A Medical Food Formulation of Griffonia simplicifolia /Magnesium for Childhood Periodic Syndrome Therapy: An Open-Label Study on Motion Sickness

Abstract

Motion sickness (MS) is a disabling condition dominated by disagreement between visually perceived movement and the vestibular system's sense of movement, with symptoms like dizziness, fatigue, and nausea, and other autonomic disabling symptoms. Preparations of Griffonia simplicifolia, containing high concentrations of 5-HTP, might be effective for serotonin-related disorders, including MS. Therefore, the aim of the present study is to assess the efficacy and safety of the G. simplicifolia/magnesium complex in a pediatric population with MS. The Griffonia/magnesium complex (50 and 200 mg, respectively) was orally administered as a prophylactic therapy for MS twice a day for 3 months to group A, and no therapy for MS was administered to group B. The MS clinical signs were recorded by parents or, where possible, directly from children by a specific module, which included validated questions for the diagnoses that were administered to all subjects and parents of both groups. Two study groups were matched for age (P=.224), sex (P=.801), and z-score body–mass index (P=.173). At T0, all recruited subjects in both groups complained about MS. After 3 months (T1), group A showed an MS prevalence of 36%, significantly lower than MS prevalence in group B (73%) (P<.001). The findings of the present study suggest the role of the Griffonia/magnesium complex as a potential treatment with middle-term efficacy even for MS.

Introduction

Motion sickness (MS) cannot be identified properly as a true sickness in the strict sense of the word, but as a kind of physiological vertigo provoked during passive locomotion in vehicles, generated by unfamiliar body accelerations, to which the person has not adapted, or by an intersensory conflict between vestibular and visual stimuli.¹ Clinically, MS is defined by a set of four main symptoms that regularly appear: facial pallor, cold sweats, nausea, and vomiting. Other additional signs, such as sighing, yawning, hyperventilation, flatulence, drowsiness, dizziness, headache, fatigue, and postural instability, which are more variable in their appearance and duration, can be also observed.²

MS is included under the denomination of childhood periodic syndromes, several recurrent, transient, and otherwise unexplained symptoms and signs generally described as being precursors of migraine, even though not exclusively linked to it.³ The paucity of large studies with representative population samples on the subject is a barrier to an evidence-based characterization of the childhood periodic syndromes and for the research stimuli about these disabling symptoms.

One of the most established theories that explains in which circumstances MS arises is the sensory conflict theory proposed in the last decades, postulating its origin from a sensory mismatch between actual versus expected invariant patterns of vestibular, visual, and somatosensory inputs,⁴ leading to an activation of vestibule-autonomic pathways involved in producing nausea and vomiting.⁵

Since the cerebellum integrates labyrinthine and nonlabyrinthine inputs that reflect body position in space, it has long been hypothesized as playing a major role in generating MS,^6
–8 as evidenced by the effects on animal models with ablation of the posterior cerebellar vermis.⁹

MS indiscriminately tends to affect air, sea, road, and space travelers; both humans and animals possessing an intact vestibular apparatus can get MS given the right quality and quantity of provocative stimulation, although there are wide and consistent individual differences in the degree of susceptibility.¹⁰

Moreover, MS is very frequent during childhood,^4,11 and some symptoms may be considered as the effect of the autonomic activation (i.e., pallor, cold sweating), even if the putative hemodynamic modifications in cerebral flow remain unclear,^8,12 as the particular susceptibility of some individuals has not yet been explained.¹³

In general, MS pathogenesis seems to be much more complex than expected, considering the many neurotransmitter systems involved, such as the Fos-LI neurons that can change the neuronal plasticity in the caudal vestibular nucleus,¹⁴ the endocannabinoid system,^15,16 substance P,¹⁷ and calcitonin gene-related peptide.¹⁸

The MS pathophysiology seems to be complex, although two main mechanisms may be identified: conflict between visual and vestibular/proprioceptive signals and conflict between canal and otolith signals (intralabyrinthine conflict).

Nonpharmacologic treatments include efforts to control gastric motility, such as wearing a wristband that stimulates the P6 acupressure point, and efforts to affect the vestibular, visual, and proprioceptive systems, such as facing forward, riding at the front of a boat, and looking toward the horizon, among others.¹⁹

Among the treatments of MS in childhood are an effective care that has been identified in escaping the motion or behavior measures, such as pleasant music²⁰ or verbal suggestions combined with a conditioning procedure,^21,22 adaptation, and drug treatment. Moreover, the pharmacological treatments coded for MS are not specifically tailored for the pediatric age, but rather borrowed from adults, such as dexamethasone,²³ baclofen, meclizine, dimenhydrinate plus cinnarizine and promethazine plus d-amphetamine,^24,25 and scopolamine.^26,27 Other drugs are ginger root²⁸ and triptans²⁹ for the possibility of any overlapping between the pathophysiology of MS and that of migraine.^30

–34 However, all these drugs present many relevant side effects, such as sleepiness, dry mouth, dizziness, vertigo, confusion, insomnia, tremors, or delirium.³⁵

All these drugs cited are currently used in adulthood for MS acute treatment, and no prophylactic therapy has been coded yet for adults affected. Moreover, these drugs may be considered only for off-label prescriptions in childhood.

In general, all the drugs described are neither recommended nor prescription is possible in Italy for pediatric age, when drugs with minimal side effects should be preferred. In this light, the nonpharmacological treatment as in other clinical conditions such as nutraceutical preparations^36
–38 should be preferred as prophylaxis of MS in children and also because all drugs are just for the acute treatment.

About the role of serotonin (5-HT) in MS development,³⁹ a preparation for potential use in MS prophylaxis is the seed extract from Griffonia simplicifolia Baill. (family Caesalpinaceae). These seeds are rich in 5-hydroxy-l-tryptophan (5-HTP), a direct precursor of serotonin. In fact, the administration of 5-HTP to animals increases 5-HT levels in the central nervous system (CNS).^40

–43

Theoretically, a medical food formulation comprising G. simplicifolia, containing high concentrations of 5-HTP, might be effective for serotonin-related disorders, including MS.³⁸

Therefore, the aim of the present study is to assess the efficacy and safety of the G. simplicifolia/magnesium complex for prophylaxis of pediatric MS.

Materials and Methods

Sample size

The primary outcome for power calculation was the MS symptoms intensity measured with a 100-mm visual analogue scale (VAS). Prior data indicated a difference of 100 mm in the VAS measurements observed before medical food complex prophylactic intake. The difference in the response of matched pairs distributed with a standard deviation of four could be considered clinically significant. To detect a clinically relevant difference between each group, 28 subjects assigned to each group were necessary (power ≥85%, alpha 0.05, delta 2).

Study population

A cohort of 254 prepubertal children was referred for MS between September 2012 and December 2013 to the Center for Childhood Headache of the Department of Child and Adolescent Neuropsychiatry of Second University of Naples.

After recruitment, all children were divided into two samples (group A and group B) comprising 127 subjects in each group (Table 1).

Table 1.

Age, Sex, z-Score Body–Mass Index, and VAS Differences Between the Group of Children Affected by Motion Sickness Treated with the Griffonia/Magnesium Complex (50 and 200 mg, Respectively) Twice a Day as Prophylactic Administration (Group A) and Group Affected by Motion Sickness Without Any Prophylactic Treatment (Group B)

	Group A (n=127)	Group B (n=127)	P
Age	7.69±2.32	8.02±1.98	.224
Sex ratio (M/F)	72/55	69/58	.801
z-BMI	0.52±0.17	0.49±0.18	.173
VAS values	7.42±1.05	7.18±1.97	.227

The t-test and Chi-square test, where appropriated, were applied. P-values<.05 were considered statistically significant.

VAS, visual analogue scale; z-BMI, z-score body–mass index.

Exclusion criteria were neurological or psychiatric symptoms, mental retardation (IQ ≤70), overweight (body–mass index [BMI] ≥85th percentile), or obesity (BMI ≥95th percentile).

Study design

The G. simplicifolia/magnesium complex (50 and 200 mg, respectively) (Periodar^®), disposable in Italy for the periodic syndromes treatment, was orally administered as prophylactic therapy for MS b.i.d. (twice a day) for 3 months to group A, and no therapy for MS was administered to group B.

The MS clinical signs were recorded by parents or, where possible, directly from children by a specific module, which included validated questions for the diagnosis (does your child complain about feeling sick or feel sick when in a car, bus, airplane, or ship ride?) as reported by Arruda et al. in 2010.³

Informed consent was obtained from all parents or guardians and, when possible directly, also from the children.

To verify the efficacy of the Griffonia/magnesium complex treatment, we compared the MS severity (VAS values) and prevalence after 3 months of treatment in group A and after 3 months of observation in group B (without prophylactic treatment).

The prevalence of MS was evaluated as the number of MS episodes/number of locomotion in vehicles. This prevalence was 100% at baseline in each group.

The Clinical Departmental University Ethics Committee approved the study (protocol number 13/2012), which was conducted according to the criteria of the Declaration of Helsinki as revised in 2000. Therefore, in this study, we did not use a placebo group.

Statistical analysis

To compare the characteristics of two samples (age, sex, and z-BMI) and the MS prevalence at T1 between the two study groups, the Chi-square test and t-test, where appropriate, were applied. P-values<.05 were considered statistically significant.

All data were coded and analyzed using the commercially available STATISTICA 6.0 package for Windows (StatSoft, Inc., Tulsa, OK, USA).

Results

The two study groups were not significantly different for age (P=.224), sex (P=.801), z-BMI (P=.173), and VAS values at T0 (P=.227) (Table 1).

At T0, all recruited subjects in both groups complained about MS.

After 3 months (T1), group A showed a significantly lower prevalence (36% vs. 73%; P<.001) and severity (VAS values) of MS symptoms than group B (2.59±0.14 vs. 6.91±2.08; P<.001). Moreover, group A showed significantly lower VAS values at T1 than T0 (2.59±0.14 vs. 7.42±1.05; P<.001).

No relevant adverse effects were recorded, except sporadic diarrhea and stomachache during the first 2 days of treatment and only in four subjects (3.14% of the subjects of group A).

Discussion

The main finding of the present study can be summarized in the identification of nonbehavioral and nonpharmacological prophylactic treatments for the pediatric MS, with no relevant adverse effects and good tolerability in a large sample of subjects with a medical food formulation of G. simplicifolia/magnesium and more than 50% reduction compared with the nontreatment group.

Overall, the treatment of MS with herbal supplements containing 5-HTP has not been well studied. The topic of the present research can be considered relevant as most of the management strategies for MS are not approved for the pediatric population

In this light, the efficacy and safety of the medical food complex, G. simplicifolia/magnesium, may be identified as the first choice treatment in this disabling symptomatology.

In general, pharmacological studies indicate that serotonin (5-HT) may be involved in MS³⁹ with a direct influence of 5-HT levels within the CNS on development of MS symptoms.^44,45

In particular, the studies by Drummond^44,45 suggested that depleted brain serotonin activity may be involved in vestibulo-ocular disturbances during MS even if other neurotransmitters systems are involved in MS, such as the GABA.^46,47

In this picture, our findings of the improvement of MS symptoms after the Griffonia/magnesium complex administration can be interpreted. In our article, the clinical effectiveness of Griffonia seems to be increased with the magnesium supplementation. Conversely, magnesium is considered as a nonpharmacological agent, with good efficacy in some clinical conditions,^{48

–56} and the recommended dose is 400 mg/daily.⁵⁷ We were not, however, able to document the specific synergism between magnesium and Griffonia; however, several mechanisms could be postulated to explain these effects. In fact, magnesium is able to (i) reduce the catecholamine release, and then prevent central sensitization caused by peripheral nociceptive stimulation,⁵⁸ and (ii) block the entrance of ions such as calcium through the bounding to the NMDA and endocannabinoid receptor.⁵⁹

Alternatively, there are no studies about the specific effect of magnesium on MS symptoms; therefore, we could only speculate for a putative synergism with the 5-HT levels due to the Griffonia administration.

Moreover, MS can impact the children's affected quality of life and their intrafamiliar and peer relationships, limiting the opportunities for recreation and travel and potentially causing parental stress and poor social activities.

On the other hand, because of three factors (the unknown pathophysiology, the absence of controlled drug trials, and a placebo response as high as 70% with the coded drugs for MS treatment), therapy management of MS remains empiric rather than evidence-based, and the therapies include the avoidance of potential triggers, prophylactic pharmacologic therapy, abortive pharmacologic therapy, supportive care during an episode, and general family support.⁶⁰

In our study, the group A children received prophylactic treatment for MS symptoms. However, it is necessary to emphasize that in agreement with the Declaration of Helsinki no placebo group had been formed because it has been judged as not ethical in pediatric age.

On the other hand, we have to take into account some limitations of the current study: (i) it contains no outcomes data other than the presence of reported MS after 3 months, even if the MS symptoms amelioration cannot be considered as a placebo effect, because of the complexity of clinical manifestation of the MS due to the autonomic activation that cannot be simulated, neither blocked nor voluntarily; (ii) the study is an open-label (nonblinded study) trial; and (iii) the quantity of the 5-HTP content in G. simplicifolia is neither evaluated nor standardized, but the current nutraceutical preparations available in Italy contain the same dose of G. simplicifolia.

In this light, our results could be interpreted as a new approach to the disturbance; in fact, the use of medical food formulation in the treatment of MS could be considered a new, safe, and effective approach to the disturbance in the middle term.

Footnotes

Acknowledgment

The Periodar^® blisters were kindly provided to the patients by Steve Jones srl, Sesto Fiorentino (FI), Italy.

Author Disclosure Statement

All authors declare that they have no competing interests.

References

Brandt

, Daroff

: The multisensory physiological and pathological vertigo syndromes. Ann Neurol, 1980; 7:195–203.

Paillard

, Lamôré

, Etard

, et al.: Is there a relationship between odors and motion sickness?. Neurosci Lett, 2014; 566:326–330.

Arruda

, Guidetti

, Galli

, Albuquerque

, Bigal

: Childhood periodic syndromes: A population-based study. Pediatr Neurol, 2010; 43:420–424.

Reason

, Brand

: Motion Sickness. Academic Press, London, 1975.

Yates

, Miller

, Lucot

: Physiological basis and pharmacology of motion sickness: An update. Brain Res Bull, 1998; 47:395–406.

Cohen

, Dai

, Raphan

: The critical role of velocity storage in production of motion sickness. Ann N Y Acad Sci, 2003; 1004:359–376.

Cohen

, Dai

, Yakushin

, Raphan

: Baclofen, motion sickness susceptibility and the neural basis for velocity storage. Prog Brain Res, 2008; 171:543–553.

Yates

, Catanzaro

, Miller

, McCall

: Integration of vestibular and emetic gastrointestinal signals that produce nausea and vomiting: Potential contributions to motion sickness. Exp Brain Res, 2014; 232:2455–2469.

Catanzaro

, Miller

, Cotter

, McCall

, Yates

: Integration of vestibular and gastrointestinal inputs by cerebellar fastigial nucleus neurons: Multisensory influences on motion sickness. Exp Brain Res, 2014; 232:2581–2589.

10.

Oosterveld

: Motion sickness. J Travel Med, 1995; 2:182–185.

11.

Money

: Motion sickness. Physiol Rev, 1970; 50:1–39.

12.

Bles

, Bos

, Kruit

: Motion sickness. Curr Opin Neurol, 2000; 13:19–25.

13.

Bosser

, Gauchard

, Brembilla-Perrot

, Marçon

, Perrin

: Experimental evaluation of a common susceptibility to motion sickness and vasovagal syncope in children. Brain Res Bull, 2007; 71:485–492.

14.

Cai

, Wang

, Chen

, et al.: Decreased Fos protein expression in rat caudal vestibular nucleus is associated with motion sickness habituation. Neurosci Lett, 2010; 480:87–91.

15.

Strewe

, Feuerecker

, Nichiporuk

, et al.: Effects of parabolic flight and spaceflight on the endocannabinoid system in humans. Rev Neurosci, 2012; 23:673–680.

16.

Choukèr

, Kaufmann

, Kreth

, et al.: Motion sickness, stress and the endocannabinoid system. PLoS One, 2010; 5:e10752.

17.

Horii

, Nakagawa

, Uno

, et al.: Implication of substance P neuronal system in the amygdala as a possible mechanism for hypergravity-induced motion sickness. Brain Res, 2012; 1435:91–98.

18.

Xiaocheng

, Zhaohui

, Junhui

, et al.: Expression of calcitonin gene-related peptide in efferent vestibular system and vestibular nucleus in rats with motion sickness. PLoS One, 2012; 7:e47308.

19.

Herron

: The ups and downs of motion sickness. Am J Nurs, 2010; 110:49–51.

20.

Keshavarz

, Hecht

: Pleasant music as a countermeasure against visually induced motion sickness. Appl Ergon, 2014; 45:521–527.

21.

Horing

, Weimer

, Schrade

, et al.: Reduction of motion sickness with an enhanced placebo instruction: An experimental study with healthy participants. Psychosom Med, 2013; 75:497–504.

22.

Paillard

, Quarck

, Paolino

, et al.: Motion sickness susceptibility in healthy subjects and vestibular patients: Effects of gender, age and trait-anxiety. J Vestib Res, 2013; 23:203–209.

23.

Zheng

, Wang

, Mo

, Li

: Dexamethasone alleviates motion sickness in rats in part by enhancing the endocannabinoid system. Eur J Pharmacol, 2014; 727:99–105.

24.

Weerts

, Pattyn

, Van de Heyning

, Wuyts

: Evaluation of the effects of anti-motion sickness drugs on subjective sleepiness and cognitive performance of healthy males. J Psychopharmacol, 2013; 28:655–664.

25.

Rubio

, Weichenthal

, Andrews

: Motion sickness: Comparison of metoclopramide and diphenhydramine to placebo. Prehosp Disaster Med, 2011; 26:305–309.

26.

Spinks

, Wasiak

: Scopolamine (hyoscine) for preventing and treating motion sickness. Cochrane Database Syst Rev, 2011; CD002851. DOI: 10.1002/14651858.CD002851.pub4.

27.

Simmons

, Phillips

, Lojewski

, et al.: The efficacy of low-dose intranasal scopolamine for motion sickness. Aviat Space Environ Med, 2010; 81:405–412.

28.

Palatty

, Haniadka

, Valder

, Arora

, Baliga

: Ginger in the prevention of nausea and vomiting: A review. Crit Rev Food Sci Nutr, 2013; 53:659–669.

29.

Furman

, Marcus

, Balaban

: Rizatriptan reduces vestibular-induced motion sickness in migraineurs. J Headache Pain, 2011; 12:81–88.

30.

Brey

: Both migraine and motion sickness may be due to low brain levels of serotonin. Neurology, 2005; 65:E9–E10.

31.

Furman

, Marcus

: Migraine and motion sensitivity. Continuum (Minneap Minn), 2012; 18:1102–1117.

32.

Furman

, Marcus

: A pilot study of rizatriptan and visually-induced motion sickness in migraineurs. Int J Med Sci, 2009; 6:212–217.

33.

Marcus

, Furman

, Balaban

: Motion sickness in migraine sufferers. Expert Opin Pharmacother, 2005; 6:2691–2697.

34.

Takeda

, Morita

, Horii

, et al.: Neural mechanisms of motion sickness. J Med Invest, 2001; 48:44–59.

35.

Lin

, Chen

, Chang

, et al.: Delirium due to scopolamine patch in a 4-year-old boy. J Formos Med Assoc, 2011; 110:208–211.

36.

Esposito

, Ruberto

, Pascotto

, Carotenuto

: Nutraceutical preparations in childhood migraine prophylaxis: Effects on headache outcomes including disability and behaviour. Neurol Sci, 2012; 33:1365–1368.

37.

Esposito

, Carotenuto

: Ginkgolide B complex efficacy for brief prophylaxis of migraine in school-aged children: An open-label study. Neurol Sci, 2011; 32:79–81.

38.

Carotenuto

, Esposito

: Nutraceuticals safety and efficacy in migraine without aura in a population of children affected by neurofibromatosis type I. Neurol Sci, 2013; 34:1905–1909.

39.

Cuomo-Granston

, Drummond

: Migraine and motion sickness: What is the link?. Prog Neurobiol, 2010; 91:300–312.

40.

Bogdanski

, Wissbach

, Udenfriend

: Pharmacological studies with the serotonin precursor, 5-hydroxytryptophan. J Pharmacol Exp Ther, 1958; 122:182–194.

41.

Denoyer

, Kitahama

, Sallanon

, Touret

, Jouvet

: 5-Hydroxytryptophan uptake and decarboxylating neurons in the cat hypothalamus. Neuroscience, 1989; 31:203–211.

42.

Arai

, Karasawa

, Nagatsu

: Exogenous L-5-hydroxytryptophan is decarboxylated in neurons of the substantia nigra par compacta and locus coeruleus of the rat. Brain Res, 1995; 669:145–149.

43.

Kitahama

, Jouvet

, Fujimiya

, Nagatsu

, Arai

: 5-Hydroxytryptophan (5-HTP) uptake and decarboxylation in the kitten brain. J Neural Transm, 2002; 109:683–689.

44.

Drummond

: Effect of tryptophan depletion on symptoms of motion sickness in migraineurs. Neurology, 2005; 65:620–622.

45.

Drummond

: Tryptophan depletion increases nausea, headache and photophobia in migraine sufferers. Cephalalgia, 2006; 26:1225–1233.

46.

Wang

, Li

, Chen

, et al.: Temporal change in NMDA receptor signaling and GABAA receptor expression in rat caudal vestibular nucleus during motion sickness habituation. Brain Res, 2012; 1461:30–40.

47.

Levine

, Chillas

, Stern

, Knox

: The effects of serotonin (5-HT3)receptor antagonists on gastric tachyarrhythmia and the symptoms of motion sickness. Aviat Space Environ Med, 2000; 71:1111–1114.

48.

Rodríguez-Moran

, Guerrero-Romero

: Oral magnesium supplementation improves the metabolic profile of metabolically obese, normal-weight individuals: A randomized double-blind placebo-controlled trial. Arch Med Res, 2014; 45:388–393.

49.

Simental-Mendía

, Rodríguez-Morán

, Guerrero-Romero

: Oral magnesium supplementation decreases C-reactive protein levels in subjects with prediabetes and hypomagnesemia: A clinical randomized double-blind placebo-controlled trial. Arch Med Res, 2014; 45:325–330.

50.

Komiya

, Su

, Chen

, Habas

, Runnels

: Magnesium and embryonic development. Magnes Res, 2014; 27:1–8.

51.

Makrides

, Crosby

, Bain

, Crowther

: Magnesium supplementation in pregnancy. Cochrane Database Syst Rev, 2014; 4:CD000937.

52.

Ozgür Keşkek

, Kırım

, Karaca

, Saler

: Low serum magnesium levels and diabetic foot ulcers. Pak J Med Sci, 2013; 29:1329–1333.

53.

Karandish

, Tamimi

, Shayesteh

, Haghighizadeh

, Jalali

: The effect of magnesium supplementation and weight loss on liver enzymes in patients with nonalcoholic fatty liver disease. J Res Med Sci, 2013; 18:573–579.

54.

Tarighat Esfanjani

, Mahdavi

, Ebrahimi Mameghani

, et al.: The effects of magnesium, L-carnitine, and concurrent magnesium-L-carnitine supplementation in migraine prophylaxis. Biol Trace Elem Res, 2012; 150:42–48.

55.

Taylor

: Nutraceuticals and headache: The biological basis. Headache, 2011; 51:484–501.

56.

Sun-Edelstein

, Mauskop

: Alternative headache treatments: Nutraceuticals, behavioral and physical treatments. Headache, 2011; 51:469–483.

57.

Sun-Edelstein

, Mauskop

: Role of magnesium in the pathogenesis and treatment of migraine. Expert Rev Neurother, 2009; 9:369–379.

58.

Soave

, Conti

, Costa

, Arcangeli

: Magnesium and anaesthesia. Curr Drug Targets, 2009; 10:734–743.

59.

Snyder

: Opiate receptors and beyond: 30 years of neural signaling research. Neuropharmacology, 2004; 47:274–285.

60.

Evans

, Marcus

, Furman

: Motion sickness and migraine. Headache, 2007; 47:607–610.