Preliminary finding of a randomized, double-blind, placebo-controlled, crossover study to evaluate the safety and efficacy of 5-hydroxytryptophan on REM sleep behavior disorder in Parkinson’s disease

Sleep disturbances in Parkinson’s disease (PD) are various, multifactorial, and result in significant morbidity, including insomnia, excessive daytime sleepiness, restless legs syndrome, and REM sleep behavior disorder (RBD) [1]. The pathological loss of muscle atonia during REM sleep, namely REM sleep without atonia (RSWA), is the neurophysiological hallmark of RBD and consists of increased sustained (tonic) or intermittent (phasic) EMG activity [2]. According to current diagnostic criteria, the diagnosis of RBD requires the presence of both RSWA and dream-enactment behaviors, either documented by video-polysomnography (v-PSG) or reported by patients and/or bed partner [2].

The serotonergic system plays a crucial role in the sleep–wake cycle and its dysfunction could be responsible for the development of sleep disturbances in PD. Animal studies have demonstrated that lesions in the raphe nucleus result in reduced sleep and lower levels of serotonin [3]. Moreover, changes in raphe nuclei following sleep deprivation included increases in the neuronal size, increased firing during wake, and downregulation of 5-HT receptors [4]. Preclinical PET studies with [11C] DASB demonstrated decreased SERT binding in sleep-deprived rats [4]. Furthermore, acute RBD can be induced by the use of antidepressants, especially serotonin reuptake inhibitors (SSRI) [5], suggesting a role of the serotonergic system in the pathogenesis of RBD.

The therapeutic strategy for RBD has been limited to symptomatic treatment, mainly because the pathophysiology of RBD is far from being completely understood. Low doses of clonazepam, 0.5–1 mg at bedtime, have been considered a first-line treatment option for RBD [6]. On the contrary, a recent small-sized randomized double-blind placebo-controlled trial has not demonstrated a clear-cut efficacy of 0.5 mg of clonazepam in ameliorating probable RBD clinical status in PD patients [7].

In other open-label trials and observational studies, doses of 3–12 mg of melatonin at bedtime have been used successfully to reduce injuries, with few adverse effects [8, 9]. Conversely, a recent study did not observe an effect of 4 mg of prolonged-released melatonin for reducing clinical symptoms of RBD in PD patients [10].

The therapeutic use of 5-hydroxytryptophan (5-HTP) bypasses the conversion of l-tryptophan (LT) into 5-HTP by the enzyme tryptophan hydroxylase, which is the rate-limiting enzyme in the synthesis of serotonin. 5-HTP crosses the blood–brain barrier and it is converted to serotonin through the aromatic l-amino-acid-decarboxylase increasing central serotonin production [11].

PD is a difficult disease to treat and can cause troublesome sleep disorders in conjunction with other comorbidities such as dementia and depression [12].

Recently, we found that 5-HTP treatment improved both levodopa-induced dyskinesias and depressive symptoms in PD patients [13, 14].

However, until now, there has been inconsistent research on the use of 5-HTP in sleep-related symptoms in PD. According to these premises, we hypothesized that 5-HTP, the direct precursor of serotonin and melatonin, would have an impact on RBD, possibly improving global sleep quality and reducing both dream-enactment behaviors and RSWA, through increased serotonergic tone [15].

Here we report the results of the first double-blind and placebo-controlled crossover trial, assessing the efficacy of the 5-HTP on RBD and global sleep quality as assessed by polysomnographic nighttime sleep parameters and a specific self-administered questionnaire.

Out of the 36 patients with PD screened for eligibility, a total of 18 (50%) patients were diagnosed with RBD according to v-PSG baseline assessment and subsequently randomized. The mean age was 67.5 ± 7.4 years with a mean disease duration of 8.1 ± 4.7 years and a mean total LEDD of 728.6 ± 509.1. Two subjects (11.1%) were taking a low dosage of clonazepam (1 mg) and alprazolam (0.25 mg), respectively, and were maintained at the same dosage during the course of the study. No other subject was taking drugs known to potentially affect RSWA. During the study a total of 14 subjects slept with the bed partner, 3 subjects slept alone, and 1 subject did not share the same bedroom.

At the baseline evaluation, the UPDRS subsections mean scores were as follows: mean UPDRS part 1 was 2.1 ± 2.2; mean UPDRS part 2 was 7.8 ± 5.3; mean UPDRS part 3 was 16.3 ± 10.6; mean UPDRS part 4 was 3.3 ± 4.3; mean total UPDRS was 30.6 ± 18.8.

We identified the group of patients that fulfilled the criteria for the UPDRS-based tremor-dominant and akinetic-rigid subtypes of PD. Six out of 18 (33.3%) patients had an akinetic-rigid phenotype and twelve (66.6%) patients had tremor-dominant phenotype [22]. The demographic and baseline clinical information is summarized in Table 1.

Patients were randomly assigned to the placebo-5-HTP arm (n = 9) and to the 5-HTP-placebo arm (n = 9). No significant differences in baseline characteristics were detected between the 2 treatment arms.

Because of logistical issues, one subject had undergone complete withdrawal at the end of the part I period. One patient did not have the last evaluation (week 16) due to the onset of acute dehydration which required hospitalization.

Sixteen patients (11 men, 5 women) completed the study and were included in the final analysis (see Fig. 1). All 16 patients demonstrated complete adherence to the experimental treatment and remained on stable doses of dopaminergic drugs until the end of the study.

This is the first randomized, double-blind, placebo-controlled, crossover, phase II proof-of-concept clinical study investigating the effects of 5-HTP on RBD and nighttime sleep parameters in patients with PD. As reported, we have detected non-significant effects of 5-HTP on both clinical and neurophysiological RBD manifestation along with a substantial placebo effect on RBD clinical status self-reported. However, the trends of some results deserve deepening and further discussion.

In the present study, we have found a statistically non-significant increase in the total percentage of REM sleep by treatment with 50 mg 5-HTP in subjects with PD. This result is in line with previous studies in which 5-HTP has been shown to improve sleep quality by increasing REM sleep [23], which has never been replicated in PD patients with PD. Serotonin might be regarded as a positive modulator for melatonin synthesis. Indeed, the rate of pineal melatonin synthesis is dependent on the free cytoplasm pool of serotonin in pinealocytes, and the drug-induced elevation of this pool stimulates melatonin formation and increases circulating melatonin levels [15]. Actually, melatonin is synthesized from serotonin through the action of arylalkylamine N-acetyltransferase (serotonin N-acetyltransferase), and it seems that serotonin N-acetyltransferase activity is stimulated by serotonin via the 5-HT2 receptor [24].

Among all sleep stages, REM sleep is the most circadian dependent. REM sleep duration, latency, and continuity are under strong circadian control [25]. Melatonin deficit leads to instability in the circadian timing system, resulting in reduced REM sleep amount during nighttime sleep. Exogenous melatonin increases REM sleep amount in patients with reduced REM sleep duration and concurs to modulate REM sleep episode duration [26]. Moreover, the medications used in PD can also affect sleep architecture and may be associated with excessive daytime sleepiness. Indeed, levodopa can result in REM suppression and increased REM latency [27].

Furthermore, subjective reports of RBD behavioral episodes improved significantly in terms of severity, although 5-HTP has not demonstrated superiority over placebo in CGI score reduction. Self-reported frequency of RBD-related episodes, namely disturbing dreams, somniloquy, or dream-enactment motor behaviors, did not show significant reduction using 5-HTP in patients with PD, compared to baseline and placebo.

According to these scientific premises, we suggest that 5-HTP might have contributed to an increase in the total percentage of REM sleep in our patients through the increase of nocturnal melatonin levels. Coherently, despite the increase of REM sleep percentage, the number and intensity of subjective reports of RBD behavioral episodes had not increased at follow-up. In fact, melatonin was found to be effective in reducing RBD episodes [8, 21].

In the present study, we have also found non-significant changes in RSWA parameters by 5-HTP in patients with PD, compared to baseline and placebo. The exact pathogenesis of RSWA is not yet completely understood. The physiological REM sleep atonia is thought to be triggered by glutamatergic and GABAergic/glycinergic brainstem inputs, by means of both motoneuron inhibition and reduced motoneuron excitation [28]. A decrease of serotoninergic activity is thought to be implicated in REM atonia mechanisms [28] and melatonin may reduce the RSWA in RBD [21].

We hypothesized that our findings on RSWA might be explained by the dual and counterbalanced increase of serotonin and melatonin in the central nervous system. Indeed, the increment of serotonergic tone may increase motoneuron activity during REM sleep-inducing RSWA [28].

In our study, a non-significant trend for decreased arousal index and the amount of WASO was found in subjects who received 5-HTP compared to placebo, contributing to ameliorate the global sleep quality. In fact, 5-HTP could improve sleep quality by modulating the arousal level and by reducing sleep instability through stabilization of sleep microstructure [29]. It is tempting to speculate that the global sleep quality improvement could explain the significant improvement in activities of daily living as assessed by UPDRS part II and the significant amelioration of depressive symptoms as reported in a parallel clinical study [13].

Moreover, patients receiving 5-HTP compared to baseline have shown a significantly reduced amount of NREM sleep stage N3 compare to baseline. The latter result might be associated with the effect of 5-HTP in modulating the frequency band and the spectra of delta waves [29]. Indeed, 5-HTP has been shown to be effective in the management of NREM sleep parasomnia, which is related to delta sleep instability [30].

The low dosage (50 mg/day) of 5-HTP may represent a limitation. In fact, the interesting trends to improve several clinical outcomes that we found may suggest that the dose of 5-HTP was too low to induce a complete beneficial effect.

Another possible limitation of this study is that all patients underwent one full-night attended v-PSG recording in the sleep laboratory with digital polysomnography, while the subsequent PSG recordings were home based. This workup setting may have caused heterogeneity of results due to a different sleep environment. However, it has been reported that RSWA has a good night-to-night agreement and seems to be more stable than video-recorded behavioral manifestations across nights [31]. Furthermore, in order to assess treatment efficacy, we analyzed the self-reported frequency of RBD episodes and the clinical global impression. A validated scale exploring RBD severity in terms of frequency and intensity of episodes is particularly needed in both clinical practice and the research field.

A further limitation of our study is the small size of our sample.

Finally, the exact dosage and duration of 5-HTP supplementation in the PD-RBD population has yet to be established.

In conclusion, our data show that 5-HTP supplementation may be effective in reducing subjective impression of the severity and frequency of the RBD episodes in patients with PD and RBD.

Nonetheless, further studies are required to confirm these preliminary data.

Department of Medical Sciences and Public Health, University of Cagliari.

Mario Meloni: conceptualization; methodology; validation; formal analysis; investigation; resources; data curation; writing-original draft; writing-review and editing; visualization.

Michela Figorilli: investigation; resources; data curation; writing-original draft; writing-review and editing; supervision.

Manolo Carta: conceptualization; methodology; writing-review and editing; supervision.

Ludovica Tamburrino: investigation; videopolysomnography settings, recordings and scoring; data curation.

Antonino Cannas: resources; movement disorders center.

Fabrizio Sanna: formal analysis; data curation; supervision.

Giovanni Defazio: resources; movement disorders center; supervision.

Monica Puligheddu: conceptualization; methodology; writing-review and editing; supervision; project administration; funding acquisition.

Open access funding provided by Università degli Studi di Cagliari within the CRUI-CARE Agreement. This work was supported by the Sleep Disorders Center, Department of Medical Sciences and Public Health, University of Cagliari.

The data that support the findings of this study are available from the corresponding author upon reasonable request.