note, quality of life (QoL) scores also improved significantly, from 5.84 to 3.77 (p = 0.023). However, common side effects included vivid dreams, headaches and abdominal pain. These results suggest that LDN is an effective and well-tolerated treatment for NCP [40].

Furthermore, in a case study by Sturn and Collin (2016), a patient with chronic pain unresponsive to conventional treatments was prescribed LDN at a dose of 3 mg per night. The patient experienced a dramatic reduction in pain symptoms within a few weeks, leading to improved daily functioning and overall quality of life. The treatment was well tolerated, with only mild and transient side effects such as nausea and vivid dreams [41]. Interestingly, Srinivasan et al (2021) conducted a clinical trial comparing LDN with amitriptyline in the treatment of painful diabetic neuropathy. The study involved 67 participants randomly assigned to receive 2 mg LDN or 10 mg amitriptyline daily. The results showed that LDN provided comparable pain reduction to amitriptyline, but with significantly fewer side effects. Patients taking LDN experienced fewer side effects, mainly mild diarrhoea, compared to frequent drowsiness in the amitriptyline group.

This study supports LDN as a promising alternative for the treatment of painful diabetic neuropathy [42]. Also, Hota et al (2016) presented the case of a 76-year-old man with diabetes-related neuropathic pain who did not respond to conventional treatments. The patient started taking LDN, gradually increasing the dose to 4 mg before bedtime. Within a few weeks, the patient reported significant pain relief and pain scores dropped from 90% to 5% on the visual analogue scale.

The patient also experienced improved sleep and reduced pain-related disruptions to daily life. Proposed mechanisms of pain relief by LDN include increased production of endogenous opioids and reduction of pro-inflammatory cytokines [43]. Furthermore, Chopra and Cooper (2013) described two cases of patients with complex regional pain syndrome (CRPS) in whom LDN treatment resulted in significant improvement. Both patients had severe symptoms unresponsive to conventional therapies. After starting LDN, one patient experienced remission of dystonic spasms, while the other showed significant improvement in fixed dystonia.

LDN's ability to antagonise the Toll-like receptor 4 pathway and attenuate activated microglia likely contributed to these results. These cases suggest that LDN may be a promising therapeutic option for CRPS, particularly for patients with symptoms refractory to traditional therapies [44].

Low-dose NaItrexone in the treatment of burning mouth syndrome

Burning Mouth Syndrome (BMS) is defined as a chronic intraoral burning sensation without any identifiable local or systemic cause.

Patients often experience persistent pain, burning, dryness and discomfort in the mouth, which significantly affects their quality of life. Current treatment options for BMS often produce unsatisfactory results. Recent case reports have explored the potential efficacy of low-dose naItrexone (LDN) as a new treatment option for BMS. In a case report by Sangalla and Miller (2023), a 62-year-old woman with a 3-year history of baking tongue pain and multiple comorbidities, including fibromyalgia, irritable bowel syndrome (IBS), headache and interstitial cystitis, was treated with low-dose naItrexone (LDN). She was prescribed a dry mouth protocol and LDN at a dose of 3 mg. After one month of treatment, the patient reported a 50% reduction in BMS pain, with no pain on waking. After two months, widespread pain due to chronic conditions was reduced by 50% and the headache had resolved. After six months, with the LDN dose adjusted to 4.5 mg, the patient maintained 50% reduction in widespread pain and BMS pain intensity at 2/10, with no reported side effects.

These findings suggest that LDN may be a feasible and effective treatment option for BMS, particularly in patients refractory to conventional treatments [45]. Similarly, Neuman and Chadwick (2021) presented the case of a woman in her seventh decade of life who had suffered from BMS refractory to conventional treatment for almost a decade. The patient experienced severe, persistent burning pain that significantly affected her quality of life.

She was treated with low-dose naItrexone (LDN) and reported a significant reduction in pain intensity after starting LDN therapy, which significantly improved her overall quality of life [46]. Taken together, these case reports suggest that low-dose naItrexone may be an effective treatment option for patients with burning mouth syndrome, especially for those who have not found relief with traditional therapies.

Low-dose naItrexone (LDN) in the treatment of cancer (animal studies)

Numerous studies have demonstrated the positive effects of low-dose naItrexone in the treatment of various cancers. By modulating the immune response and directly inhibiting tumour cell proliferation, LDN offers a promising therapeutic approach with fewer side effects than traditional chemotherapy.

A preclinical study tested whether naItrexone, an opioid antagonist, could affect the growth of ovarian cancer cells. The study examined the effects of naItrexone alone and in combination with standard anticancer therapies, such as taxol and cisplatin, on ovarian cancer cells in tissue culture and in mice with ovarian tumours.

In tissue culture, naItrexone reduced DNA synthesis and cell replication in ovarian cancer cells. In combination with taxol or cisplatin, naItrexone enhanced the anti-tumour effects of these drugs. In mice, treatment with low doses of naItrexone (LDN) inhibited tumour progression by reducing DNA synthesis and angiogenesis without affecting cell survival.

The combination of LDN with cisplatin, but not with taxol, further inhibited tumour growth and mitigated cisplatin-related toxicities such as weight loss. LDN treatment also increased the expression of opioid growth factor (OGF) and its receptor, which mediate anti-proliferative effects on ovarian cancer cells [47].

Similarly, a colorectal cancer (CRC) study investigated the mechanisms by which LDN inhibits tumour progression. The study involved treating mice with LDN and comparing their results with a control group. LDN treatment increased the expression of macrophage markers and M1 macrophage phenotypic markers, indicating an enhanced immune response.

LDN also increased the levels of apoptosis-related factors while decreasing the levels of anti-apoptotic factors, leading to increased tumour cell apoptosis and reduced tumour size. These findings suggest that LDN promotes M1-like macrophage activation and induces tumour cell apoptosis through specific signalling pathways [48]. These findings indicate that LDN has significant potential in the treatment of various cancers.

Low-dose NaItrexone in the treatment of Sjogren's syndrome

Sjogren's syndrome is a chronic autoimmune disorder characterised by inflammation of the lacrimal and salivary glands, leading to dry eyes and mouth. Patients often suffer from significant fatigue and musculoskeletal pain, which are difficult to control with existing treatments.

Recent case reports suggest that low-dose naItrexone (LDN) may be a promising new treatment for this condition. In a case report by Zashin (2019), a 47-year-old woman with long-standing symptoms of dry eyes, dry mouth, joint pain and fatigue was diagnosed with Sjogren's syndrome based on elevated inflammatory markers and positive rheumatoid factor. She did not respond to standard therapies.

After being prescribed LDN, the patient experienced a significant improvement in her symptoms. Dryness, joint pain and fatigue were significantly reduced, which greatly improved her overall quality of life. This case highlights the potential benefits of LDN in the treatment of Sjogren's syndrome, particularly in patients who do not respond to conventional treatments [49]. In another report, Zashin (2020) described two additional cases of patients with Sjogren's syndrome who responded well to LDN therapy.

The first case involved a 24-year-old woman with documented SS, with dry eyes, dry mouth, joint pain, fatigue and headaches. She showed significant clinical improvement in all symptoms after starting LDN. The second case involved a 66-year-old woman with documented SS, experiencing symptoms. She too responded positively to LDN therapy, with marked improvement in joint symptoms [50]. Taken together, these case reports suggest that LDN may be an effective treatment for Sjogren's syndrome, particularly in relieving fatigue and musculoskeletal pain.

Low-dose NaItrexone in the treatment of stiff-body syndrome

Stiff person syndrome (SPS) is a rare neurological disorder characterised by severe muscle stiffness and painful spasms, often triggered by stimuli such as noise or touch. An autoimmune component is thought to contribute to this disorder.

A case study (Zappaterra et al., 2020) involving a 59-year-old woman with SPS showed a significant improvement in symptoms after six weeks of LDN therapy. The patient experienced a reduction in pain, anxiety, depression, agoraphobia and muscle tension. This improvement persisted for 12 months, significantly improving the patient's quality of life. This case suggests that LDN may be a valuable treatment option for SPS, warranting further research to investigate its long-term benefits and mechanisms [51].

Low-dose NaItrexone in the treatment of trauma-related dissociative disorders

Low-dose naItrexone (LDN) has been investigated for its potential to treat dissociative symptoms in trauma-related disorders. In a clinical trial (Pape & Wöller, 2015) involving 15 patients, those treated with LDN at doses of 2 to 6 mg/day reported immediate and sustained positive effects.

The treatment led to clearer perception, better appraisal of reality, improved body and emotion perception and better self-regulation. These benefits were achieved with very few side effects, making LDN a promising treatment for complex post-traumatic stress disorder (PTSD) and dissociative disorders. The results suggest that LDN can improve mental health and well-being by reducing dissociation [52].

Low-dose NaItrexone for autistic children

Bouvard et al (1995) evaluated the effect of low doses of naItrexone (NTX) in children with autism for a one-month treatment period. In this double-blind study, autistic children received either naItrexone at a low dose of 0.5 mg/kg per day or placebo.

The study assessed both clinical outcomes and biochemical markers, including levels of beta-endorphin, adrenocorticotropic hormone (ACTH), norepinephrine, arginine-vasopressin and serotonin. Results indicated moderate clinical improvement in both the low-dose naItrexone and placebo groups, with slightly better overall results observed in the low-dose naItrexone group.

It is noteworthy that the children who responded best to naItrexone treatment showed significant normalisation of elevated plasma chemical parameters, particularly in terms of C-terminal levels of beta-endorphin and serotonin. These results suggest that low-dose naItrexone benefits a subgroup of children with autism, particularly those with specific plasma abnormalities related to the pro-opiomelanocortin system [53].

Low-dose NaItrexone and endorphin levels: a possible mechanism

Studies have shown that naItrexone in low doses has a significant effect on β-endorphin levels in the body. β-endorphin is a natural painkiller produced by our body and plays a role in regulating pain, immune response and overall wellbeing.

Several studies suggest that LDN acts by stimulating opioid receptors to release β-endorphin, a chemical that helps balance inflammation and interacts with opioid growth factor (OGF) and its receptor (OGFr). A recent study by Kumari et al (2023) showed that LDN has a protective or regenerative effect on the brain after hypoxia-ischaemia by increasing β-endorphin and OGF levels [54].

Mice with and without diabetes were treated with LDN after induction of hypoxia-ischaemia. LDN was administered at a specific time and compared with a control treatment (saline with phosphate buffer). The results showed that LDN increased blood levels of β-endorphin and OGF and helped diabetic mice recover better compared to mice treated with the control solution. This suggests that LDN has a protective or regenerative effect on the brain after hypoxia-ischaemia.

In another study, researchers found abnormal patterns of β-endorphin levels, with some showing extremely high levels, among 47% opiate-dependent patients [55]. LDN leads to an increase in blood levels of β-endorphins, which may be one of the ways it helps conditions such as chronic pain and autoimmune diseases by enhancing the body's natural analgesic and anti-inflammatory mechanisms.

Furthermore, a study on adolescents hospitalised for bulimia nervosa showed a reduction in the urge to overeat after administration of the opioid receptor antagonist naItrexone [56]. It is noteworthy that there was an increase in baseline plasma β-endorphin levels during naItrexone treatment. This suggests that naItrexone stimulates β-endorphin release, which may help to reduce the compulsive urge to overeat.

Conclusions

Low-dose naItrexone (LDN) offers significant therapeutic benefits for a variety of conditions. For example, people with fibromyalgia, chronic pain and autoimmune diseases have experienced symptom relief and significant improvements in quality of life with low-dose naItrexone intervention.

In addition, LDN has proven effective in treating skin conditions such as psoriasis, eczema and lichen planus due to its anti-inflammatory properties. In the case of addiction treatment, LDN has been used effectively to aid opioid detoxification and promote long-term recovery, even helping to reduce cravings and withdrawal symptoms from alcohol and nicotine.

It is also promising in mental health care, especially in reducing symptoms of depression in cases of treatment-resistant depression. In addition, LDN has been shown to improve outcomes in patients with multiple sclerosis, chronic fatigue syndrome and even burning mouth syndrome, where other treatments often fail.

Furthermore, preliminary animal studies suggest that LDN may have a role in oncology by inhibiting tumour growth and enhancing the efficacy of traditional anti-cancer therapies. Overall, LDN stands out as a low-cost, well-tolerated and versatile treatment option that has the potential to revolutionise the management of complex, chronic conditions across specialties.

Disclaimer

This article is written to educate and raise awareness of the substance discussed. It is important to note that the substance discussed is a substance and not a specific product. The information contained in the text is based on available scientific studies and is not intended as medical advice or to promote self-medication. The reader is advised to consult a qualified health professional for all health and treatment decisions.

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