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1948–2026

The International Society for Orthomolecular Medicine is saddened to announce the death of Tsuyoshi (Ken) Kitahara, who passed peacefully on June 1, 2026, surrounded by his family.

Ken was born in Tokyo and graduated from the University of Keio, Faculty of Law. Throughout his life, Ken lived in the United States, Europe, Singapore and Japan. He also travelled extensively as an international businessman. It was in search of psychiatric help for his son that Ken discovered orthomolecular medicine. When told that his son would never get well and would have to take drugs for the rest of his life, Ken decided this was not acceptable. An article on vitamin therapy for psychiatric disorders lead him to visit Dr. Abram Hoffer in Victoria in 2002. He received a level of support that was not available in Japan and committed his time and resources to ensuring that other people in his country had access to the knowledge that had benefited his son.

In 2003, along with Dr. Hiroyuki Abe and Dr. Osamu Mizukami, Ken established the Japanese Society for Orthomolecular Medicine (JSOM) to provide education and advocacy for the use of nutrients in medical practice. From that time, Ken became a regular attendee at the International Orthomolecular Medicine Today Conference in Canada, often accompanied by a large delegation of colleagues from Japan. He would bring the information learned at the conference back to Japan for dissemination to physicians and patients. Ken also engaged with nutraceutical manufacturers in North America, establishing supply chains to ensure access to a wide range of products and services. He was responsible for the Japanese translation of numerous English books and printed resources for orthomolecular medicine.

In 2011, Ken was inducted into the Orthomolecular Medicine Hall of Fame for his pioneering influence in Japan, introducing our work to thousands.

He will be remembered for his generosity, his strong commitment to serving others, and for his leading role in orthomolecular advocacy.

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September 20, 1938 – December 5, 2025

It is with profound sadness that we announce the passing of Dr. Hiroyuki Abe, MD, a distinguished pioneer in orthomolecular medicine and integrative cancer care, who died on December 5, 2025, at the age of 87, due to pneumonia.

Dr. Abe’s lifelong contributions to clinical medicine, research, and the advancement of nutritional therapies have left an indelible mark on our global medical community. His passion for improving patient outcomes through evidence-based, compassionate care distinguished him as a leader and mentor to countless physicians, researchers, and healthcare professionals.

Dr. Abe was a founding figure in orthomolecular and integrative oncology in Japan. After completing his medical education and surgical training, he devoted himself to advancing patient-centered medicine that combined conventional oncology with innovative supportive therapies, including high-dose intravenous vitamin C and other nutritional treatments.

In 1988, he established his medical foundation and subsequently the Tokyo Cancer Clinic, a place that became known not only for its comprehensive cancer care but also for its emphasis on quality of life and holistic patient support. Under his leadership, the Tokyo Cancer Clinic became a beacon of hope for many patients and families, offering compassionate care and multidisciplinary treatment approaches long before such models became widespread.

Dr. Abe’s influence extended beyond his clinic. He was a dedicated educator and a vocal advocate for orthomolecular medicine, tirelessly promoting the integration of nutrient-based therapies into mainstream care. He served as a board member of the IV Therapy Research Society, contributing his clinical insights, guiding research initiatives, and fostering international collaboration.

In recognition of his pioneering work and enduring impact, Dr. Abe was honored with induction into the Orthomolecular Medicine Hall of Fame, a testament to his commitment to advancing health through science, compassion, and innovation.

Those who knew Dr. Abe remember him not only for his intellectual rigor, clinical expertise, and visionary leadership, but also for his warm humanity, humility, and unwavering dedication to patients. He inspired many to think broadly about healing, to challenge convention wisely, and to serve with integrity.

Dr. Abe is survived by his family, colleagues, and a global community of practitioners whose lives and work were enriched by his example. His legacy will continue to inspire generations of clinicians and researchers devoted to integrative, patient-centered care.

We extend our deepest condolences to his family and all who had the privilege of knowing him. May his memory be a blessing and a lasting source of inspiration.

Author: Atsuo Yanagisawa, MD

Premenstrual syndrome (PMS) is a complex condition marked by psychological and physical symptoms that occur approximately two weeks before menstruation (Farahmand et al., 2017), which are linked to the luteal phase of the female menstrual cycle,  and resolve when menstruation ceases (Freeman, 2003). Globally, the pooled prevalence of PMS involving females of reproductive age is 47.8% (Gudipally & Sharma, 2023). Common psychological symptoms of PMS include irritability, crying, mood swings, and anxiety, whereas physical symptoms include headaches, breast tenderness, abdominal pain, and changes in appetite (Gudipally & Sharma, 2023).

The etiology of PMS involves hormonal fluctuations during the monthly menstrual cycle accompanied by reductions in estradiol and progesterone (Modzelewski et al., 2024). The progesterone metabolite allopregnanolone (ALLO), an allosteric modulator of the gamma-aminobutyric acid (GABA) receptor, has broad effects on the central nervous system (CNS), which explains its role in reducing PMS symptoms (Modzelewski et al., 2024). The role of ALLO in PMS is complex because it parallels the rise and fall of progesterone and peaks in the luteal phase  (Modzelewski et al., 2024).  ALLO acts specifically on GABA-A receptors, facilitating the inhibition of signaling in the brain, leading to the suppression of corticotopin-releasing hormone (CRH) from the hypothalamus, thus blunting the stress response and attenuating anxiety (Toufexis et al., 2004). Females with PMS have an abnormal stress response characterized by an inability to return to baseline following a stressor, and insufficient production of ALLO and/or reduced sensitivity of the GABA-A receptor to ALLO (di Scalea & Pearlstein, 2019). The abnormal stress response and associated ALLO dynamics underlie mood instability, anxiety, and other emotional symptoms (di Scalea & Pearlstein, 2019). Further complicating matters, women with PMS may exhibit elevated baseline ALLO levels or abnormal progesterone conversion. As blocking ALLO synthesis reduces these symptoms, altered ALLO metabolism likely plays a key role in symptom development (Modzelewski et al., 2024).

Based on the aforementioned data, it seems clinically plausible that treatment aimed at modulating ALLO production may facilitate improved sensitivity of the GABA-A receptor, thus helping with PMS symptoms. This is the precise reason why selective serotonin reuptake inhibitors (SSRIs) have been used to treat the more severe form of PMS – known as premenstrual dysphoric disorder – since SSRIs increase ALLO levels, assist in the restoration of normal GABAergic function, and augment stress resilience (di Scalea & Pearlstein, 2019).

Transdermal progesterone cream (TPC) should also be considered for reproductive-aged females experiencing PMS. Theoretically, TPC may facilitate baseline allopregnanolone (ALLO) production, mitigate issues associated with abnormal ALLO metabolism, and improve GABA-A receptor sensitivity to ALLO. This case report details a reproductive-aged female with severe PMS symptoms who experienced significant symptom alleviation following a combined regimen of TPC and micronutrients. Although micronutrients were utilized, clinical observations and patient feedback strongly suggested that TPC was the primary driver of therapeutic improvement.

Patient History and Background

A 45-year-old woman presented to my clinical practice on September 20, 2023, with a history of panic attacks and depression. Her medical history was notable for developmental trauma experienced during childhood and adolescence, stemming from the caregiving demands of her father’s cancer diagnosis. She had previously consulted a therapist for several years approximately 10 to 15 years prior, at which time psychiatric medication was prescribed but never initiated. Instead, she managed her symptoms through lifestyle modification.

The patient also reported a history of postpartum anxiety following the delivery of her baby girl during the coronavirus disease 2019 pandemic. Upon returning home, pandemic-related lockdown measures left the patient and her husband to care for the newborn without external support.

Current Symptomatology and Assessment

Over the last several years, the patient experienced seasonal depression, energy challenges, and significant mood fluctuations coinciding with her menstrual cycles. She reported episodes of acute anxiety triggered by her daughter’s distress, during which she practiced cognitive detachment (“checking out”) to maintain composure and remain available to assist her child.

Her menstrual cycles occurred every 28-30 days, with an occasional missed period every 4-5 cycles attributed to stress. Premenstrually, her mood was described as highly labile, accompanied by irritability, breast tenderness, backaches, and cravings for salt and sugar. These premenstrual changes precipitated interpersonal challenges, which increased in severity following the birth of her daughter. The family history was non-contributory to these presenting symptoms. Her medical history was significant for a diagnosis of polycystic ovarian syndrome.

Baseline Lifestyle and Interventions

The patient was not taking any prescribed medications. Her baseline regimen consisted of natural health products (NHPs), including:

• Vitamin D3: 2000 IU daily
• Vitamin B1: 100 mg occasionally
• Prenatal supplement: A comprehensive multiple vitamin and mineral formula

She reported no use of cannabis or other recreational substances, and rare alcohol consumption. Her energy level was rated between 4 and 8 out of 10 (with 10 being the best), showing frequent diurnal fluctuations. She typically retired to bed around 9:00 PM and achieved sleep onset within 10 min. However, sleep architecture was fragmented due to nocturnal childcare duties, with awakenings at 12:00 AM, 2:00 AM, and 5:00 AM. The final morning awakening occurred between 5:30 and 7:30 AM. She reported a highly supportive marriage and high relationship satisfaction.

Diagnosis and Management Plan

The patient was diagnosed with premenstrual syndrome (PMS). The initial treatment plan advised continuing the prenatal multiple vitamin and mineral supplement and vitamin D3, with additional NHPs, hormonal, and lifestyle interventions:

• B-complex: 1 capsule daily
• Magnesium bisglycinate: 400 mg at bedtime
• TPC: 20 mg applied daily on days 12 to 26 of each menstrual cycle
• Physical activity: Recommended exercise for approximately 20 minutes, 1 to 2 times weekly

Clinical Progress and Follow-Up

First Follow-Up (November 15, 2023)

At her first follow-up appointment, the patient reported an 80% improvement in her overall condition, noting that her social circle had observed a positive behavioral shift. Her premenstrual mood swings had ameliorated, and acute anxiety episodes occurred only a few times since initiating treatment.

The therapeutic plan was adjusted as follows:

• Omega-3 essential fatty acids: Added to provide 750 mg eicosapentaenoic acid (EPA) and 500 mg docosahexaenoic acid (DHA) daily.
• B-complex: Increased to two capsules daily.

Final Follow-Up (January 17, 2024)

At the final evaluation, the patient demonstrated approximately 80% adherence to the recommended NHP protocol. She reported an improved capacity for cognitive regulation, allowing her to navigate challenging mental states with greater ease without reverting to previous negative cycle patterns. She observed that missing doses of her NHPs or TPC correlated with a recurrence of negative mood states, reinforcing adherence.

The patient achieved a significant and satisfactory resolution of her previously distressing PMS symptoms. Her self-reported emotional baseline was calm and content, reflecting an overall improvement in her clinical well-being. She expressed high satisfaction with the treatment outcomes and appeared in good spirits. Given her clinical improvement, the patient deemed further follow-up appointments unnecessary.

Long-Term Patient Perspective

In a subsequent correspondence dated June 11, 2026, regarding the documentation of her case and response to TPC, the patient provided the following reflections:

Following the birth of my child, I found myself having challenging mood swings and fatigue. In Sept 2023, Dr. Prousky introduced me to bioidentical progesterone cream to help manage these symptoms. The PMS related stress began to mellow after a few months. The changes became profoundly life-changing, leading to a stability that I haven’t experienced before.

Discussion

TPC has demonstrated clinical utility in alleviating PMS symptoms in reproductive-aged women (Lee, Hanley & Hopkins, 1999). Lee, Hanley and Hopkins (1999) attribute these benefits to the correction of progesterone deficiency, which offsets relative estrogen dominance and counteracts stress-induced cortisol production. Although this hypothesis is clinically plausible, TPC may offer distinct neurosteroidogenic advantages. By bypassing first-pass hepatic metabolism, TPC avoids the rapid, sharp spikes in systemic ALLO associated with oral administration, which can paradoxically trigger mood symptoms in sensitive individuals. In contrast, TPC provides a sustained pool of parent progesterone for steady, localized ALLO conversion within the CNS, optimizing GABA-A receptor sensitivity. Consequently, TPC lessens affective PMS symptoms via stable GABAergic modulation, while simultaneously mitigating physical symptoms such as mastalgia, abdominal distress, and cephalgia by rebalancing the estrogen-to-progesterone ratio. This hormonal rebalancing also counteracts luteal water retention and bloating symptoms arising from increased plasma renin and aldosterone system activation in PMS, resulting from progesterone’s diuretic properties that facilitate renal sodium excretion (Rosenfeld et al., 2008).

Testing of serum progesterone levels before treatment was not necessary. I prescribe TPC empirically based on the clinical presentation and diagnosis of the patient. I have administered this treatment to many premenopausal, perimenopausal, menopausal, and postmenopausal patients. To my knowledge, I have had only one case in which TPC surprisingly worsened a patient’s mood. This patient was previously diagnosed with a mood disorder, was stable although her mood was low, and was not on any prescribed medication. She was also postmenopausal, for which her progesterone level would obviously be very low or deficient compared to her premenopausal level. Her mood worsened within a few weeks of taking 20 mg of TPC daily except on Sundays. Upon discontinuation of TPC, her mood returned to its low baseline state. Other than this patient, I cannot recall a single case of any patient worsening on TPC treatment.

If testing is clinically indicated, saliva testing would be the most accurate since the serum level is unreliable when determining the bioavailable progesterone level (Lee, 2003; Lee, Hanley & Hopkins, 1999). Saliva testing, on the other hand, reflects the tissue-active free progesterone value and shows an increase from regular TPC administration (Lee, 2003; Lee, Hanley & Hopkins, 1999). Once TPC is applied, the levels increase over the course of 3-4 hours, are maintained for another 3-4 hours, and then drop gradually over the course of another 3-4 hours (Lee, Hanley & Hopkins, 1999). Should saliva testing be desired, the approximate optimal range is between 0.3 and 0.5 ng/ml although 2 ng/ml can be considered the upper limit (Lee, Hanley & Hopkins, 1999). To date, I have not requisitioned any saliva testing at baseline or beyond when prescribing TPC and have not found it necessary when providing this treatment.

The route of administration is important. According to Lee, Hanley and Hopkins (1999), large doses of oral progesterone (i.e., often in the range of 100-400 mg per day) provide a very small amount (approximately 10%)  of circulating “real” progesterone (p. 356). In contrast, TPC at doses of 15-40 mg per day, provides a more physiological dose since progesterone passes through the skin and into the subcutaneous fat, gradually restoring progesterone levels to normal over the course of several months (Lee, Hanley & Hopkins, 1999). The correct dose of TPC is the dose that works for the patient (Lee, Hanley & Hopkins, 1999), but 20 mg/day often provides sufficient benefit although I have sometimes needed to increase the dose to 40 mg/day for symptom amelioration. In women of reproductive age, TPC is applied daily, usually 14-15 days prior to expected menses. I usually have my patients apply TPC at bedtime because it can assist with restorative sleep. Although TPC is usually devoid of adverse effects, in premenopausal women who have been progesterone deficient for many years, the application of TPC can sometimes cause water retention, cephalgia, breast engorgement and mastalgia. These unpleasant symptoms will abate in 2 weeks, sometimes lasting as long as 2-3 months, due to the temporary increased estrogen receptor sensitivity that can happen when progesterone deficiency is being corrected (Lee, Hanley & Hopkins, 1999).

Published evidence evaluating the clinical efficacy of progesterone in PMS is lacking. A Cochrane review included only two studies for analysis, which encompassed 280 patients between 18 and 45 years of age (Ford et al., 2012). The progesterone dose and delivery methods were different, which meant that the studies could not be combined for the meta-analysis. Based on the limited data, the trial results could not prove or disprove the clinical efficacy of progesterone as a treatment for PMS. However, none of the published studies included in the analysis used TPC as a treatment for PMS.

While there are many evidence-based orthomolecular and herbal medicine options for PMS, such as vitamin B1 (Abdollahifard et al., 2014), vitamin B6 (Ebrahimi et al., 2012; Retallick-Brown et al., 2020; Wyatt et al., 1999), magnesium (Facchinetti et al., 1991; Fathizadeh et al., 2010), calcium (Arab et al., 2020; Shobeiri et al., 2017), potassium (Okeahialam, 2017; Takacs, 1998), broad-spectrum micronutrients (Retallick-Brown et al., 2020), chasteberry extract (Csupor et al., 2019), and saffron extract (Mohammadi & Karimi, 2026), I assert that TPC is the most etiological treatment for PMS given its positive impact on ALLO dynamics, luteal phase optimization, and balancing the estrogen-to-progesterone ratio.

Limitations

The positive effects of TPC may have worked synergistically with the other recommended treatments. Since the patient had been taking micronutrients before working with me, it is more likely that the noted benefits were a consequence of TPC treatment. It is also impossible to generalize the positive benefits noted here for other patients struggling with PMS. While a significant criticism is the absence of randomized controlled trials (RCTs) evaluating TPC for PMS, the comprehensive work of the late Dr. Lee, MD., has shown this treatment to be both efficacious and safe when prescribed to patients struggling with disabling PMS symptoms. In one of Dr. Lee’s earliest volumes on natural progesterone, he reported on its clinical efficacy:

More than a decade ago, after reading of the work of of Dr. Katherina Dalton in London, who defined PMS and found success using high-dose progesterone administered as rectal suppositories, I decided to add natural progesterone cream to my treatment of patients with PMS. The results were most impressive. The majority (but not all) of these patients reported remarkable improvement in their symptoms, including the elimination of their premenstrual water retention and weight gain. I have received hundreds of phone calls and letters from women and their doctors over the past few years who report that PMS has been alleviated with the use of natural progesterone (1996, p. 231).

Conclusion

While I hope that a well-constructed RCT on TPC for PMS is conducted in the future, the positive outcome in this case is quite ordinary given my clinical experience with this treatment. TPC is safe and often effective in treating PMS. The benefits, as noted by the patient in this case, improved her PMS symptoms by 80% and afforded her life-changing stability. For interested clinicians, all references referring to the late Dr. John R. Lee, MD., is a recommended resource (Lee, 1996; Lee, 2003; Lee, Hanley & Hopkins, 1999), as is his website (https://www.johnleemd.com/).

Ethics Statement

This case report was prepared in accordance with the CARE Case Report Guidelines. Written informed consent was obtained from the patient for publication of this de-identified case report. All identifying information has been removed or altered to protect patient privacy.

Conflict of Interest Statement

The author declares no conflicts of interest related to this case report.

Funding

No external funding was received for preparation of this case report.

Author Contributions

Dr. Jonathan Prousky conceived the clinical intervention, managed the case, and prepared the manuscript.

References

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Alcohol use disorder (AUD) remains associated with high relapse rates, even among individuals who demonstrate insight, motivation, and engagement in psychotherapy (Volkow et al., 2016). While psychological and behavioral interventions remain foundational, their effectiveness may depend partly on whether the neurobiological capacity required to tolerate stress, regulate emotion, and implement coping strategies is physiologically available during high-risk periods.

Chronic alcohol use is known to disrupt blood glucose regulation, deplete key micronutrients (including B vitamins and magnesium), and alter amino acid availability relevant to neurotransmitter synthesis (Martin et al., 2003; Thomson & Marshall, 2006; White & Sirohi, 2024). Clinically, these disruptions may manifest as fatigue, anxiety, impaired stress tolerance, emotional volatility, sleep disruption, and heightened relapse vulnerability. Many patients with AUD describe relapse not as a conscious decision to pursue pleasure, but as an urgent attempt to relieve internal tension, dysregulation, exhaustion, or anxiety arising during predictable physiological states (Koob & Le Moal, 2001; Oba-Yamamoto et al., 2021). This case report proposes that biochemical stabilization – through targeted nutritional and amino acid support – may be a necessary precondition for effective psychological engagement in alcohol use disorder.

Orthomolecular approaches aim to restore depleted biochemical substrates using nutrients normally present in the human body (Pfeiffer, 1975). While mechanistic and deficiency-based literature is substantial, there remains a relative scarcity of detailed clinical case reports documenting how targeted biochemical stabilization may alter relapse vulnerability and engagement with psychological treatment.

Patient Information

The patient is a perimenopausal woman in her early 50s with a more than 25-year history of AUD. Her course was characterized by repeated cycles of abstinence followed by relapse. Periods of abstinence typically lasted weeks to months, with one extended period of approximately three years more than 15 years prior to presentation. Since that time, she described a persistent “merry-go-round” of relapse and recovery, which she found increasingly distressing and demoralizing. In the years preceding presentation, the patient also reported increasing sleep disruption, heightened stress sensitivity, and worsening anxiety during the perimenopausal transition. These symptoms appeared to compound existing relapse vulnerability, particularly during periods of fatigue and emotional overwhelm.

Relapse episodes were unpredictable in duration. Once alcohol use resumed, she could not reliably anticipate whether drinking would be limited to a single evening or escalate into weeks or months of daily use before regaining control.

She was married and parenting one child at home. She had previously engaged in psychotherapy and recovery-oriented supports and demonstrated high insight and motivation to stop drinking. Upon clinical presentation, she expressed desperation to interrupt the repeated relapse cycle.

Clinical Findings

A consistent relapse pattern emerged over time. The patient reported that her highest-risk window occurred in the early evening, typically after returning home from work. During this period, she often experienced a combination of physical exhaustion, psychological stress, and heightened anxiety. These states were accompanied by strong urges to drink, experienced not primarily as reward-seeking, but as relief-seeking responses to internal tension, anxiety, exhaustion, and physiological dysregulation.

Additional features included:

• Irregular eating patterns earlier in the day
• Tendency to skip or under-eat breakfast
• Anxiety-driven cravings rather than reward-seeking
• Fragmented sleep with frequent nighttime awakenings, particularly during periods of drinking
• Increasing difficulty tolerating stress despite psychological insight

Baseline (Pre-intervention):

• 25+ years of AUD with repeated abstinence-relapse cycles
• Longest prior sobriety: 3 years, more than 15 years ago
• Frequent early-evening cravings associated with stress and fatigue
• Anxiety-driven urges and poor sleep continuity

Intervention Period (Weeks 1–2):

• Immediate implementation of structured meals with non-negotiable protein intake
• Introduction of targeted amino acid and micronutrient support
• Rapid reduction in craving intensity

Early Follow-Up (First Month):

• One brief drinking episode within the first month
• Post-relapse review and refinement of “crisis protocols”
• Temporary increase in anxiolytic amino acid support

Ongoing Follow-Up (Months 2–16):

• No further alcohol use
• Sustained sleep improvement
• Increased engagement with therapy and social activities
• Continued abstinence at 16 months

Diagnostic Assessment

Formal laboratory testing was not central to the clinical assessment. Instead, a capacity-based framework was applied, informed by symptom patterns and alcohol use history.

Clinical considerations included:

• Blood sugar instability, suggested by late-day fatigue, anxiety, and urgency that improved rapidly with regular protein intake (Lieber, 2003; Oba-Yamamoto et al., 2021).
• Neurotransmitter dysregulation, particularly affecting serotonergic and inhibitory tone, consistent with anxiety-driven cravings. Chronic alcohol exposure is known to alter reward, stress, and inhibitory systems, including dopaminergic and gamma-aminobutyric acid-ergic pathways (Koob & Le Moal, 2001; Volkow et al., 2016).
• Micronutrient depletion, commonly associated with long-term alcohol use and stress, particularly involving B vitamins and magnesium, which are essential for neurotransmitter synthesis and nervous system regulation (Martin et al., 2003; Thomson & Marshall, 2006; White & Sirohi, 2024).

Rather than framing relapse as a failure of motivation or insight, the working hypothesis was that repeated episodes occurred during predictable physiological states in which stress tolerance and inhibitory control were compromised (Koob & Le Moal, 2001; Volkow et al., 2016).

Therapeutic Intervention

A foundational intervention focused on stabilizing blood sugar through consistent protein intake:

• Non-negotiable breakfast containing protein
• Protein every 4 hours, with a minimum target of 20 grams per meal
• Emphasis on regular meals to prevent late-day metabolic crashes

This structure was framed as recovery infrastructure rather than dietary optimization.

Amino Acid Support

Amino acids were selected based on the patient’s symptom profile and used in a symptom-guided manner to support mood regulation, stress tolerance, and craving management.

Interventions included:

• 5-hydroxytryptophan (5-HTP; 100 mg nightly) to support serotonergic tone, sleep continuity, and mood stability (Birdsall, 1998)
• L-theanine (200 mg twice daily) for anxiety modulation, used both regularly and during acute craving states (Hidese et al., 2019)
• L-glutamine (2–5 g as needed) during craving episodes, including in beverage form (Rogers & Pelton, 1957; Williams, 1967)

During periods of increased vulnerability, L-theanine dosing was temporarily increased to 200 mg three times daily. Interventions were adjusted based on response and tolerability.

Micronutrients and Essential Fats

Additional support included:

• A comprehensive daily multivitamin/mineral
• B-complex supplementation, recognizing the established role of B vitamins in neurological function and the high prevalence of deficiency in individuals with AUD; dosed as a high-potency broad-spectrum B-complex (approximately 25–50 mg of most B vitamins) (Martin et al., 2003; Thomson & Marshall, 2006)
• Omega-3 essential fatty acids, to support neuroinflammation modulation and neuronal membrane function, dosed at approximately 2000 mg combined eicosapentaenoic acid/docosahexaenoic acid daily (Su et al., 2015)
• Magnesium glycinate (400 mg nightly), to support nervous system regulation and sleep quality (Rawji et al., 2024), given the high prevalence of magnesium depletion in individuals with AUD (Rivlin, 1994)

All interventions were individualized and adjusted based on response and tolerability. The patient was seen weekly during early stabilization, then monthly through the 16-month follow-up period.

Follow-Up and Outcomes

The patient reported a rapid reduction in cravings following stabilization of meal timing and protein intake. Within approximately 10 days, cravings that previously felt overwhelming became manageable and responsive to non-alcohol interventions such as amino acids.

Sleep improved substantially. The patient reported frequent middle-of-the-night awakenings, heightened nighttime anxiety, and worsening sleep continuity during the perimenopausal transition before later transitioning to sleeping through the night more consistently as stabilization progressed.

Engagement in psychotherapy improved markedly. The patient described an increased ability to tolerate emotionally challenging sessions, apply therapeutic tools during stress, and remain regulated between sessions. As stability increased, she also re-engaged socially, joining clubs and reviving personal interests that had previously fallen away during cycles of drinking.

After a single drinking episode within the first month of care, no further alcohol use occurred. At 16 months of follow-up, the patient remained abstinent and reported sustained improvements in stress tolerance, sleep, and quality of life.

Discussion

This case highlights a clinically common but under-documented phenomenon: repeated relapse in AUD despite insight, motivation, and psychological support. In this patient, relapse vulnerability clustered around predictable physiological states – particularly early evening periods of fatigue, anxiety, and metabolic depletion.

Importantly, cravings were experienced not primarily as reward-seeking, but as relief-seeking responses to internal tension, anxiety, exhaustion, and physiological dysregulation. This distinction may reflect a shift from hedonic to regulatory drivers of alcohol use, in which alcohol functions as a rapid means of restoring perceived internal equilibrium rather than producing pleasure.

Biological Capacity as a Precondition for Psychological Work

The intervention did not replace psychotherapy; rather, it appeared to restore the patient’s capacity to benefit from it. Chronic alcohol use is associated with dysregulation in stress and reward systems, which can impair executive function and emotional regulation during high-risk periods (Koob & Le Moal, 2001; Volkow et al., 2016).

Once blood sugar stability and anxiety regulation improved, psychological strategies became accessible during moments when they had previously failed. Clinically, this pattern is frequently observed: patients may possess insight and motivation, yet remain unable to implement behavioral strategies during periods of physiological distress.

This capacity-based framing offers a complementary perspective to existing psychological models of relapse, emphasizing the role of an individual’s physiological state in determining access to coping strategies and behavioral control.

Blood Sugar Stability and Craving Vulnerability

The rapid reduction in cravings following structured protein intake suggests that metabolic instability may play a significant role in relapse risk for some individuals with AUD. Fluctuations in blood glucose have been associated with increased craving and emotional instability in alcohol-dependent populations (Gold et al., 1985; Lieber, 2003). Preventing late-day metabolic decline appeared central to reducing anxiety-driven urges in this case, particularly given the patient’s pattern of under-eating earlier in the day followed by heightened vulnerability in the evening.

Amino Acids as Symptom-Guided Support

Amino acids were used not as direct anti-addiction agents, but as targeted support for underlying neurobiological processes involved in mood regulation, stress tolerance, and craving vulnerability.

Chronic alcohol use is associated with dysregulation of neurotransmitter systems, including serotonergic, dopaminergic, and inhibitory pathways, which depend in part on the availability of amino acid precursors and micronutrient cofactors (Koob & Le Moal, 2001; Volkow et al., 2016).

From a biochemical perspective, amino acids such as 5-HTP (Birdsall, 1998) and L-glutamine (Rogers & Pelton, 1957; Williams, 1967)  serve as precursors for neurotransmitters involved in mood and stress regulation, while compounds such as L-theanine may influence excitatory-inhibitory balance (Hidese et al., 2019). Nutritional psychiatry research further supports the role of nutrient availability in modulating brain function and emotional regulation (Jacka et al., 2017).

Within this framework, amino acids were used to support regulation during periods of increased vulnerability. The ability to interrupt cravings acutely with non-alcohol-based interventions, such as L-glutamine or L-theanine, provided an alternative pathway for managing distress in real time.

Clinical observations from earlier studies suggest that targeted nutrient and amino acid support may influence craving and emotional stability in individuals with substance use disorders, although high-quality controlled trials remain limited (Blum et al., 1988; Blum et al., 2011).

Limitations

As a single case report, causality cannot be established. Improvements likely reflected the combined effects of multiple concurrent interventions, including nutritional stabilization, amino acid and micronutrient support, psychotherapy, recovery-oriented social support, behavioral structure, and natural recovery processes. Laboratory confirmation of nutrient deficiencies was limited, and the relative contribution of any single intervention cannot be isolated. Additionally, perimenopausal hormonal changes may have contributed both to symptom burden and to subsequent improvements in sleep and stress regulation over time. Further case series and controlled studies are needed to better evaluate the role of orthomolecular and food-based approaches in supporting relapse prevention and psychological engagement in AUD.

Conclusion

In this patient, recovery appeared limited not by lack of motivation or insight, but by insufficient biological capacity to sustain change under stress. Targeted orthomolecular support appeared to stabilize physiology, reduce craving vulnerability, and enable psychological recovery to take hold.

These findings suggest that, for some individuals, addressing underlying physiological instability may be a necessary precondition for effective engagement in psychological and behavioral interventions. This case supports further exploration of orthomolecular and nutrition-based approaches as foundational components of AUD treatment.

Ethics Statement

This case report was prepared in accordance with the CARE Case Report Guidelines. Written informed consent was obtained from the patient for publication of this de-identified case report. All identifying information has been removed or altered to protect patient privacy.

Conflict of Interest Statement

The author declares no conflicts of interest related to this case report.

Funding

No external funding was received for preparation of this case report.

Author Contributions

Heather Dale conceived the clinical intervention, managed the case, and prepared the manuscript.

References

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Blum, K., Liu, Y., Shriner, R., & Gold, M. S. (2011). Reward circuitry dopaminergic activation regulates food and drug craving behavior. Current pharmaceutical design, 17(12), 1158–1167. https://doi.org/10.2174/138161211795656819

Blum, K., Trachtenberg, M. C., & Ramsay, J. C. (1988). Improvement of inpatient treatment of the alcoholic as a function of neurotransmitter restoration: a pilot study. The International journal of the addictions, 23(9), 991–998. https://doi.org/10.3109/10826088809058853

Hidese, S., Ogawa, S., Ota, M., Ishida, I., Yasukawa, Z., Ozeki, M., & Kunugi, H. (2019). Effects of L-Theanine Administration on Stress-Related Symptoms and Cognitive Functions in Healthy Adults: A Randomized Controlled Trial. Nutrients, 11(10), 2362. https://doi.org/10.3390/nu11102362

Jacka, F. N., Pasco, J. A., Mykletun, A., Williams, L. J., Hodge, A. M., O’Reilly, S. L., Nicholson, G. C., Kotowicz, M. A., & Berk, M. (2010). Association of Western and traditional diets with depression and anxiety in women. The American journal of psychiatry, 167(3), 305–311. https://doi.org/10.1176/appi.ajp.2009.09060881  

Jacka, F. N., O’Neil, A., Opie, R., Itsiopoulos, C., Cotton, S., Mohebbi, M., Castle, D., Dash, S., Mihalopoulos, C., Chatterton, M. L., Brazionis, L., Dean, O. M., Hodge, A. M., & Berk, M. (2017). A randomised controlled trial of dietary improvement for adults with major depression (the ‘SMILES’ trial). BMC medicine, 15(1), 23. https://doi.org/10.1186/s12916-017-0791-y

Koob, G. F., & Le Moal, M. (2001). Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 24(2), 97–129. https://doi.org/10.1016/S0893-133X(00)00195-0

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Metabolic dysfunction–associated steatotic liver disease (MASLD), previously termed non‑alcoholic fatty liver disease, is the hepatic manifestation of metabolic syndrome and is strongly associated with obesity, insulin resistance, dyslipidemia, and type 2 diabetes mellitus (Powell et al., 2021; Younossi et al., 2016). Global prevalence estimates suggest that MASLD affects approximately one quarter of the adult population and represents one of the most rapidly increasing causes of chronic liver disease worldwide  (Powell et al., 2021; Younossi et al., 2016).

The progression of MASLD from simple steatosis to steatohepatitis and fibrosis reflects complex interactions among metabolic, inflammatory, and oxidative mechanisms. Insulin resistance promotes hepatic lipogenesis and impairs fatty‑acid oxidation, leading to triglyceride accumulation within hepatocytes. Lipotoxic intermediates, mitochondrial dysfunction, and reactive oxygen species generation subsequently promote hepatocellular injury and activation of hepatic stellate cells responsible for extracellular matrix deposition and fibrogenesis (Begriche et al., 2013; Friedman, 2008; Tilg et al., 2021).

Weight reduction and improvement in insulin sensitivity remain the most widely recognized interventions associated with improvement in MASLD (Powell et al., 2021). However, reversal of advanced fibrosis is inconsistently observed and often requires substantial metabolic recovery (Armstrong et al., 2016). In metabolic liver disease the orthomolecular medicine framework includes supporting mitochondrial metabolism, maintaining membrane phospholipid integrity, correcting micronutrient insufficiencies, and reducing oxidative stress (Ames, 2006; Begriche et al., 2013; Zeisel, 2012).

This report describes regression of advanced hepatic fibrosis in a patient with MASLD treated with an integrated orthomolecular and metabolic rehabilitation strategy.

Case Presentation

A 58‑year‑old male presented with newly diagnosed type 2 diabetes mellitus accompanied by fatigue, reduced exercise tolerance, and metabolic instability. Medical history included long‑standing obesity and dyslipidemia consistent with metabolic syndrome (see Table 1 for all of the patient’s baseline clinical metrics). Alcohol consumption was minimal and there was no history of viral hepatitis, autoimmune liver disease, or exposure to hepatotoxic medications.

Baseline laboratory evaluation demonstrated severe hyperglycemia with HbA1c of 10.2% and fasting glucose of 12.7 mmol/L. Lipid profile revealed elevated total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides consistent with insulin resistance.

Transient elastography (FibroScan) demonstrated liver stiffness of 13.5 kPa corresponding to advanced hepatic fibrosis (F3) with severe steatosis. Baseline body weight was 283 lb with a body mass index of 39.5 kg/m².

Table 1. Baseline Clinical Metrics

Treatment Protocol

A comprehensive metabolic rehabilitation program was initiated incorporating dietary modification, progressive weight reduction, orthomolecular micronutrient therapy, intravenous nutrient infusions, phosphatidylcholine therapy, endocrine optimization, and conventional pharmacotherapy with metformin (Table 2).

Dietary modification emphasized reduction of refined carbohydrates and caloric moderation to improve insulin sensitivity and facilitate gradual weight reduction. Oral orthomolecular therapy included broad micronutrient support designed to restore enzymatic cofactors required for mitochondrial metabolism and antioxidant defense systems.

Intravenous nutrient therapy incorporated magnesium, B‑complex vitamins, and antioxidant support. Phosphatidylcholine infusions were utilized to support hepatocyte membrane integrity and lipid export mechanisms. Phosphatidylcholine is required for assembly and secretion of very‑low‑density lipoproteins responsible for transporting triglycerides out of hepatocytes (van der Veen et al., 2017).

Ethylenediaminetetraacetic acid  (EDTA) chelation therapy was implemented as part of the orthomolecular program. Transition metals such as iron can catalyze hydroxyl radical formation through the Fenton reaction. In this reaction ferrous iron reacts with hydrogen peroxide to generate hydroxyl radicals capable of initiating lipid peroxidation and cellular injury within hepatocytes (Day & James, 1998). Chelation reduces redox‑active transition metals capable of catalyzing hydroxyl radical formation, thereby reducing oxidative stress.

Table 2. Comprehensive Metabolic Rehabilitation Program

Results

At baseline in July 2024 laboratory evaluation demonstrated hepatocellular injury with alanine aminotransferase (ALT) 90 U/L and aspartate aminotransferase (AST) 48 U/L, with gamma-glutamyl transferase (GGT) 55 U/L. Glycemic control was markedly abnormal with hemoglobin A1c of 10.2%. Dyslipidemia was also present, including triglycerides of 3.84 mmol/L and HDL cholesterol of 0.87 mmol/L.

Following implementation of metabolic and orthomolecular interventions, progressive improvement was observed. Over approximately twelve months, the patient experienced substantial metabolic improvement accompanied by normalization of biochemical markers of hepatic injury and regression of hepatic fibrosis. Body weight decreased from 283 lb at presentation to 216 lb at the most recent follow-up.

Hemoglobin A1c (HbA1c) declined from 10.2% to 5.9% within four months and remained in the non-diabetic range thereafter. Liver enzymes normalized during follow-up, with ALT declining from 90 U/L at baseline to 27 U/L within four months and measuring 20 U/L at the most recent follow-up. AST and GGT also normalized during follow-up.

Serial transient elastography demonstrated progressive improvement in liver stiffness measurements. Liver stiffness decreased from 13.5 kPa at baseline (F3 fibrosis) to 7.2 kPa (F1 fibrosis) and subsequently to 5.7 kPa, corresponding to minimal fibrosis (F0–F1). These structural improvements occurred in parallel with metabolic recovery including weight loss and normalization of liver enzyme levels.

Serial laboratory measurements are summarized in Table 3 and FibroScan measurements in Table 4.

Table 3. Serial Metabolic and Biochemical Measurements

Table 4. FibroScan Progression

Discussion

The regression of hepatic fibrosis observed in this case occurred in the context of substantial metabolic improvement. There were notable corrections of several upstream drivers of hepatocellular injury with the implementation of a comprehensive orthomolecular treatment strategy. MASLD pathogenesis is closely linked to mitochondrial dysfunction, oxidative stress, and activation of hepatic stellate cells responsible for extracellular matrix deposition and progressive fibrosis (Friedman, 2008; Tilg & Moschen, 2010; Powell et al., 2021). Changes in liver stiffness of this magnitude on transient elastography are generally considered consistent with meaningful changes in hepatic fibrosis stage when accompanied by clinical and metabolic improvement (Powell et al., 2021).

Mitochondrial dysfunction is central to MASLD pathophysiology. Impaired β-oxidation of fatty acids leads to accumulation of lipotoxic intermediates and increased production of reactive oxygen species. Oxidative stress promotes hepatocellular injury and inflammatory signaling that ultimately activates fibrogenic pathways and stellate cell activation (Begriche et al., 2013; Sanyal et al., 2015; Tilg et al., 2021).

Activation of hepatic stellate cells represents a central event in hepatic fibrogenesis (Friedman, 2008; Kisseleva & Brenner, 2021). In response to hepatocellular injury and inflammatory signaling, stellate cells undergo phenotypic transformation into activated myofibroblast-like cells that produce extracellular matrix proteins including type I and type III collagen (Friedman, 2008). Progressive accumulation of collagen and other matrix components leads to architectural distortion of the liver and increasing fibrosis stage (Friedman, 2008; Kisseleva & Brenner, 2021). When the underlying drivers of hepatocellular injury are reduced, stellate cell activation may diminish and matrix remodeling pathways can permit partial regression of fibrosis (Kisseleva & Brenner, 2021).

Fibrosis regression is believed to occur when the balance between extracellular matrix deposition and degradation shifts toward matrix remodeling (Kisseleva & Brenner, 2021). Resolution of hepatic injury can reduce stellate cell activation while increasing activity of matrix metalloproteinases responsible for degradation of accumulated collagen (Kisseleva & Brenner, 2021; Powell et al., 2021). Experimental and clinical studies have demonstrated that under appropriate metabolic conditions hepatic fibrosis can partially regress through remodeling of the extracellular matrix and gradual resorption of fibrotic scar tissue (Kisseleva & Brenner, 2021; Powell et al., 2021).

Orthomolecular medicine seeks to restore optimal biochemical conditions required for cellular metabolism, emphasizing the role of micronutrients as enzymatic cofactors in mitochondrial respiration and antioxidant defense pathways (Ames, 2006; Begriche et al., 2013; Corbin & Zeisel, 2012). Micronutrients function as cofactors for numerous enzymatic reactions involved in mitochondrial respiration, antioxidant defense, and detoxification pathways. Restoration of micronutrient sufficiency may therefore support mitochondrial function and metabolic resilience, particularly in metabolic disorders characterized by impaired oxidative metabolism (Ames, 2006; Begriche et al., 2013).

Phosphatidylcholine plays an important role in hepatic lipid transport and membrane structure (Corbin & Zeisel, 2012; van der Veen, et al., 2017). Adequate phosphatidylcholine availability is required for assembly and secretion of very-low-density lipoproteins responsible for exporting triglycerides from hepatocytes (van der Veen et al., 2017). Impaired phosphatidylcholine availability has been associated with hepatic lipid accumulation and steatosis (Corbin & Zeisel, 2012; van der Veen, et al., 2017). Phospholipid support may therefore assist in reducing hepatic lipid accumulation and maintaining hepatocyte membrane integrity (Corbin & Zeisel, 2012).

A further mechanism relevant to orthomolecular therapy involves reduction of metal-catalyzed oxidative stress. Transition metals such as iron can catalyze the Fenton reaction, in which ferrous iron reacts with hydrogen peroxide to generate highly reactive hydroxyl radicals (Day & James, 1998; Begriche et al., 2013), as noted below:

Fe²⁺ + H₂O₂ → Fe³⁺ + OH⁻ + OH•

Hydroxyl radicals can induce lipid peroxidation, protein oxidation, and deoxyribonucleic acid damage within hepatocytes. Iron-catalyzed oxidative injury has been implicated in the progression of fatty liver disease and hepatic fibrosis (Day & James, 1998; Begriche et al., 2013; Powell et al., 2021).

EDTA chelation therapy forms stable complexes with several metal ions including iron and copper, thereby reducing their participation in catalytic oxidative reactions and representing one component of the broader strategy aimed at reducing oxidative stress. By binding redox-active metals, EDTA chelation therapy may reduce oxidative injury and inflammatory signaling within hepatic tissue (Begriche et al., 2013). Although the precise contribution of EDTA chelation therapy cannot be isolated in a single case, reduction of metal-mediated oxidative injury represents a biologically plausible mechanism supporting hepatic recovery.

Weight reduction and improvement in insulin sensitivity likely played a major role in this patient’s improvement. Sustained weight loss has been associated with histologic improvement and regression of fibrosis in metabolic liver disease (Armstrong et al., 2016; Powell et al., 2021). Metformin therapy was continued during treatment; however, metformin alone has not consistently demonstrated reversal of hepatic fibrosis in MASLD (Sanyal et al., 2015). The combined orthomolecular strategy addressing oxidative stress, mitochondrial function, membrane integrity, and micronutrient sufficiency may have contributed to the observed fibrosis regression.

Conclusion

This case demonstrates regression of advanced hepatic fibrosis in a patient with MASLD treated with a comprehensive metabolic and orthomolecular therapeutic approach. Improvement occurred in parallel with substantial metabolic recovery and normalization of liver enzyme levels.

Orthomolecular strategies targeting mitochondrial function, oxidative stress reduction, micronutrient sufficiency, membrane phospholipid support, and reduction of metal-catalyzed oxidative injury represent biologically plausible mechanisms contributing to hepatic recovery.

While causality cannot be established from a single case, the findings highlight the potential role of comprehensive metabolic restoration approaches in supporting reversal of liver injury in metabolic liver disease and support further investigation into orthomolecular strategies in MASLD management.

Ethics Statement

This case report was prepared in accordance with the CARE Case Report Guidelines. Written informed consent was obtained from the patient for publication of this de-identified case report. All identifying information has been removed or altered to protect patient privacy.

Conflict of Interest Statement

The author declares no conflicts of interest related to this case report.

Funding No external funding was received for preparation of this case report.

Author Contributions

Dr. Gannage conceived the clinical intervention, managed the case, and prepared the manuscript.

References

Armstrong, M. J., Gaunt, P., Aithal, G. P., Barton, D., Hull, D., Parker, R., Hazlehurst, J. M., Guo, K., LEAN trial team, Abouda, G., Aldersley, M. A., Stocken, D., Gough, S. C., Tomlinson, J. W., Brown, R. M., Hübscher, S. G., & Newsome, P. N. (2016). Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet (London, England), 387(10019), 679–690. https://doi.org/10.1016/S0140-6736(15)00803-X

Ames B. N. (2006). Low micronutrient intake may accelerate the degenerative diseases of aging through allocation of scarce micronutrients by triage. Proceedings of the National Academy of Sciences of the United States of America, 103(47), 17589–17594. https://doi.org/10.1073/pnas.0608757103

Begriche, K., Massart, J., Robin, M. A., Bonnet, F., & Fromenty, B. (2013). Mitochondrial adaptations and dysfunctions in nonalcoholic fatty liver disease. Hepatology (Baltimore, Md.), 58(4), 1497–1507. https://doi.org/10.1002/hep.26226

Corbin, K. D., & Zeisel, S. H. (2012). Choline metabolism provides novel insights into nonalcoholic fatty liver disease and its progression. Current opinion in gastroenterology, 28(2), 159–165. https://doi.org/10.1097/MOG.0b013e32834e7b4b

Day, C. P., & James, O. F. (1998). Steatohepatitis: a tale of two “hits”?. Gastroenterology, 114(4), 842–845. https://doi.org/10.1016/s0016-5085(98)70599-2

Friedman S. L. (2008). Hepatic fibrosis — overview. Toxicology, 254(3), 120–129. https://doi.org/10.1016/j.tox.2008.06.013

Kisseleva, T., & Brenner, D. A. (2008). Mechanisms of fibrogenesis. Experimental biology and medicine (Maywood, N.J.), 233(2), 109–122. https://doi.org/10.3181/0707-MR-190

Powell, E. E., Wong, V. W., & Rinella, M. (2021). Non-alcoholic fatty liver disease. Lancet (London, England), 397(10290), 2212–2224. https://doi.org/10.1016/S0140-6736(20)32511-3

Sanyal, A. J., Friedman, S. L., McCullough, A. J., Dimick-Santos, L., American Association for the Study of Liver Diseases, & United States Food and Drug Administration (2015). Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration Joint Workshop. Hepatology (Baltimore, Md.), 61(4), 1392–1405. https://doi.org/10.1002/hep.27678

Tilg, H., & Moschen, A. R. (2010). Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology (Baltimore, Md.), 52(5), 1836–1846. https://doi.org/10.1002/hep.24001

Tilg, H., & Effenberger, M. (2020). From NAFLD to MAFLD: when pathophysiology succeeds. Nature reviews. Gastroenterology & hepatology, 17(7), 387–388. https://doi.org/10.1038/s41575-020-0316-6

van der Veen, J. N., Kennelly, J. P., Wan, S., Vance, J. E., Vance, D. E., & Jacobs, R. L. (2017). The critical role of phosphatidylcholine and phosphatidylethanolamine metabolism in health and disease. Biochimica et biophysica acta. Biomembranes, 1859(9 Pt B), 1558–1572. https://doi.org/10.1016/j.bbamem.2017.04.006

Younossi, Z. M., Koenig, A. B., Abdelatif, D., Fazel, Y., Henry, L., & Wymer, M. (2016). Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology (Baltimore, Md.), 64(1), 73–84. https://doi.org/10.1002/hep.28431

Autism spectrum disorder (ASD) is a biologically heterogeneous condition involving oxidative stress, mitochondrial dysfunction, immune dysregulation, altered methylation capacity, and gastrointestinal disturbance (James et al., 2004; Rossignol & Frye, 2012). Regressive ASD commonly emerges between 9 and 24 months, coinciding with intense synaptogenesis, immune calibration, microbiome maturation, and heightened mitochondrial demand (Rossignol & Frye, 2012).

Cerebral folate transport impairment associated with FRα autoantibodies has been reported in subsets of ASD (Ramaekers et al., 2007). Folinic acid has demonstrated benefit in selected populations (Frye et al., 2018). This report describes a child with regressive ASD treated with layered orthomolecular stabilization followed by empiric leucovorin therapy and subsequent FRα antibody confirmation.

Case Report

A female child demonstrated typical development through 11 months of age, including reciprocal smiling, babbling, and age-appropriate motor milestones. At 11 months, regression occurred with loss of expressive language, reduced eye contact, irritability, repetitive behaviors, and alternating bowel patterns. Past medical history included maternal hyperemesis, formula feeding, gastroesophageal reflux disease, asthma, and multiple antibiotic exposures. At age 2, the patient’s weight was 13 kg and her baseline ATEC score was 60.

Clinical Findings

Upon clinical presentation there was notable echolalia, hand flapping, limited spontaneous communication, and gastrointestinal instability with undigested food. Organic acid testing demonstrated elevated arabinose and increased succinic and citric acid intermediates, suggesting fungal overgrowth (Herman & Herman, 2022) and mitochondrial stress (West et al., 2014)

Timeline

• Typical development (0–11 months)
• Patient regression (11 months)
• Plateau with patient development yielded ATEC score of 60
• Foundational orthomolecular stabilization plan implemented along with subcutaneous vitamin B12 injections
• There was partial recovery but it plateaued
• Empiric use of leucovorin
• Notable developmental acceleration
• FRα antibody testing was positive

Therapeutic Intervention

Phase 1 – Foundational Stabilization
Gluten-free, casein-free diet; probiotic and digestive enzymes; botanical hepatic support (milk thistle tincture) and chlorophyll; nystatin; multivitamin with therapeutic amounts of vitamin B6, methylfolate, magnesium, and vitamin C; Acetyl-L-carnitine, Coenzyme Q10, biotin; omega-3 essential fatty acids and cholecalciferol.

Phase 2 – Redox and Methylation Support
Subcutaneous vitamin B12 injections at 75 mcg/kg (1000 mcg per dose at 13 kg). Improvements included increased eye contact and emergence of expressive language.

Phase 3 – Empiric Folinic Acid
Leucovorin initiated at 2.5 mg twice daily and titrated to 7.5 mg twice daily. Marked acceleration followed with sentence formation and enhanced social reciprocity.

Phase 4 – FRα Antibody Confirmation
Binding antibody positive (1.363 OD); blocking antibody negative.

Follow-up and Outcomes

The Post-B12 phase reflected recovery of lost skills. The post-leucovorin phase demonstrated developmental acceleration beyond the prior plateau. The parents reported substantial improvements in language, connection, and functional participation. The repeat ATEC score decreased from 60 to 33. No adverse effects were observed.

Discussion

ASD is increasingly recognized as a condition characterized by systems-level dysregulation rather than isolated neurodevelopmental divergence (Rossignol & Frye, 2012; Frye, 2020). The present case illustrates how multiple biological domains (redox balance, mitochondrial function, gastrointestinal integrity, immune modulation, and folate transport) may interact sequentially in a child with regressive autism. Importantly, the case highlights not merely therapeutic responsiveness, but the importance of intervention sequencing.

Dietary Foundations in ASD

Dietary intervention formed a foundational component of stabilization. Subsets of children with ASD demonstrate altered intestinal permeability, immune dysregulation, and reduced microbial diversity, factors that may contribute to systemic inflammation and altered neurochemical signaling (Hsiao et al., 2013; Kang et al., 2017). Increased gut permeability may permit translocation of dietary antigens and pro-inflammatory mediators capable of influencing central nervous system excitatory-inhibitory balance (Hsiao et al., 2013).

In addition to antigenic load, dietary chemical exposures – including food additives and other bioactive compounds – have been hypothesized to contribute to excitatory signaling stress in vulnerable individuals (Piwowarczyk et al., 2018). While clinical evidence for gluten- and casein-restricted diets remains heterogeneous (Piwowarczyk et al., 2018), reduction of dietary antigen and chemical burden may plausibly modulate immune activation and downstream redox demand.

In this case, dietary stabilization preceded methylation and folate-directed interventions. Lowering inflammatory and excitatory burden may have reduced overall redox demand, enhancing responsiveness to subsequent mitochondrial and neurochemical support. This sequencing reflects a systems-based approach in which gastrointestinal and immune stabilization precede targeted neurochemical intervention.

Gastrointestinal-Immune Interface

Gastrointestinal dysfunction is common in ASD and may contribute to systemic immune activation (Hsiao et al., 2013; Kang et al., 2017). Dysbiosis can influence neurodevelopment through short-chain fatty acid modulation, tryptophan–kynurenine pathway shifts, cytokine-mediated neuroinflammation, and increased intestinal permeability (Hsiao et al., 2013). Elevated arabinose in this case suggested fungal overgrowth. Nystatin, botanical hepatic support (milk thistle), and chlorophyll were introduced to reduce microbial burden and inflammatory load. Reduction of peripheral immune activation may decrease central neuroinflammatory signaling (Hsiao et al., 2013). This is relevant because folate receptor expression can be influenced by inflammatory mediators (Ramaekers et al., 2007). Thus, microbiome stabilization may indirectly enhance folate transport dynamics.

Redox Instability and Methylation Dysfunction

Impaired methylation and glutathione redox imbalance have been consistently described in subsets of children with ASD (James et al., 2004). Reduced glutathione (GSH) levels and altered GSH to oxidized glutathione ratios suggest chronic oxidative stress and impaired detoxification capacity (James et al., 2004). Because glutathione is central to mitochondrial protection, immune modulation, and neurotransmitter metabolism, redox instability may represent an upstream vulnerability node (Rossignol & Frye, 2012).

Vitamin B12 functions as a cofactor for methionine synthase, linking the folate cycle to homocysteine remethylation and glutathione recycling (James et al., 2009). Subcutaneous methylcobalamin therapy has been shown to improve glutathione redox status and may correlate with behavioral gains (James et al., 2009).

In the present case, vitamin B12 administration was associated with recovery of previously lost developmental skills. This suggests restoration of impaired function rather than acquisition of new skills and implies that metabolic bottlenecks, rather than irreversible neurodegeneration, were present. Without redox stabilization, downstream interventions may have been less effective.

Mitochondrial Vulnerability

Mitochondrial dysfunction has been documented in a significant subset of individuals with ASD, including abnormalities in oxidative phosphorylation, electron transport chain activity, and Krebs cycle intermediates (Rossignol & Frye, 2012; Frye, 2020).

Elevated organic acid markers such as succinic acid may reflect mitochondrial inefficiency or compensatory metabolic stress (Frye, 2020). The developing brain is highly energy dependent; synaptic plasticity and dendritic arborization are adenosine triphosphate (ATP)-intensive processes (Rossignol & Frye, 2012). Mitochondrial inefficiency during a developmental window may amplify vulnerability to regression (Rossignol & Frye, 2012).

Carnitine, CoQ10, and B-vitamin cofactors support mitochondrial membrane stability and ATP production (Frye, 2020). In this case, mitochondrial support preceded leucovorin therapy, reinforcing the principle that adequate cellular energy production may be prerequisite to effective folate-dependent neurotransmitter synthesis.

Folate Receptor Alpha Dysfunction

Cerebral folate deficiency associated with FRα autoantibodies represents a mechanistically plausible contributor to ASD in a subset of patients (Ramaekers et al., 2007). Binding and blocking antibodies may reduce folate transport efficiency at the choroid plexus, leading to relative central nervous system folate insufficiency despite normal serum folate (Ramaekers et al., 2007).

Folinic acid bypasses dihydrofolate reductase and may partially overcome receptor-mediated transport inefficiency. Randomized controlled trials have demonstrated improvements in verbal communication in children with ASD, particularly in those positive for FRα antibodies (Frye et al., 2018).

In this case, leucovorin was introduced empirically based on phenotype, i.e., persistent expressive plateau despite redox stabilization and positive response to methyl donor intervention (methylcobalamin and vitamin B6). Clinical acceleration followed, characterized by sentence formation, emotional reciprocity, and increased spontaneous communication.

FRα antibody testing was performed after clinical response and demonstrated positive binding antibodies (1.363 OD). Laboratory confirmation strengthened mechanistic plausibility, but was not required for clinical decision-making.

Recovery Versus Acceleration

A distinction in this case is the separation between recovery and acceleration. Vitamin B12 therapy corresponded with recovery of previously lost developmental skills. Leucovorin therapy corresponded with acceleration beyond the prior plateau.

Acceleration implies enhanced network integration rather than mere restoration and may reflect improved synaptic methylation dynamics, enhanced monoamine synthesis, stabilized redox environment permitting efficient folate utilization, and improved mitochondrial ATP supply enabling neuroplastic adaptation.

Sequencing as a Therapeutic Principle

Orthomolecular intervention may be most effective when structured hierarchically rather than applied as isolated nutrient escalation.

The observed therapeutic arc followed:
1. Terrain stabilization (diet, microbiome, liver support)
2. Redox and mitochondrial correction
3. Empiric targeted escalation (leucovorin)
4. Mechanistic confirmation (FRα antibodies)

While folinic acid may benefit subsets of patients, its magnitude of effect may depend on pre-existing metabolic stability.

Developmental Window and Neuroplasticity

The patient’s regression occurred during a period of intense synaptogenesis and immune calibration. Early therapeutic intervention likely harnessed intact neuroplasticity to optimize recovery. The distinction between regression and recovery suggests that timely metabolic intervention during developmental vulnerability windows may alter trajectory.

Limitations

As a single case, findings cannot be generalized. Although post-treatment ATEC scoring demonstrated meaningful improvement (60 to 33), clinical outcomes remain observational and parent-informed. Controlled studies are required to determine reproducibility, optimal sequencing strategies, and predictive biomarkers of therapeutic response.

Conclusion

Sequential orthomolecular intervention followed by empiric leucovorin produced developmental acceleration in this child with regressive ASD. FRα antibody positivity provided mechanistic support, but was not required for initial decision-making. A systems-based orthomolecular sequencing approach may optimize clinical outcomes in biologically complex neurodevelopmental disorders.

Ethics Statement

This case report was prepared in accordance with the CARE Case Report Guidelines. Written informed consent was obtained from the patient for publication of this de-identified case report. All identifying information has been removed or altered to protect patient privacy.

Conflict of Interest Statement

The author declares no conflicts of interest related to this case report.

Funding

No external funding was received for preparation of this case report.

Author Contributions

Dr. Gannage conceived the clinical intervention, managed the case, and prepared the manuscript.

References

Frye, R. E., Rincon, N., McCarty, P. J., Brister, D., Scheck, A. C., & Rossignol, D. A. (2024). Biomarkers of mitochondrial dysfunction in autism spectrum disorder: A systematic review and meta-analysis. Neurobiology of disease, 197, 106520. https://doi.org/10.1016/j.nbd.2024.106520

Frye, R. E., Slattery, J., Delhey, L., Furgerson, B., Strickland, T., Tippett, M., Sailey, A., Wynne, R., Rose, S., Melnyk, S., Jill James, S., Sequeira, J. M., & Quadros, E. V. (2018). Folinic acid improves verbal communication in children with autism and language impairment: a randomized double-blind placebo-controlled trial. Molecular psychiatry, 23(2), 247–256. https://doi.org/10.1038/mp.2016.168

Herman, A., & Herman, A. P. (2022). Could Candida Overgrowth Be Involved in the Pathophysiology of Autism?. Journal of clinical medicine, 11(2), 442. https://doi.org/10.3390/jcm11020442

Hsiao, E. Y., McBride, S. W., Hsien, S., Sharon, G., Hyde, E. R., McCue, T., Codelli, J. A., Chow, J., Reisman, S. E., Petrosino, J. F., Patterson, P. H., & Mazmanian, S. K. (2013). Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell, 155(7), 1451–1463. https://doi.org/10.1016/j.cell.2013.11.024

James, S. J., Cutler, P., Melnyk, S., Jernigan, S., Janak, L., Gaylor, D. W., & Neubrander, J. A. (2004). Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. The American journal of clinical nutrition, 80(6), 1611–1617. https://doi.org/10.1093/ajcn/80.6.1611

James, S. J., Melnyk, S., Fuchs, G., Reid, T., Jernigan, S., Pavliv, O., Hubanks, A., & Gaylor, D. W. (2009). Efficacy of methylcobalamin and folinic acid treatment on glutathione redox status in children with autism. The American journal of clinical nutrition, 89(1), 425–430. https://doi.org/10.3945/ajcn.2008.26615

Kang, D. W., Adams, J. B., Gregory, A. C., Borody, T., Chittick, L., Fasano, A., Khoruts, A., Geis, E., Maldonado, J., McDonough-Means, S., Pollard, E. L., Roux, S., Sadowsky, M. J., Lipson, K. S., Sullivan, M. B., Caporaso, J. G., & Krajmalnik-Brown, R. (2017). Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome, 5(1), 10. https://doi.org/10.1186/s40168-016-0225-7

Piwowarczyk, A., Horvath, A., Łukasik, J., Pisula, E., & Szajewska, H. (2018). Gluten- and casein-free diet and autism spectrum disorders in children: a systematic review. European journal of nutrition, 57(2), 433–440. https://doi.org/10.1007/s00394-017-1483-2

Ramaekers, V. T., Blau, N., Sequeira, J. M., Nassogne, M. C., & Quadros, E. V. (2007). Folate receptor autoimmunity and cerebral folate deficiency in low-functioning autism with neurological deficits. Neuropediatrics, 38(6), 276–281. https://doi.org/10.1055/s-2008-1065354

Rossignol, D. A., & Frye, R. E. (2012). Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Molecular psychiatry, 17(3), 290–314. https://doi.org/10.1038/mp.2010.136

West, P. R., Amaral, D. G., Bais, P., Smith, A. M., Egnash, L. A., Ross, M. E., Palmer, J. A., Fontaine, B. R., Conard, K. R., Corbett, B. A., Cezar, G. G., Donley, E. L., & Burrier, R. E. (2014). Metabolomics as a tool for discovery of biomarkers of autism spectrum disorder in the blood plasma of children. PloS one, 9(11), e112445. https://doi.org/10.1371/journal.pone.0112445

In 1998 I published the results of a study in the Journal of Orthomolecular Medicine titled “Potassium: A New Treatment for  Premenstrual Syndrome” (Takacs, 1998). The paper described a small pilot study in which a specific protocol using potassium supplements eliminated severe premenstrual syndrome (PMS) in all participants. Today, severe PMS is frequently referred to as premenstrual dysphoric disorder (PMDD). In 2017, a small open clinical trial using the potassium protocol for PMS was published by cardiologist Dr. Basil Okeahialam (Okeahialam, 2017), who learned of my study while on sabbatical in the United States. His study results are consistent with those I reported and concluded that potassium supplementation warranted further investigation.

Since the completion of my study, women from around the world have from time-to-time contacted me asking about the protocol. In this communication, I wish to comment on my original paper with some additional observations from my conversations with women over the past 40 years. I am not a healthcare professional. When requesting the protocol, all women are first asked to check with their doctor to ensure that potassium is medically safe for them to take.

Overall, women with severe PMS, but few complicating conditions, seem to respond well to the potassium protocol. Any lack of progress is usually traced to too low a dose of potassium or a source of phosphorus-free calcium inadvertently added into the diet. About 10% of women needed to double the dose from the one used in the original study to notice improvement.  Regardless of symptom severity, it always takes three full cycles on potassium to become free of symptoms. Potassium needs to be started very early in the first cycle to notice a difference in that cycle. One of the most interesting observations in the study group was a change in the timing of the symptoms. For the first cycle on potassium only, symptoms often extended further into the period than usual before abating.

There are always new treatments and medications being discovered and popularized. There is no way of knowing a priori which might interfere with the protocol or not. However, I have noted some conditions or medications for which the potassium protocol has not been helpful. For example, one woman with polycystic ovarian syndrome, a condition marked by hormone imbalances, did not seem to respond. Using albuterol to treat asthma, even once per month, seemed to negate benefits from potassium treatment. Commonly prescribed selective serotonin reuptake inhibitors (SSRIs), which should never be stopped abruptly, also seemed to interfere. Some individuals had positive results with the protocol by reducing SSRIs use under professional guidance. Women using hormone treatment to manage their PMS will likely need to adjust their dosage. For example, one woman in the study already using natural progesterone suppositories found that her usual dose seemed too high by her second cycle on potassium. In response, she reduced and eventually stopped hormone treatment. Her situation was complicated in that she also took levothyroxine and had severe chemical and mold sensitivities, but the potassium worked for her. Potassium-depleting situations, such as some illnesses, especially coronavirus disease, can cause temporary setbacks.

Of course, I still do not know the mechanism by which a mild-to-moderate potassium deficiency, one that is not necessarily severe enough to show up in the standard serum test, might cause PMS. I am always trying to learn more and keep my observations current in an updated potassium protocol written specifically for the woman with PMS. Should readers have questions for me, or would like a copy of the protocol, please email me.

Conflict of Interest Statement

The author declares she has no conflict of interest.

References

Okeahialam, B. N. (2017). Potassium treatment for premenstrual syndrome. Medical Journal of Obstetrics and Gynecology, 5(2), 1101. https://www.jscimedcentral.com/jounal-article-pdf/Medical-Journal-of-Obstetrics-and-Gynecology/obstetrics-5-1101.pdf

Takacs, B.E. (1998). Potassium: A new treatment for premenstrual syndrome.  J Orthomol Med, 13(4), 215-222. https://orthomolecular.org/library/jom/1998/pdf/1998-v13n04-p215.pdf

Dear Readers of the Journal of Orthomolecular Medicine (JOM),

My editorship with JOM ended in 2017, but I never lost touch with the philosophy, community, or clinical practice of orthomolecular medicine. At that time, I simply needed to focus on other work. As luck would have it, I have now returned as Editor, and I am deeply grateful for this second opportunity to be part of something I am truly passionate about: the dissemination of clinically relevant information on the value, efficacy, and practice of orthomolecular medicine.

When Linus Pauling first coined the term orthomolecular in his seminal paper in Science (1968), it was quickly embraced by his colleague, Dr. Abram Hoffer, because it perfectly captured the essence of what Hoffer had already been researching, publishing, and practicing. The word orthomolecular not only defined his work—it also created a vital publishing and communication vehicle for clinicians in the field, allowing them to share their findings without being unfairly silenced by the dominant medical journals of the time.

Many decades later, that silencing is thankfully far less overt, though it still exists in subtle ways. Numerous journals now publish work that is orthomolecular in nature, even if it is not explicitly labeled as such. Given this evolving landscape, we at JOM have decided to refine our focus and create a unique publishing niche—one that honors the past, present, and future of orthomolecular medicine.

Moving forward, JOM will focus on case reports and case series. Our goal is to make the journal a repository of clinically relevant, experience-based knowledge that clearly demonstrates both the efficacy and the challenges of using substances normally found in the human body and brain as therapeutic tools. We want JOM to immediately support real-world clinicians by offering practical insights they can apply directly in patient care. Simply put, JOM will assist practitioners in the excellent and demanding work of evaluating and managing patients from an orthomolecular perspective, in integration with all forms of medicine.

As we begin this exciting re-engineering of JOM, we are now inviting submissions for Volume 41, Number 1. We warmly encourage your submission of case reports highlighting the therapeutic use of nutrients, vitamins, minerals, amino acids, hormones, and other biochemical substances in restoring and maintaining optimal mental and physical health.

Please note that submissions should conform to the CARE Case Report Guidelines, an internationally endorsed framework designed to increase accuracy, transparency, and the utility of published information.

As I said at the outset, I am thrilled to be back. Even more so, I am excited to help evolve the journal by publishing meaningful, clinically useful case reports and case series that truly serve our community.

Thank you again for this opportunity, and I wish you all a terrific 2026.

Sincerely,

Jonathan Prousky, ND, MSc, MA

Editor, Journal of Orthomolecular Medicine

References

Pauling L. (1968). Orthomolecular psychiatry. Varying the concentrations of substances normally present in the human body may control mental disease. Science (New York, N.Y.), 160(3825), 265–271. https://doi.org/10.1126/science.160.3825.265

“As in clinical work, it is the single case which is the stimulus for further enquiry” (Osmond, 1962, xii). This prophetic excerpt from Niacin Therapy In Psychiatry was made by the long-time collaborator of Dr. Abram Hoffer, Dr. Humphry Osmond, in reference to an astounding reversal of a schizophrenic teenager in 1952. Here is a brief description of this case:

Towards the end of May, another opportunity arose to try niacin. A seventeen-year-old boy, C. C., was admitted with an acute schizophrenic illness in February. This had started only a few days before admission. He was excited, overactive, silly and at times deluded. He responded transiently to ECT and was put on deep insulin but this had to be stopped after less than ten comas because he developed rightsided facial palsy. During the next three weeks his mental condition worsened steadily until he was lying in his bed, naked, hallucinated, lalling in an incomprehensible way, urinating and defecating where he lay. His family, who were much attached to him, were distressed about this obvious deterioration since ECT and insulin could not be given. On May 28th he was started on 5 grams of niacin and 5 grams of ascorbic acid divided into five doses daily. A chance for the better was noticed within twenty four hours and ten days later he was described as “almost normal.” A Rorschach test done within three weeks of the new treatment being given showed “some anxiety” still remaining which was hardly surprising but no perceptual anomalies. Vitamins were stopped on the 27th of June and he was watched for three weeks before leaving hospital for his home on July 21st. A follow up three years later showed that he was in good health and had finished Grade XII. He has not been in hospital since (Osmond, 1962, xi-xii).

Shortly after this clinical reversal, Dr. Hoffer and his team conducted further studies (e.g., Hoffer et al., 1957) to determine the clinical efficacy of therapeutic doses of niacin and niacinamide. These astounding results confirmed what was observed in this noted case, and have been documented meticulously by Hoffer in this journal and others for decades until his death in 2009. Imagine what life would have been like for the thousands of schizophrenic patients had Hoffer ignored the result of that single case?

On a related note, the treatment of schizophrenia was fundamentally transformed by neuroleptics – originally called major tranquilizers and now known as typical and atypical antipsychotics. While preliminary psychiatric testing of chlorpromazine (CPZ) took place at the Villejuif psychiatric hospital in Paris (Chertok, 1982, as cited in Stip, 2002), it was Drs. Delay, Deniker, and Harl who first published comprehensive reports on its use. They demonstrated that CPZ did not simply sedate agitated patients, but actively targeted psychotic symptoms like hallucinations and delusions (Delay, Deniker, & Harl, 1952, as cited in Stip, 2015), effectively launching the era of modern psychopharmacology. The rest, as they say, is history.

My late father had Parkinson’s disease (PD) and died at the age of seventy-six in 2010. For years prior to his death, the most important treatment providing quality of life benefits was Sinemet, a combination of levodopa (L-3,4-dihydroxyphenylalanine; L-DOPA) and carbidopa. By allowing more L-DOPA to enter his brain and boost dopamine production, the medication significantly lessened his tremors, stiffness, and slow movement. One can only imagine the delayed suffering that would have unfolded to the countless millions of patients globally if Dr. Walter Birkmayer had not given 50 mg of L-DOPA intravenously to patient L.S. in July 1961 (Foley, 2003). Here is an excerpt (as documented by Foley, 2003, p. 469) from the seminal paper originally written in German by Birkmayer and Hornykiewicz (1961).

The effect of a single intravenous injection of L-DOPA in Parkinson’s disease was, in short, the total abolition or the substantial reduction of akinesia. Patients who, when lying in their beds, could not sit themselves up, who could, when sitting, could not stand, or who, when standing, could not start walking, were able to accomplish these tasks with ease after L-DOPA. They walked with the normal associated swinging movements, they could even run and spring. The voiceless, aphonic speech, with its unclear, palillalic articulation, became as strong and clear as that of normal persons. The patients could, for a short period, carry out motor activities to a degree which had been thus far achieved by no other medicament. This DOPA effect reached its peak within 2-3 hours and lasted (to a lesser degree) for 24 hours.

At present, L-DOPA treatment remains the international gold standard and the most effective symptomatic treatment for PD. On a related note, there was an epidemic of encephalitis lethargica (EL), sometimes referred to as “sleeping sickness,” that spanned across the globe beginning in the winter of 1916-17, and continued into the 1930s (Hoffman & Vilensky, 2017).  EL is a neurological disorder that has acute and chronic phases, though both phases tend to be mixed, and is initially characterized by “excessive sleepiness, disorders of ocular motility, fever, and movement disorders, although virtually any neurological sign or symptom could be exhibited, with day-today, and even hour-by-hour shifts in symptomatology” (p.2247). The chronic phase, on the other hand, can last months to years, and is marked clinically by severe “parkinsonian-like signs” (p. 2247). The film Awakenings, directed by Penny Marshall, portrays the story of a neurologist, Dr. Malcolm Sayer, who brought patients with EL back to life by administering L-DOPA – albeit, for a temporary period of time – because he noted advanced Parkinsonian symptoms among his patients with EL (“Awakenings,” n.d.). This movie was based on the remarkable book with the same title by neurologist Dr. Oliver Sacks (1999), documenting his work with EL patients from around 1966 to 1969. Here is a passage from Dr. Sacks about his most famous patient from that period, Leonard, whom he had first seen in the spring of 1966 and who later exhibited a remarkable response to L-DOPA treatment:

L-DOPA was started in early March 1969 and raised by degrees to 5.0 gm. a day. Little effect was seen for two weeks, and then a sudden ‘conversion’ took place, The rigidity vanished from all his limbs, and he felt filled with an access of energy and power; he became able to write and type once again, to rise from his chair, to walk with some assistance, and to speak in a loud and clear voice – none of which had been possible since his twenty-fifth year. In the latter part of March, Mr L. enjoyed a mobility, a health, and a happiness which he had not known in thirty years. Everything about him filled him with delight: he was like a man who had awoken from a nightmare or a serious illness, or a man released from entombment or prison, who is suddenly intoxicated with the sense and beauty of everything around him (pp. 184-185).

As these historical milestones demonstrate, individual case reports remain the foundation of discovery, and form the basis of how early clinical observations on treatment can uniquely transform the routine care of patients. All medical students become acculturated into their future clinician roles because of the case report. During clerkships, internships, and residencies, medical students report on their cases and determine individualized care based on how their patients respond to treatment while under their care. It is the hope of this editor and the journal that our case reports will not only inspire work in orthomolecular medicine, but perhaps transform the routine care of patients in a manner similar to the pioneering work of these notable and brilliant clinicians.

Jonathan E. Prousky, ND, MSc, MA

Editor

References

“Awakenings.” (n.d.). In Wikipedia. Retrieved June 7, 2026, from https://en.wikipedia.org/wiki/Awakenings

Birkmayer, W., & Hornykiewicz, O. (1961). Wiener klinische Wochenschrift, 73, 787–788.

Chertok L. (1982). 30 ans après. La petite histoire de la découverte des neuroleptiques [30 years later. The story of the discovery of neuroleptics]. Annales medico-psychologiques, 140(9), 971–976.

Delay, J., Deniker, P., & Harl, J. M. (1952). Utilisation en thérapeutique psychiatrique d’une phénothiazine d’action centrale élective (4560 RP) [Therapeutic use in psychiatry of phenothiazine of central elective action (4560 RP)]. Annales medico-psychologiques, 110(2 1), 112–117.

Foley P. (2003). Beans, roots and leaves: a brief history of the pharmacological therapy of parkinsonism. Wurzburger medizinhistorische Mitteilungen, 22, 215–234. https://opus.bibliothek.uni-wuerzburg.de/files/85/dissfoley.pdf

Hoffer, A., Osmond, H., Callbeck, M., & Kahan, I. (1957). Treatment of schizophrenia with nicotinic acid and nicotinamide. Journal of Clinical & Experimental Psychopathology, 18(2), 131-158.

Hoffman, L. A., & Vilensky, J. A. (2017). Encephalitis lethargica: 100 years after the epidemic. Brain : a journal of neurology, 140(8), 2246–2251. https://doi.org/10.1093/brain/awx177

Osmond, H. (1962). Introduction. In N. Kugelmass (Ed.), Niacin therapy in psychiatry (ix-xii).  Charles C Thomas. https://ia802906.us.archive.org/1/items/in.ernet.dli.2015.145919/2015.145919.Niacin-Therapy-In-Psychiatry.pdf

Sacks, O. (1999). Awakenings. Vintage Books.

Stip E. (2015). Who pioneered the use of antipsychotics in North America? Canadian journal of psychiatry, 60(3 Suppl 2), S5–S13. https://pmc.ncbi.nlm.nih.gov/articles/PMC4418623/pdf/cjp-2015-vol60-april-supplement-s5-s13.pdf

Stip E. (2002). Happy birthday neuroleptics! 50 years later: la folie du doute. European psychiatry : the journal of the Association of European Psychiatrists, 17(3), 115–119. https://doi.org/10.1016/s0924-9338(02)00639-9