Therapeutic Use of Melatonin for Gastrointestinal Motility and Hypersomnolence in a Patient With Pineal Cyst Pathology

Abstract

Patient: Female, 59-year-old

Final Diagnosis: Pineal gland tumor

Symptoms: Hypersomnolence • constipation

Clinical Procedure: —

Specialty: Psychiatry

Objective: Unusual or unexpected effect of treatment

Background

Pineal gland cysts are believed to alter the production and release of melatonin, which can impact the sleep/wake cycle and gastrointestinal motility. The optimal management and treatment strategies for benign symptomatic pineal gland cysts are not yet fully determined.

Case Report

This case report explores the effects of therapeutic melatonin supplementation on gastrointestinal (GI) motility and hypersomnolence in a 59-year-old woman with a benign pineal gland cyst. Melatonin was initiated and titrated based on response to 30 mg nightly. The patient experienced significant improvements in bowel movement regularity (improving from 1 every 5–7 days to daily) and hypersomnolence (reduction in number and dosage of stimulant medications and adverse effects) with this high-dose melatonin supplementation. Mood improvements in anxiety and depressive symptoms were also observed, with anxiety (GAD-7) scores experiencing a clinically significant decrease from the severe to moderate range. Amantadine and sertraline were used in conjunction with melatonin. This case highlights the potential broader implications and benefits of high-dose melatonin use in patients with symptomatic benign pineal gland cysts.

Conclusions

Treatment with high-dose melatonin was associated with improvements in hypersomnolence and GI motility. The report is limited by being a single case with lack of a control group, and use of concurrent medications. Larger, controlled studies are needed to further explore the mechanisms involved in the relationships between melatonin, GI functioning, and sleep dysregulation.

Introduction

Pineal gland cysts are often discovered as incidental findings in neuroimaging studies, and they are typically considered benign and asymptomatic. Pineal gland cysts are present in about 350 million people worldwide, occurring more commonly in women (3: 1 female-to-male ratio) [1]. They can occur at any age but are more common in individuals 21 to 30 years old. Pineal gland cysts are usually relatively small, with 80% being <10 mm [1]. When symptoms occur, the most common are headaches, hemorrhage, nausea and vomiting, loss of consciousness, hydrocephalus, and oculomotor disorders [1].

Melatonin is a hormone that plays a crucial role in regulating the circadian rhythm, the primary cycle that controls our sleep–wake state [1]. Melatonin is primarily synthesized by the pineal gland. Although their exact effect is not fully understood, the presence of pineal gland cysts is speculated to alter production of melatonin. Studies show that pineal gland masses can lead to an increase or decrease in melatonin production, depending on cyst location [2]. Idiopathic hypersomnia is a sleep disorder characterized by excessive daytime sleepiness despite adequate or prolonged nighttime sleep. Previous case reports demonstrate the efficacy of melatonin supplementation in the treatment of hypersomnia symptoms in patients after pinealectomy and those with pineal gland cysts and tumors, further highlighting the association between the pineal gland and melatonin synthesis [3–6]. With a favorable adverse effects profile, melatonin supplementation is an appealing treatment option [7,8].

Outside of the brain, melatonin is linked to many other integral body functions, including GI motility, meal timing, memory formation, and the systemic inflammatory cascade [1]. The GI tract produces melatonin at a substantial rate, with local levels far exceeding that produced by the pineal gland [9,10]. Furthermore, melatonin acts as a local modulator in the intestines, creating a variety of effects impacting gut motility and inflammation [11,12]. Melatonin deficiency can be associated with the common gastrointestinal problem of chronic constipation. Despite this, the extent to which melatonin supplementation can improve GI symptoms in patients with pineal gland pathology remains relatively unexplored and is a promising therapeutic possibility without significant potential for adverse effects.

Although the pathway responsible for melatonin synthesis begins with tryptophan and ends with melatonin, one of the major intermediates of the pathway is serotonin, a key neuromodulator whose deficiency is associated with depression. There is also a significant link between major depressive disorder (MDD) and circadian rhythm disruption. Patients with MDD often have alterations in their circadian rhythm, and studies show therapeutic improvement after treatment with agomelatine, a melatonin analog that increases melatonin receptor density in the brain. A study by Zhao et al also suggests that there is an increased prevalence of pineal cysts in patients with MDD, further linking dysregulations in circadian rhythm and melatonin release with MDD [13].

This case report explores the potential links among pineal gland cysts, melatonin deficiency, chronic constipation, and idiopathic hypersomnia. It extends the known benefits of melatonin supplementation for hypersomnolence in this population by demonstrating novel therapeutic benefits for GI functioning and potentially other symptoms. Specifically, it examines a case where high-dose melatonin supplementation was associated with notable improvements in GI function, hypersomnolence symptomology, memory, and mood, suggesting potential promising therapeutic applications in similar clinical scenarios for non-surgical treatment options of stable, benign pineal gland cysts.

Case Report

A 59-year-old woman with a history of anxiety, depression, and hypersomnolence presented to an outpatient behavioral health clinic with mood symptoms, excessive daytime sleepiness, chronic GI discomfort, short-term memory impairment, brain fog, and bowel movement irregularity (primarily constipation). The patient’s medical history included a stable, benign 5×8 mm pineal gland cyst, which was monitored through serial magnetic resonance imaging (MRI) scans and did not require neurosurgical intervention. The patient’s electroencephalogram (EEG) was normal, and neuropsychological assessment for memory impairment was unremarkable. Over the prior 20 years, the patient underwent multiple assessments and interventions for GI discomfort, constipation, and hypersomnolence, which excluded major alternative diagnoses and did not result in sustained symptom improvement. Lab test results for zinc, copper, vitamin C, vitamin B1, vitamin B12, vitamin D, TSH, T4, CRP, and ANA were all within normal limits. Vitamin B6 was very mildly elevated. The patient’s family history included alcohol use disorder, stroke, heart disease, MDD, and diabetes mellitus.

Gastrointestinal Background

Our patient’s GI discomfort and constipation had been investigated with GI mapping and colonoscopies, which were unremarkable. She tried various interventions, including a gluten-free diet for 1 year and 15 different supplements taken intermittently for several years, including Triphala. She also tried a multitude of medications such as Trulance, Linzess, stimulant laxatives, and fiber powder, resulting in only mild improvements in symptoms. We ruled out secondary causes for constipation, including anatomic abnormalities (normal imaging), metabolic disorders (normal TSH, electrolytes including calcium, magnesium, and potassium), and neurologic conditions (normal EEG, neuropsychological testing).

Hypersomnolence Background

Hypersomnolence was investigated thoroughly by the Sleep Medicine team. In terms of differential diagnoses, polysomnography documented only mild sleep apnea, with minimal response to nightly CPAP use, and a normal EEG result excluded seizure disorders. The Sleep Medicine team completed extensive trials of stimulants, wake-promoting agents, and other medications, including solriamfetol, high-dose methylphenidate IR and ER, amphetamine/dextroamphetamine salts, armodafinil, lorazepam, duloxetine, and bupropion, none of which provided sustained benefit. The persistence of symptoms despite optimized treatment for sleep apnea and the lack of response to standard central hypersomnolence treatments suggested an underlying pathophysiologic mechanism beyond typical idiopathic hypersomnia or insufficient sleep syndrome. The patient did not have symptom relief with these medications, and additionally experienced adverse effects of anxiety and jaw clenching with high-dose stimulants.

Treatment and Management

Treatment consisted of 12 visits over the course of 12 months (357 days). For a detailed timeline of the treatment course and subjective symptoms, see Figure 1. Medication changes are depicted in Figures 2 and 3, and mood symptoms are shown in Figure 4. Melatonin was started to address GI motility and hypersomnolence. Melatonin was initiated at 10 mg, as the patient had trialed lower doses without clinical effect. The dose was further titrated based on response and tolerability. After partial response to lower doses (10–20 mg), it was ultimately titrated up to 30 mg nightly. Dose-response meta-analysis demonstrates that melatonin’s effects on sleep parameters peak at approximately 4 mg/day, but this reflects typical insomnia treatment and not potential melatonin deficiency states from pineal pathology, where replacement needs may be substantially higher. Using higher doses and mechanisms are plausible given that gut melatonin levels normally far exceed blood concentrations (400 times more melatonin in the gut than pineal gland), and melatonin modulates GI smooth-muscle activity, enteric nervous system signaling, and motility patterns through MT1 and MT2 receptors [10]. Systematic reviews of high-dose melatonin (≥10 mg) in adults demonstrate a favorable safety profile. A meta-analysis of 79 studies involving 3861 participants found that melatonin did not cause detectable increases in serious adverse events or withdrawals due to adverse events, although it did increase minor adverse effects like drowsiness, headache, and dizziness [14]. Long-term data on high-dose melatonin use is limited, necessitating an individualized approach for each patient.

Figure 1.

Timeline describing each of the patient’s clinic visits, including subjective feelings, medication changes, and significant clinical information corresponding to each visit.

Figure 2.

Medication changes throughout treatment.

Figure 3.

Medication changes throughout treatment, excluding sertraline, amantadine, and solriamfetol for enhanced clarity and scaling in the other drugs.

Figure 4.

Scores on anxiety (GAD-7) and depression (PHQ-9) scales throughout treatment. Day 1 represents baseline scores.

To further address hypersomnolence and decrease unpleasant medication adverse effects, amantadine was initiated at 100 mg and titrated up to 200 mg twice daily, and the scheduled stimulants (methylphenidate ER 20 mg BID and IR 10 mg BID) were both ultimately discontinued as the patient no longer required them. Sertraline was also titrated up from the baseline dose of 100 mg to 200 mg.

Gastrointestinal Symptom Improvements

High-dose melatonin resulted in significant improvement in GI motility and bowel movement regularity, resolving long-standing constipation that was resistant to previous interventions. The patient reported having daily bowel movements within 1 month of titrating to an effective dose of melatonin, compared to her previous pattern of having 1 bowel movement every 5 to 7 days. She also had improved stool consistency and no longer required supplements or other medication. Multiple discussions were held with the patient regarding the limited research and lack of established guidelines for this treatment-resistant pathology. The option of measuring melatonin levels was considered, but due to the absence of standardized reference ranges, such testing was unlikely to be clinically informative and could incur unnecessary costs. The patient was informed that high-dose melatonin use in this context is experimental and off-label; informed consent was obtained. Given the generally favorable safety profile of melatonin and the patient’s persistent, treatment-resistant symptoms, she elected to proceed with this therapeutic trial. Her liver function, kidney function, glucose level, and blood pressure did not demonstrate any significant changes from baseline with high-dose melatonin.

Hypersomnolence Symptom Improvements

A simplified regimen of melatonin and amantadine ultimately effectively managed the patient’s hypersomnolence. Methylphenidate IR was initially continued at a reduced dose on an as-needed basis but was ultimately discontinued as the patient did not need it. This allowed for a significant reduction in the number and dosage of stimulant medications (Figures 2, 3), which minimized unpleasant adverse effects and helped the patient feel more like her normal self.

Mood and Cognition Symptoms

The patient also noted improvements in mood, brain fog, and memory, as shown in subjective descriptions in Figure 1. She “occasionally has bad days,” but otherwise felt like her old self for the first time in 15 years. The patient’s anxiety and depression symptoms on standardized symptom measure scales (GAD-7 and PHQ-9, respectively) throughout treatment are depicted in Figure 4. GAD-7 total scores range from 0 to 21, with scores categorized as mild (0–4), mild (5–9), moderate (10–14), and severe (15–21). PHQ-9 total scores range from 0 to 27, with scores categorized as minimal (0–4), mild (5–9), moderate (10–14), moderately severe (15–19), and severe (20–27). In particular, our patient’s anxiety symptoms decreased from the severe to the moderate range (decrease from baseline GAD-7 score of 20 to final score of 14). This 6-point score decrease is considered clinically significant [15]. PHQ-9 depression scores were in the moderate to moderately severe range throughout treatment, ranging from 13 to 17. Notably, these mood changes were reported while on a stable sertraline dose of 200 mg. Unfortunately, inferential statistical tests (eg, paired t tests) beyond these descriptive statistics are not possible to use for comparing pre-post changes in a single individual, as these tests require a sampling distribution across multiple individuals.

Although depression and anxiety were present, the constellation of treatment-refractory GI dysmotility, hypersomnolence, cognitive symptoms, and structural pineal pathology pointed toward a primary neuroendocrine mechanism rather than psychiatric-driven symptoms. Studies show that psychiatric disorders can cause subjective hypersomnolence problems that often do not correlate with objective sleepiness measures, whereas our patient had documented functional impairment requiring multiple wake-promoting agents [16]. The concurrent improvement in GI and sleep symptoms with melatonin supplementation supports pineal cyst-related melatonin deficiency as the primary etiology rather than independent functional or psychiatric disorders.

Discussion

This case highlights melatonin’s potential role in enhancing GI motility and hypersomnolence, particularly in patients with pineal gland cysts. Our patient presented with significant bowel discomfort and chronic constipation that were resistant to years of treatment with over 15 supplements and various prescription medications. High-dose melatonin supplementation completely resolved her GI symptoms, normalizing gut motility, stool consistency, and bowel movement frequency. Although the long-term effects of high-dose melatonin are relatively unknown, follow-up lab work and vital signs monitoring did not show changes from baseline blood pressure, glucose, liver, or kidney function. Melatonin supplementation typically has dosages ranging from 0.5 to 5 mg, with higher dosages previously not being considered to be more therapeutically beneficial [17]. However, our patient’s symptom relief suggests that higher doses may be worth considering in those with pineal gland masses who may have altered melatonin levels.

Further, a simplified regimen of melatonin and amantadine effectively managed the patient’s hypersomnolence, allowing for discontinuation of solriamfetol and methylphenidate. She experienced great improvements in hypersomnolence symptoms with this simplified treatment regimen, characterized by clinical improvements, reduced adverse medication effects, and improved quality of life. Along with the hypersomnolence improvement, the patient also reported reduction in brain fog and subjective memory issues. The successful management of these previously treatment-resistant symptoms underscores the importance of personalized treatment approaches in complex cases. Our patient also experienced mood improvements, as demonstrated by responses on standardized depression and anxiety symptom questionnaires and subjective comments. She felt much more like herself again, for the first time in 15 years. Sertraline was the primary treatment for depression. Although sertraline was increased by 100 mg after the patient’s first visit, she continued to have mood improvement through her last visit, amidst sertraline stability. The clinical association between melatonin and depression adds further consideration for possible mood benefits of high-dose melatonin in this case. Further, it is possible that the improvement in her sleep from the melatonin supplementation was an indirect contribution to her overall improved mood.

This case report has several limitations. As a single case report, findings may not be generalizable. Without a control group, the specific effect of melatonin on symptoms cannot be definitively isolated from other factors, such as placebo effects, natural fluctuations, seasonal variations, and concurrent use of amantadine and sertraline. Amantadine and sertraline doses were also adjusted during this time, so it is also possible that these could have contributed to the patient’s symptom improvements as well. However, it is less likely that the increase in amantadine would have led to the patient’s improvements because the typical adverse effects of amantadine are restlessness, insomnia, agitation, and GI upset [18]. Further, some of the symptoms the patient presented with and experienced improvement with cannot be objectively measured. As a result, improvement in these areas (eg, mood and cognition symptoms) is primarily reliant upon the patient’s subjective report, in addition to clinician observations. We utilized standardized symptom scales of depression and anxiety symptoms to increase the measurement validity of these symptoms, yet it remains based on patient self-report. Finally, the evidence basis for the proposed mechanism remains limited to animal experiments and select case reports. These limitations highlight the need for larger, controlled studies to further explore our preliminary findings and to investigate relevant mechanisms of action.

While the mechanisms remain speculative, melatonin’s effects on the circadian rhythm and enteric nervous system could explain the observed improvements for this patient. Melatonin is produced by enterochromaffin cells in the gastrointestinal mucosa [9,10]. It binds to MT1 and MT2 receptors in the gut, influencing smooth-muscle activity and enteric nervous system signaling and interacting with other neurotransmitters, including serotonin and cholecystokinin [10,19]. Activation of these receptors can modulate smooth-muscle contractility, either directly or via enteric neurons and can affect motility patterns, including the migrating motor complex [20]. Melatonin also seems to play a role in decreasing inflammation within the GI tract by mediating the inflammatory cascade locally [12,21–23]. When the rate-limiting step in melatonin synthesis was knocked out in mice, they had significantly increased rates of leaky gut syndrome, Alzheimer disease, and pan-metabolic disorders [24].

These results agree with case reports in other pineal gland pathologies, documenting improved hypersomnolence with melatonin treatment [4–6]. An adolescent girl with a pineal gland cyst experienced improvements in sleep/wake cycle regulation and symptoms with 14-mg melatonin supplementation [4]. Similarly, a man in his 20s with a pineal gland cyst and nocturnal headaches reported a 70% relief in his symptoms with 6 mg of melatonin [5]. A woman in her 20s also reported improvement in somnolence with 2 mg of melatonin after pinealectomy [6]. These reports agree with our results and suggest that melatonin supplementation can help compensate for the altered sleep/wake cycles and other symptoms for patients with pineal gland pathologies. While there are no current evidence-based clinical practice guidelines, melatonin supplementation could be included in a pineal gland cyst treatment regimen to alleviate hypersomnolence symptoms [3]. The pineal gland is essential in establishing the circadian rhythm, but whether pineal gland cysts directly impact this remains unclear.

Conclusions

High-dose melatonin supplementation was associated with significant improvements in GI motility and hypersomnolence in this patient, suggesting it as a possible therapeutic adjuvant for similar clinical presentations. This patient had a small, symptomatic pineal cyst with no neurosurgical options for treatment. This is the first documented use of high-dose melatonin for gastrointestinal dysfunction in pineal cyst pathology. While previous case reports have demonstrated efficacy of melatonin supplementation for hypersomnolence in patients with pineal gland cysts and after pinealectomy (using doses ranging from 2 to 14 mg) [25,26], this case uniquely extends those findings in 2 important ways: (1) the use of higher doses (30 mg) than previously reported, and (2) most notably, the novel demonstration of therapeutic benefit for GI motility and chronic constipation. The existing literature on melatonin for pineal pathology focuses exclusively on sleep–wake cycle regulation, while studies on melatonin’s GI effects are limited to irritable bowel syndrome populations without pineal pathology [9,25–28]. Given its favorable adverse effects profile, treatment with high-dose melatonin is a low-risk option worthy of further investigation in similar cases, and larger, controlled studies are needed to confirm the efficacy and to clarify the mechanisms of action. This could be particularly beneficial in patients with pineal gland pathologies, given the potential disruptions in melatonin synthesis. Although previous case reports have demonstrated the efficacy of melatonin supplementation in treating hypersomnia symptoms after pinealectomy and in patients with pineal cysts and tumors, this case report uniquely addresses a gap in the literature by demonstrating the benefits of melatonin supplementation on GI functioning. Further research is warranted to elucidate the mechanisms by which melatonin affects GI function and inflammation. More research is also needed to explore the broader applications of melatonin in treating sleep dysregulation, GI disorders, and pineal pathology.