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Ultimate Sleep Formula


Valerian extract (root)

Critical evaluation of the effect of valerian extract on sleep structure and sleep quality* http://europepmc.org/abstract/med/10761819


A carefully designed study assessed the short-term (single dose) and long-term (14 days with multiple dosages) effects of a valerian extract on both objective and subjective sleep parameters. The investigation was performed as a randomized, double-blind, placebo-controlled, cross-over study. Sixteen patients (4 male, 12 female) with previously established psychophysiological insomnia (ICSD-code 1.A.1.), and with a median age of 49 (range: 22 to 55), were included in the study. The main inclusion criteria were reported primary insomnia according to ICSD criteria, which was confirmed by polysomnographic recording, and the absence of acute diseases. During the study, the patients underwent 8 polysomnographic recordings: i.e., 2 recordings (baseline and study night) at each time point at which the short and long-term effects of placebo and valerian were tested. The target variable of the study was sleep efficiency. Other parameters describing objective sleep structure were the usual features of sleep-stage analysis, based on the rules of Rechtschaffen and Kales (1968), and the arousal index (scored according to ASDA criteria, 1992) as a sleep microstructure parameter. Subjective parameters such as sleep quality, morning feeling, daytime performance, subjectively perceived duration of sleep latency, and sleep period time were assessed by means of questionnaires. After a single dose of valerian, no effects on sleep structure and subjective sleep assessment were observed. After multiple-dose treatment, sleep efficiency showed a significant increase for both the placebo and the valerian condition in comparison with baseline polysomnography. We confirmed significant differences between valerian and placebo for parameters describing slow-wave sleep. In comparison with the placebo, slow-wave sleep latency was reduced after administration of valerian (21.3 vs. 13.5 min respectively, p<0.05). The SWS percentage of time in bed (TIB) was increased after long-term valerian treatment, in comparison to baseline (9.8 vs. 8.1% respectively, p<0.05). At the same time point, a tendency for shorter subjective sleep latency, as well as a higher correlation coefficient between subjective and objective sleep latencies, were observed under valerian treatment. Other improvements in sleep structure – such as an increase in REM percentage and a decrease in NREM1 percentage – took place simultaneously under placebo and valerian treatment. A remarkable finding of the study was the extremely low number of adverse events during the valerian treatment periods (3 vs. 18 in the placebo period). In conclusion, treatment with a herbal extract of radix valerian are demonstrated positive effects on sleep structure and sleep perception of insomnia patients, and can, therefore, be recommended for the treatment of patients with mild psychophysiological insomnia.

Reference: Donath, F., et al. “Critical evaluation of the effect of valerian extract on sleep structure and sleep quality.” Pharmacopsychiatry 33.2 (2000): 47-53.DOI: 10.1055/s-2000-7972

Aqueous extract of valerian root (Valeriana officinalis L.) improves sleep quality in man* http://www.sciencedirect.com/science/article/pii/0091305782902647


The effect of an aqueous extract of valerian (Valeriana officinalis L.) root on subjectively rated sleep measures was studied on 128 people. Each person received 9 samples to test (3 containing placebo, 3 containing 400 mg valerian extract and 3 containing a proprietary over-the-counter valerian preparation). The samples, identified only by a code number, and presented in random order, were taken on non-consecutive nights. Valerian produced a significant decrease in subjectively evaluated sleep latency scores and a significant improvement in sleep quality; the latter was most notable among people who considered themselves poor or irregular sleepers, smokers, and people who thought they normally had long sleep latencies. Night awakenings, dream recall, and somnolence the next morning were relatively unaffected by valerian. With the proprietary valerian-containing preparation, the only change was a significant increase in reports of feeling more sleepy than normal the next morning. Thus the questionnaire, simple to use and non-invasive, provides a sensitive means for detecting the effects of mild sedatives on different aspects of sleep in man. It also allows identification within the test population of the subgroups most affected.

Reference: Leathwood, Peter D., et al. “Aqueous extract of valerian root (Valeriana officinalis L.) improves sleep quality in man.” Pharmacology Biochemistry and Behavior 17.1 (1982): 65-71.doi:10.1016/0091-3057(82)90264-7

Effect of valerian on human sleep* http://link.springer.com/article/10.1007/BF00432503


The effect of an aqueous extract of valerian root on sleep was studied in two groups of healthy, young subjects. One group (N=10) slept at home, the other (N=8) in the sleep laboratory. Sleep was evaluated on the basis of questionnaires, self-rating scales, and, night-time motor activity. In addition, polygraphic sleep recordings and spectral analysis of the sleep EEG was performed in the laboratory group. Under home conditions, both doses of valerian extract (450 and 900 mg) reduced perceived sleep latency and wake time after sleep onset. Night-time motor activity was enhanced in the middle third of the night and reduced in the last third. The data suggest a dose-dependent effect. In the sleep laboratory, where only the higher dose of valerian was tested, no significant differences from placebo were obtained. However, the direction of the changes in the subjective and objective measures of sleep latency and wake time after sleep onset, as well as in night-time motor activity, corresponding to that observed under home conditions. There was no evidence for a change in sleep stages and EEG spectra. The results indicate that the aqueous valerian extract exerts a mild hypnotic action.

Reference: Balderer, Gisela, and Alexander A. Borbély. “Effect of valerian on human sleep.” Psychopharmacology 87.4 (1985): 406-409.

Valerian for Sleep: A Systematic Review and Meta-Analysis* http://www.sciencedirect.com/science/article/pii/S0002934306002750


Insomnia affects approximately one-third of the adult population and contributes to increased rates of absenteeism, health care use, and social disability. Extracts of the roots of valerian (Valeriana officinalis) are widely used for inducing sleep and improving sleep quality. A systematic review of randomized, placebo-controlled trials of valerian for improving sleep quality is presented. An extensive literature search identified 16 eligible studies examining a total of 1093 patients. Most studies had significant methodologic problems, and the valerian doses, preparations, and length of treatment varied considerably. A dichotomous outcome of sleep quality (improved or not) was reported by 6 studies and showed a statistically significant benefit (relative risk of improved sleep = 1.8, 95% confidence interval, 1.2-2.9), but there was evidence of publication bias in this summary measure. The available evidence suggests that valerian might improve sleep quality without producing side effects. Future studies should assess a range of doses of standardized preparations of valerian and include standard measures of sleep quality and safety.

Reference: Bent, Stephen, et al. “Valerian for sleep: a systematic review and meta-analysis.” The American journal of medicine 119.12 (2006): 1005-1012.doi:10.1016/j.amjmed.2006.02.026

Double-blind study of a Valerian preparation* http://www.sciencedirect.com/science/article/pii/0091305789900828


Valerian root contains two substances of special pharmacological interest—valepotriates and sesquiterpenes. The former, which has been used for standardization of the drug, is cytotoxic. The latter has no such effect. Both have sedative effects. A double-blind test has been carried out on a preparation (VALERINA NATT) containing primarily sesquiterpenes. When compared with placebo it showed a good and significant effect on poor sleep (p<0.001). Forty-four percent reported perfect sleep and 89% reported improved sleep from the preparation. No side effects were observed.

Reference: Lindahl, Olov, and Lars Lindwall. “Double-blind study of a valerian preparation.” Pharmacology Biochemistry and Behavior 32.4 (1989): 1065-1066.doi:10.1016/0091-3057(89)90082-8

Characterization of the central nervous depressant activity of a commercially available valerian root extract.* http://europepmc.org/abstract/med/8352816


The evaluation of a commercially available valerian root extract (Valdispert) revealed pronounced sedative properties in the mouse with respect to a reduction in motility and an increase in the thiopental sleeping-time. A direct comparison with diazepam and chlorpromazine revealed a moderate sedative activity for the tested extract. The extract showed only weak anticonvulsive properties.

Reference: Leuschner, J., J. Müller, and M. Rudmann. “Characterisation of the central nervous depressant activity of a commercially available valerian root extract.” Arzneimittel-Forschung 43.6 (1993): 638-641.

Valerian extract and valerenic acid are partial agonists of the 5-HT5a receptor in vitro* http://www.sciencedirect.com/science/article/pii/S0169328X0500197X


Insomnia is the most frequently encountered sleep complaint worldwide. While many prescription drugs are used to treat insomnia, extracts of valerian (Valeriana officinalis L., Valerianaceae) are also used for the treatment of insomnia and restlessness. To determine novel mechanisms of action, radioligand binding studies were performed with valerian extracts (100% methanol, 50% methanol, dichloromethane [DCM], and petroleum ether [PE]) at the melatonin, glutamate, and GABAA receptors, and 8 serotonin receptor subtypes. Both DCM and PE extracts had strong binding affinity to the 5-HT5a receptor, but only weak binding affinity to the 5-HT2b and the serotonin transporter. Subsequent binding studies focused on the 5-HT5a receptor due to the distribution of this receptor in the suprachiasmatic nucleus of the brain, which is implicated in the sleep–wake cycle. The PE extract inhibited [3H]lysergic acid diethylamide (LSD) binding to the human 5-HT5a receptor (86% at 50 μg/ml) and the DCM extract inhibited LSD binding by 51%. Generation of an IC50 curve for the PE extract produced a biphasic curve, thus GTP shift experiments were also performed. In the absence of GTP, the competition curve was biphasic (two affinity sites) with an IC50 of 15.7 ng/ml for the high-affinity state and 27.7 μg/ml for the low-affinity state. The addition of GTP (100 μM) resulted in a right-hand shift of the binding curve with an IC50 of 11.4 μg/ml. Valerenic acid, the active constituent of both extracts, had an IC50 of 17.2 μM. These results indicate that valerian and valerenic acid are new partial agonists of the 5-HT5a receptor.

Dietz, Birgit M., et al. “Valerian extract and valerenic acid are partial agonists of the 5-HT 5a receptor in vitro.” Molecular Brain Research 138.2 (2005): 191-197.doi:10.1016/j.molbrainres.2005.04.009

A systematic review of valerian as a sleep aid: Safe but not effective* http://www.sciencedirect.com/science/article/pii/S1087079207000421


Valerian is an herb that is widely available in a variety of commercial preparations and is commonly used as a sleep aid. A recent systematic review and meta-analysis of valerian concluded that evidence in support of the effectiveness of the herb was inconclusive. Therefore, in an effort to more closely examine this issue, a systematic review was conducted to examine the evidence on the efficacy of valerian as a sleep aid with specific attention to the type of preparations tested and the characteristics of the subjects studied. A comprehensive search of studies investigating valerian was conducted through computerized databases and hand searches of reference lists. Standardized forms were used to summarize findings and standardized criteria were used to assess study quality. Out of 592 articles initially identified, a total of 36 articles describing 37 separate studies met criteria for review: 29 controlled trials evaluated for both efficacy and safety, and eight open-label trials evaluated for safety only. Most studies found no significant differences between valerian and placebo either in healthy individuals or in persons with general sleep disturbance or insomnia. None of the most recent studies, which were also the most methodologically rigorous, found significant effects of valerian on sleep. Overall, the evidence, while supporting that valerian is a safe herb associated with only rare adverse events, does not support the clinical efficacy of valerian as a sleep aid for insomnia.

Reference: Taibi, Diana M., et al. “A systematic review of valerian as a sleep aid: safe but not effective.” Sleep medicine reviews 11.3 (2007): 209-230.doi:10.1016/j.smrv.2007.03.002

Effect of valerian, Valeriana edulis, on sleep difficulties in children with intellectual deficits: randomized trial* http://www.sciencedirect.com/science/article/pii/S0944711304701142


Serious sleep problems are common in children with an intellectual deficit (ID) and are often the source of much distress for both the child and caregivers. As yet, no satisfactory long-term treatment exists for intransigent sleep difficulties in children with an ID. Valerian, Valeriana spp., has been used for thousands of years to induce relaxation and sleep. Scientific investigation of valerian’s sleep promoting ability in humans, whilst limited, has yielded promising findings. This initial study aimed to explore valerian’s potential for assisting in the treatment of sleep problems in children with an ID. Five children with varying intellectual deficits and different primary sleep problems underwent eight continuous weeks of monitoring via sleep diaries, adhering to a double-blind, placebo controlled and randomized design. Compared to baseline and placebo, valerian treatment led to significant reductions in sleep latencies and nocturnal time awake, lengthened total sleep time and improved sleep quality. The treatment was apparently most effective in children with deficits that involved hyperactivity. Although the findings are preliminary and in need of replication, there is evidence to suggest that valerian may be useful in the safe and effective long-term treatment of intransigent sleep difficulties in children with ID’s, and therefore warrants further investigation.

Reference: Francis, A. J. P., and R. J. W. Dempster. “Effect of valerian, Valeriana edulis, on sleep difficulties in children with intellectual deficits: randomised trial.” Phytomedicine 9.4 (2002): 273-279.doi:10.1078/0944-7113-00110

A double-blind, placebo-controlled investigation of the effects of two doses of a valerian preparation on the sleep, cognitive and psychomotor function of sleep-disturbed older adults* http://onlinelibrary.wiley.com/doi/10.1002/ptr.1574/abstract


One of the most popular herbal remedies for the alleviation of sleep problems is valerian. However, research into valerian is sparse, and studies differ greatly with respect to design, measures, and preparations used. This clinical study used standardized sleep EEG and psychometric tests to evaluate the clinical efficacy of a valerian preparation (Li 156).

A placebo-controlled three-way crossover clinical trial was completed using 16 (5 male and 11 female) sleep-disturbed participants (aged 50 to 64 years, mean age 55.9, SD 4.68). Participants slept overnight in a sleep laboratory, following a 21:00 hours dose of valerian 300 mg, valerian 600 mg, or placebo (double-blind). EEG sleep was recorded for each participant at 23:00 hours until 07:00 hours when a psychometric evaluation was performed the morning after a dose. Test periods were separated by six days washout period.

Results showed no significant effect between valerian 300 mg, valerian 600 mg or placebo on any EEG parameter or psychometric measure. This suggests valerian at these doses is ineffective as an acute dose for sleep problems. However, valerian is widely used and is traditionally sedative. Therefore, more research is required into therapeutic dose, types of valerian preparation, and the optimum period of use for therapeutic effect. Copyright © 2004 John Wiley & Sons, Ltd.

Reference: Diaper, A., and I. Hindmarch. “A double‐blind, placebo‐controlled investigation of the effects of two doses of a valerian preparation on the sleep, cognitive and psychomotor function of sleep‐disturbed older adults.” Phytotherapy Research 18.10 (2004): 831-836.DOI: 10.1002/ptr.1574

Efficacy and safety of herbal stimulants and sedatives in sleep disorders* http://www.sciencedirect.com/science/article/pii/S108707929990093X


Worldwide use of herbal medicines is increasing, following regulatory and manufacturing developments. Herbs are attractive alternative medications to many patients with sleep disorders, who may be averse to using conventional drugs. We review here the most common herbal stimulants and sedatives. Caffeine, in herbal teas, black tea, coffee, soft drinks, and pharmaceuticals, is used widely to control sleepiness, but more research is needed on its use in sleep disorders. Ephedra, and its constituent ephedrine are used in both stimulant and weight loss preparations, sometimes with caffeine; safety concerns have arisen with this practice. Yohimbe is another herb used in stimulant and body-building preparations which have safety concerns. Asian and Siberian ginseng has been traditionally used for fatigue, and have some supportive experimental evidence for this use. Herbal sedatives also have some evidence for efficacy; the observations that certain plant flavonoid compounds bind to benzodiazepine receptors adds interest to their use. Valerian and kava have received the most research attention; both have decreased sleep onset time and promoted deeper sleep in small studies, and kava also shows anxiolytic effects. German chamomile, lavender, hops, lemon balm, and passionflower are reputed to be mild sedatives but need much more experimental examination.

Reference: Gyllenhaal, Charlotte, et al. “Efficacy and safety of herbal stimulants and sedatives in sleep disorders.” Sleep Medicine Reviews 4.3 (2000): 229-251.doi:10.1053/smrv.1999.0093

A randomized, double-blind, placebo-controlled, prospective clinical study to demonstrate clinical efficacy of a fixed valerian hops extract combination (Ze 91019) in patients suffering from a non-organic sleep disorder* http://onlinelibrary.wiley.com/doi/10.1002/ptr.2167/abstract


Valerian and hops are traditionally used as sleep aids. Since the fixed extract combination (Ze 91019) as a whole is considered the active compound, the clinical efficacy must be demonstrated for this extract combination. The present clinical study aimed to demonstrate a superiority of the fixed extract combination in comparison with placebo in patients suffering from non-organic insomnia (ICD 10, F 51.0–51.2). Objective sleep parameters were registered by means of a transportable home recorder system (QUISI). The primary outcome was the reduction in sleep latency (SL2) which had to be prolonged at baseline (≥30 min) as inclusion criteria. The treatment period lasted for 4 weeks with either placebo, single valerian extract (Ze 911) or the fixed valerian hops extract combination (Ze 91019). The amount of the single valerian extract was identical to that amount contained in the fixed extract combination, i.e. 500 mg valerian extract siccum. In the extract combination 120 mg hops extract siccum was added. Both the extracts were prepared with 45% methanol m/m with a drug–extract ratio of 5.3:1 (valerian) and 6.6:1 (hops), respectively. The fixed extract combination was significantly superior to the placebo in reducing the sleep latency whilst the single valerian extract failed to be superior to the placebo. The result underlined the plausibility for adding hops extract to the valerian extract. Copyright © 2007 John Wiley & Sons, Ltd.

Reference: Koetter, U., et al. “A randomized, double blind, placebo-controlled, prospective clinical study to demonstrate clinical efficacy of a fixed valerian hops extract combination (Ze 91019) in patients suffering from non‐organic sleep disorder.” Phytotherapy research 21.9 (2007): 847-851.DOI: 10.1002/ptr.2167

Cardiac Complications and Delirium Associated With Valerian Root Withdrawal* http://jama.jamanetwork.com/article.aspx?articleid=1152388

Reference: Garges, Harmony P., Indu Varia, and P. Murali Doraiswamy. “Cardiac complications and delirium associated with valerian root withdrawal.” Jama 280.18 (1998): 1566-1567.

Tolerability and efficacy of valerian/lemon balm in healthy volunteers (a double-blind, placebo-controlled, multicentre study)* http://www.sciencedirect.com/science/article/pii/S0367326X99000180


This clinical study was conducted to evaluate the tolerability and efficacy of a new galenic formulation of a herbal sleeping aid, a valerian/lemon balm combination, to treat minor sleep disorders. The study was performed according to a randomized, placebo-controlled, double-blind, parallel group, multicentre design with healthy volunteers. Primary parameters were the assessment of the overall tolerability and the incidence of adverse events. Secondary parameters included laboratory tests, physical examination and assessments of well-being and sleep quality. The preparation proved to be well tolerated by most subjects (93% of the participants in the valerian/lemon balm group and 91% in the placebo group). There was no statistically significant difference concerning the frequency of adverse events between the two treatment groups (valerian/lemon balm 29%, placebo 28%) and no serious adverse events were reported. No significant changes were seen in regard to laboratory tests, physical examination and rating of well-being. In contrast, the valerian/lemon balm group revealed a significantly higher quality of sleep (33%) compared to the placebo group (9%), P-value=0.04. In conclusion, these results indicate that this valerian/lemon balm formulation is well tolerated.

Reference: Cerny, A., and K. Schmid. “Tolerability and efficacy of valerian/lemon balm in healthy volunteers (a double-blind, placebo-controlled, multicentre study).”Fitoterapia 70.3 (1999): 221-228. doi:10.1016/S0367-326X(99)00018-0

A combination of valerian and lemon balm is effective in the treatment of restlessness and dyssomnia in children* http://www.sciencedirect.com/science/article/pii/S0944711306000250


Efficacy and tolerability of a combined valerian/lemon balm preparation1 were investigated in an open, multicentre study in children less than 12 years suffering from restlessness and nervous dyskoimesis. Patients were dosed individually by the investigators. In total, 918 children were evaluated for therapeutic efficacy and tolerability. A distinct and convincing reduction in severity was found for all symptoms in the investigators’ and parents’ ratings. The core symptoms dyssomnia and restlessness were reduced from “moderate/severe” to “mild” or “absent” in most of the patients. In total, 80.9% of the patients who suffered from dyssomnia experienced an improvement for this symptom and 70.4% of the patients with restlessness improved clearly. For the other listed symptoms the total improvement was 37.8% on average. Both, parents and investigators assessed efficacy as to be “very good” or “good” (60.5% and 67.7%, respectively). The tolerability of Euvegal® forte was considered as “good” (in 96.7% of the patients it was judged to be “very good” or “good”). No study medication-related adverse events occurred.

In conclusion, Euvegal® forte was effective in the treatment of younger children with restlessness and dyssomnia and it was very well tolerated.

Reference: Müller, S. F., and S. Klement. “A combination of valerian and lemon balm is effective in the treatment of restlessness and dyssomnia in children.”Phytomedicine 13.6 (2006): 383-387. doi:10.1016/j.phymed.2006.01.013

Attenuation of Laboratory-Induced Stress in Humans After Acute Administration of Melissa officinalis (Lemon Balm)* http://journals.lww.com/psychosomaticmedicine/Abstract/2004/07000/Attenuation_of_Laboratory_Induced_Stress_in_Humans.22.aspx


Objective: Melissa officinalis (lemon balm) is contemporaneously used as a mild sedative and/or calming agent. Although recent research has demonstrated modulation of mood in keeping with these roles, no studies to date have directly investigated the effects of this herbal medication on laboratory-induced psychological stress.

Methods: In this double-blind, placebo-controlled, randomized, balanced crossover experiment, 18 healthy volunteers received two separate single doses of a standardized M. officinalis extract (300 mg, 600 mg) and a placebo, on separate days separated by a 7-day washout period. Modulation of mood was assessed during predose and 1-hour postdose completions of a 20-minute version of the Defined Intensity Stressor Simulation (DISS) battery. Cognitive performance on the four concurrent tasks of the battery was also assessed.

Results: The results showed that the 600-mg dose of Melissa ameliorated the negative mood effects of the DISS, with significantly increased self-ratings of calmness and reduced self-ratings of alertness. In addition, a significant increase in the speed of mathematical processing, with no reduction in accuracy, was observed after ingestion of the 300-mg dose.

Conclusion: These results suggest that the potential for M. officinalis to mitigate the effects of stress deserves further investigation.

Reference: Kennedy, David O., Wendy Little, and Andrew B. Scholey. “Attenuation of laboratory-induced stress in humans after acute administration of Melissa officinalis (Lemon Balm).” Psychosomatic medicine 66.4 (2004): 607-613.

Modulation of mood and cognitive performance following acute administration of Melissa officinalis (lemon balm)* http://www.sciencedirect.com/science/article/pii/S0091305702007773


Melissa officinalis (lemon balm) is a traditional herbal medicine, which enjoys contemporary usage as a mild sedative, spasmolytic and antibacterial agent. It has been suggested, in light of in vitro cholinergic binding properties, that Melissa extracts may effectively ameliorate the cognitive deficits associated with Alzheimer’s disease. To date, no study has investigated the effects on cognition and mood of administration of Melissa to healthy humans. The present randomised, placebo-controlled, double-blind, balanced-crossover study investigated the acute effects on cognition and mood of a standardised extract of M. officinalis. Twenty healthy, young participants received single doses of 300, 600 and 900 mg of M. officinalis (Pharmaton) or a matching placebo at 7-day intervals. Cognitive performance was assessed using the Cognitive Drug Research (CDR) computerised test battery and two serial subtraction tasks immediately prior to dosing and at 1, 2.5, 4 and 6 h thereafter. In vitro IC50 concentrations for the displacement of [3H]-(N)-nicotine and [3H]-(N)-scopolamine from nicotinic and muscarinic receptors in human occipital cortex tissue were also calculated. Results, utilising the cognitive factors previously derived from the CDR battery, included a sustained improvement in Accuracy of Attention following 600 mg of Melissa and time- and dose-specific reductions in both Secondary Memory and Working Memory factors. Self-rated “calmness,” as assessed by Bond–Lader mood scales, was elevated at the earliest time points by the lowest dose, whilst “alertness” was significantly reduced at all time points following the highest dose. Both nicotinic and muscarinic binding were found to be low in comparison to the levels found in previous studies.

Reference: Kennedy, D. O., et al. “Modulation of mood and cognitive performance following acute administration of Melissa officinalis (lemon balm).”Pharmacology Biochemistry and Behavior 72.4 (2002): 953-964. doi:10.1016/S0091-3057(02)00777-3

Modulation of Mood and Cognitive Performance Following Acute Administration of Single Doses of Melissa Officinalis (Lemon Balm) with Human CNS Nicotinic and Muscarinic Receptor-Binding Properties* http://www.wholehealthmedia.com/Melissa%20officinalis%20article.pdf

Reference: Kennedy, D. O., et al. “Modulation of mood and cognitive performance following acute administration of single doses of Melissa officinalis (Lemon balm) with human CNS nicotinic and muscarinic receptor-binding properties.”Neuropsychopharmacology 28.10 (2003): 1871-1881.

Valerian/lemon balm use for sleep disorders during menopause* http://www.sciencedirect.com/science/article/pii/S1744388113000601


The onset of Menopause in women is frequently associated with sleep disruption with hot flushes intensifying problems. Thus the use of supplementary drugs to ameliorate these symptoms is of significance.


The purpose of this research was to determine whether valerian/lemon balm could assist by enhancing sleep patterns in this client group.


100 women aged 50–60 years who complained of sleep disorders were studied. Subjects were selected randomly in a sampling method utilizing two groups of 50 people (intervention group with valerian/lemon balm and placebo group). The Pittsburgh Sleep Quality Index (PSQI) was administered pre and post-intervention.


A significant difference was observed with reduced levels of sleep disorders amongst the experimental group when compared to the placebo group.


Valerian/lemon balm may assist in reducing symptoms of sleep disorder during the menopause.

Reference: Taavoni, S., and H. Haghani. “Valerian/lemon balm use for sleep disorders during menopause.” Complementary therapies in clinical practice 19.4 (2013): 193-196. doi:10.1016/j.ctcp.2013.07.002


Gamma-vinyl GABA (vigabatrin): clinical experience in adult and adolescent patients with intractable epilepsy.


Clinical experience with gamma-vinyl GABA (GVG, vigabatrin) has accumulated mainly in Europe, where the drug has been licensed in several countries since 1989. Short-term efficacy studies in adolescent and adult patients with intractable drug-resistant epilepsy have shown that approximately 50% exhibit a reduction in seizure frequency of one-half or more but rarely complete seizure control. The best results are in patients with partial seizures with or without secondarily generalization. GVG responders have been followed for periods of up to 5 years, and overall 10-20% may exhibit subsequent seizure breakthrough, as probably occurs with any drug in such chronic patients. The most common side effect is drowsiness. Reversible behavior disorders, psychoses, and depression rarely occur in predisposed individuals. No new long-term side effects have been reported but vigilance is necessary. Studies of GVG as a first-line drug in newly diagnosed epileptic patients are proceeding.

Reynolds, E. H. “Gamma-vinyl GABA (vigabatrin): clinical experience in adult and adolescent patients with intractable epilepsy.” Epilepsia 33 (1992): S30-4.

GABA mechanisms and sleep


GABA is the main inhibitory neurotransmitter of the CNS. It is well established that activation of GABAA receptors favors sleep. Three generations of hypnotics are based on these GABAA receptor-mediated inhibitory processes. The first and second generation of hypnotics (barbiturates and benzodiazepines respectively) decrease waking, increase slow-wave sleep and enhance the intermediate stage situated between slow-wave sleep and paradoxical sleep, at the expense of this last sleep stage. The third generation of hypnotics (imidazopyridines and cyclopyrrolones) act similarly on waking and slow-wave sleep but the slight decrease of paradoxical sleep during the first hours does not result from an increase of the intermediate stage. It has been shown that GABAB receptor antagonists increase brain-activated behavioral states (waking and paradoxical sleep: dreaming stage). Recently, a specific GABAC receptor antagonist was synthesized and found by i.c.v. infusion to increase waking at the expense of slow-wave sleep and paradoxical sleep.

Since the sensitivity of GABAC receptors for GABA is higher than that of GABAA and GABAB receptors, GABAC receptor agonists and antagonists, when available for clinical practice, could open up a new era for therapy of troubles such as insomnia, epilepsy, and narcolepsy. They could possibly act at lower doses, with fewer side effects than currently used drugs. This paper reviews the influence of different kinds of molecules that affect sleep and waking by acting on GABA receptors.

Gottesmann, Claude. “GABA mechanisms and sleep.” Neuroscience 111.2 (2002): 231-239.

GABA release in the locus coeruleus as a function of sleep/wake state


GABA, glutamate, and glycine release in the locus coeruleus were measured as a function of sleep/wake state in the freely-behaving cat using the microdialysis technique. GABA release was found to increase during rapid-eye-movement sleep as compared to waking values. GABA release during slow-wave sleep was intermediate between that of waking states and rapid-eye-movement sleep. The concentration of glutamate and glycine in microdialysis samples was unchanged across sleep and wake states. Our findings are consistent with the hypothesis that GABAergic inhibition is responsible for the cessation of discharge in locus coeruleus neurons during REM sleep.

The data suggest that a population of GABAergic neurons innervating the locus coeruleus are selectively active during rapid-eye-movement sleep.

Nitz, D., and J. M. Siegel. “GABA release in the locus coeruleus as a function of sleep/wake state.” Neuroscience 78.3 (1997): 795-801.

Lemon Balm

Essential Oil Component in Flower of Lemon Balm (Melissa officinalis L.)* https://www.researchgate.net/profile/Omid_Karami/publication/26624870_Essential_Oil_Component_in_Flower_of_Lemon_Balm_(Melissa_officinalis_L.)/links/545ab9f50cf2c46f664387bf.pdf


This research focuses on the analysis of the chemical composition lemon balm essential oil.

The essential oil of flowers was obtained by steam distillation with a Clevenger apparatus. The

chemical components of the essential oil of lemon balm were analyzed by capillary GC and GC/MS

and 12 substances were identified. The flower oil contained trans-carveol (28.89%), Citronellol

(25.24%), -3-carene (5.26%), citronellal (4.9%), Geraniol (2.2%), 1-octene-3-ol (2.03%) and

spathulenol (2.06%). The trans-carveol in flowers was dominant among components.

Reference: Adinee, Jafer, Khosro Piri, and Omid Karami. “Essential oil component in flower of lemon balm (Melissa officinalis L.).” American Journal of Biochemistry and Biotechnology 4.3 (2008): 277-278.

Lemon Balm and Lavender herbal essential oils: Old and new ways to treat emotional disorders?* http://www.sciencedirect.com/science/article/pii/S0953711208000525


Nature is the best chemist. Novel therapeutics derived from natural sources is clearly a worthwhile strategy and has long historical pedigree. Anxiety, depression and psychotic disorders lack ideal medications based on a limited understanding of the underlying causes of these complaints. Many of the current therapeutics display lack of efficacy and/or multiple side effects. There is growing evidence that essential oils derived from plants have useful properties in relieving emotional disorders, particularly those seen in neurodegenerative diseases. This review focuses on two essential oils derived form Melissa and Lavender plants, both of which have useful anti-agitation properties in humans, the former having an additional beneficial property of maintaining attention in patients suffering from dementia.

Reference: Abuhamdah, Sawsan, and Paul L. Chazot. “Lemon Balm and Lavender herbal essential oils: Old and new ways to treat emotional disorders?.”Current Anaesthesia & Critical Care 19.4 (2008): 221-226. doi:10.1016/j.cacc.2008.05.005

Anxiolytic effects of a combination of Melissa Officinalis and Valeriana Officinalis during laboratory induced stress* http://onlinelibrary.wiley.com/doi/10.1002/ptr.1787/abstract


Melissa Officinalis (lemon balm) and Valeriana Officinalis (valerian) have been used both traditionally and contemporaneously as mild sedatives, anxiolytics, and hypnotics. Recent research has suggested that both may attenuate laboratory induced stress. As the two herbs are most often sold in combination with each other the current study assessed the anxiolytic properties of such a combination during laboratory-induced stress.

Reference: Kennedy, David O., et al. “Anxiolytic effects of a combination of Melissa ofcinalis and Valeriana Officinalis during laboratory induced stress.”Phytotherapy research 20.2 (2006): 96-102. DOI: 10.1002/ptr.1787

Enrichment of antioxidant compounds from lemon balm (Melissa officinalis) by pressurized liquid extraction and enzyme-assisted extraction* http://www.sciencedirect.com/science/article/pii/S0021967313003932


In this work, enzyme-assisted extraction (EAE) and pressurized liquid extraction (PLE) are applied for the extraction of natural compounds from lemon balm (Melissa officinalis). Cellulase, endo-β-1,4 xylanase and pectinase were studied in order to degrade cell wall of lemon balm leaves and to release phenolic compounds. On the other hand, in order to compare the performance obtained with EAE, PLE using water and ethanol was employed maintaining 150 °C as extraction temperature. The obtained extracts were characterized in terms of antioxidant capacity by using DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging and Trolox equivalent antioxidant capacity (TEAC) in vitro assays, whereas the Folin–Ciocalteu procedure was employed to estimate the total phenols content. On the other hand, extracts were chemically characterized by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The results showed that EAE enhanced the total phenolic content and the antioxidant capacity compared to a non-enzymatic control. PLE extracts presented a higher amount of phenols and antioxidant capacity than enzyme-assisted extracts, reaching the highest values on water extracts (193.18 mg gallic acid/g extract and EC50 = 6.81 μg/mL). Among the bioactive phenolic compounds identified in lemon balm, rosmarinic acid was the main component, although other important compounds were also identified, such as caffeic acid derivatives (salvianolic acids, lithospermic acid) and rosmarinic acid derivatives (rosmarinic acid hexoside, sagerinic acid, sulfated rosmarinic acid). The present study confirms that EAE and PLE can be considered alternative methods for the extraction of natural compounds with biological activity from natural sources.

Reference: Miron, T. L., Miguel Herrero, and Elena Ibáñez. “Enrichment of antioxidant compounds from lemon balm (Melissa officinalis) by pressurized liquid extraction and enzyme-assisted extraction.” Journal of Chromatography A1288 (2013): 1-9. doi:10.1016/j.chroma.2013.02.075

Alternative and Complementary Therapies* http://online.liebertpub.com/doi/abs/10.1089/act.2004.10.309


Anxiety is a common ailment in our society. However, the drugs available to treat mild-to-moderate anxiety, particularly benzodiazepines, are problematic because they can cause injury, produce side-effects, and create dependence. Nervine herbs have been widely used historically to treat mild to- moderate cases of anxiety, and these herbs appear to be very safe, nonaddictive but their properties as anxiolytics have been poorly researched.

This article discusses the clinical uses of a number of nervines: oat seed (Avena spp.), Hawthorn (Crataegus spp.), California poppy (Eschscholzia californica), lavender (Lavandula spp.), chamomile (Matricaria recutita), lemon balm (Melissa officinalis), passionflower (Passiflora spp.), skullcap (Scutellaria lateriflora), and verbena (also called vervain; Verbena spp.).

Reference: Abascal, Kathy, and Eric Yarnell. “Nervine herbs for treating anxiety.”Alternative & Complementary Therapies 10.6 (2004): 309-315. doi:10.1089/act.2004.10.309.

Chamomile flower

Blood lactate levels in 31 female dogs with pyometra.* http://www.cabdirect.org/abstracts/20093019973.html;jsessionid=A6FAE7807651D2207DFA09547DB7C198


Canine pyometra is a life-threatening disease common in countries where spaying of dogs is not routinely performed. The disease is associated with endotoxemia, sepsis, systemic inflammatory response syndrome (SIRS) and a 3-4% mortality rate. Blood lactate analysis is clinically valuable in predicting prognosis and survival, evaluating tissue perfusion and treatment response in human and veterinary critical care settings. The aims of the present study were to investigate (1) the blood lactate levels of female dogs with pyometra by a hand-held analyzer and (2) if these levels are related with the clinical status or other biochemical or hematological disorders. Methods: In total 31 female dogs with pyometra admitted for surgical ovariohysterectomy and 16 healthy female control dogs were included in the present study. A complete physical examination including SIRS-status determination was performed. Blood samples for lactate concentrations, hematological and biochemical parameters, acid-base and blood gas analysis and other laboratory parameters were collected and subsequently analyzed. The diagnosis pyometra was verified with histopathological examination of the uterus and ovaries. Increased hospitalization length and presence of SIRS were used as indicators of outcome. Results: In the pyometra group the median blood lactate level was 1,6 mmol l-1 (range <0.8-2.7 mmol l-1). In the control group the median lactate level was 1,2 mmol l-1 (range <0.8-2.1 mmol l-1). Of the 31 bitches, 19 (61%) fulfilled 2 or more criteria for SIRS at inclusion, 10 bitches (32%) fulfilled 3 of the SIRS criteria whereas none accomplished more than 3 criteria. Lactate levels did not differ significantly between the pyometra and control group, or between the SIRS-positive and SIRS negative dogs with pyometra. Increased lactate concentration (>2.5 mmol l-1) was demonstrated in one female dog with pyometra (3%) and was not associated with longer hospitalization or presence of SIRS. Lactate measurement was not indicative of peritonitis. None of the bitches died during or within two months of the hospital stay. The measurements of temperature, heart rate, respiratory rate, percentage landforms of neutrophilic granulocytes, α2-globulins, creatinine, pvCO2, TCO2, and base excess showed significant differences between the SIRS-positive and the SIRS negative pyometra cases. Conclusion: Increased blood lactate concentrations were demonstrated in 3% (1/31), and SIRS was present in 61% (19/31) of the female dogs with pyometra. Preoperative lactate levels were not related to the presence of SIRS or prolonged hospitalization. Lactate measurement was not indicative of peritonitis. The value of a single and repeated lactate analysis in more severely affected cases remains to be determined.

Reference: Blumenthal, Mark, Alicia Goldberg, and Josef Brinckmann. Herbal Medicine. Expanded Commission E monographs. Integrative Medicine Communications, 2000.

Supercritical fluid extraction of chamomile flower heads: Comparison with conventional extraction, kinetics, and scale-up* http://www.sciencedirect.com/science/article/pii/S0896844607000496


Supercritical fluid extraction of chamomile flower heads was performed on semi-continuous extraction apparatus in the lab scale using carbon dioxide as a solvent. The results of high-pressure experiments were compared with those obtained with Soxhlet extraction, steam distillation, and maceration. The obtained extracts were analyzed by HPLC on α-bisabolol, matricide and chamazulene content and by a gravimetrical method on essential oil and wax content. The highest content of active components in extracts and highest extraction yield were obtained using SFE at 250 bar and 40 °C. At this extraction conditions, the two-step separation was used to optimize the separation of essential oil from unwanted components. Dynamic behavior of the SFE with single step separation runs was analyzed using two mathematical models for describing the constant rate period and subsequent falling rate period. Based on the experimental data, external mass transfer coefficient, diffusion coefficient and diffusivity in solid phase were estimated. Results showed the acceptable agreement of calculated and experimental data.

Based on the parameters determined in the lab scale the extraction process was successfully transferred to the pilot scale.

Reference: Kotnik, Petra, Mojca Škerget, and Željko Knez. “Supercritical fluid extraction of chamomile flower heads: Comparison with conventional extraction, kinetics, and scale-up.” The Journal of Supercritical Fluids 43.2 (2007): 192-198. doi:10.1016/j.supflu.2007.02.005

Headspace–solid-phase microextraction fast GC in combination with principal component analysis as a tool to classify different chemotypes of chamomile flower-heads (Matricaria recutita L.)* http://onlinelibrary.wiley.com/doi/10.1002/pca.919/abstract


Headspace–solid-phase microextraction gas chromatography-principal component analysis (HS-SPME GC-PCA) is proposed as a complementary or alternative method to essential oil (EO) GC-PCA in order to discriminate between flower-heads of chamomile of different chemotypes. Ninety-two EOs and the headspaces sampled by HS-SPME of the corresponding chamomile flower-heads were examined by conventional GC and fast GC (F-GC) and the results submitted to statistical analysis by PCA. HS-SPME F-GC-PCA showed itself to be a rapid technique by which to distinguish chamomile flower-head chemotypes a produced results in agreement with the accepted EO classification. Using this method, the analysis time was reduced from at least 4.5 h with EO conventional GC to less than 1 h with HS-SPME F-GC. This approach can thus successfully be used as an analytical decision maker in order to reduce the number of time-consuming EO conventional GC analyses by limiting them to those samples that cannot unequivocally be classified. The EO conventional GC and HS-SPME F-GC results of PCA were very uniform, but they did not provide quantitative correlations between the components as determined by the two methods. A different statistical approach and a larger number of samples will be needed in order to correlate components in the headspace sampled by SPME and those in the corresponding EO quantitatively through a function. Copyright © 2006 John Wiley & Sons, Ltd.

Reference: Rubiolo, Patrizia, et al. “Headspace–solid‐phase microextraction fast GC in combination with principal component analysis as a tool to classify different chemotypes of chamomile flower‐heads (Matricaria recutita L.).” Phytochemical analysis 17.4 (2006): 217-225. DOI: 10.1002/pca.919

Production of Chamomile, Chamomilla Recutita (L.) Rauschert, in Slovakia* http://www.tandfonline.com/doi/abs/10.1300/J044v01n01_05


Selections of chamomile, Chamomilla Recutita (L.) Rauschert, have resulted in the development of types with higher oil concentrations and considerable differences in essential oil constituents. Tests on mechanical chamomile harvesters indicated a vacuum system worked best for transport of flower heads preventing damage to the tissue.

Reference: Salamon, Ivan. “Production of chamomile, Chamomilla Recutita (L.) Rauschert, in Slovakia.” Journal of Herbs, Spices & Medicinal Plants 1.1-2 (1992): 37-45. DOI:10.1300/J044v01n01_05

Induction of somatic embryogenesis and in vitro flowering from inflorescences of chamomile (Chamomilla Recutita L.)* http://link.springer.com/article/10.1007/s002990050643


A protocol has been developed for the induction of somatic embryogenesis from flower explants of chamomile (Chamomilla Recutita L.). The effects of several plant growth regulators [α-naphthylacetic acid (NAA), 2,4-dichlorophenoxyacetic acid, 6-benzyl adenine (BA) and kinetin (Kin), alone or in combination] and the flower type (disk or ray flower) were investigated. Both types of flowers responded to the callus and shoot induction treatments, but formation of globular somatic embryos took place only on disk-flower-derived explants after 2–4 weeks of culture on a Murashige and Skoog (MS) medium supplemented either with 8.87 μm BA and 1.07 μm NAA or with 26.8 μm NAA and 11.5 μm Kin. However, fully developed, cotyledonary-stage somatic embryos could be induced only on the NAA/Kin medium, 10 weeks after culture initiation. Germination of the embryos and plant regeneration took place after subculture for 4–5 weeks onto a medium of the same composition. Plantlets regenerated from embryos flowered in vitro on an MS medium supplemented with 8.87 μm BA and 1.07 μm NAA. The significance of the results with respect to chamomile micropropagation and the utilization of wild populations in breeding programs is discussed.

Reference: Kintzios, S., and A. Michaelakis. “Induction of somatic embryogenesis and in vitro flowering from inflorescences of chamomile (Chamomilla Recutita L.).” Plant cell reports 18.7-8 (1999): 684-690. DOI 10.1007/s002990050643

Patterns and perceptions of complementary/alternative medicine among pediatricians and patients’ mothers: a review of the literature* http://link.springer.com/article/10.1007/s00431-003-1313-9


For many families and their children, the use of complementary/alternative medicine (CAM) is an accepted adjunct or alternative to conventional therapy, even if data available in the literature regarding risks and adverse drug reactions (ADRs) pertaining to childhood populations are scarce. Moreover, despite widespread and increasing use of CAM, there are limited data on how pediatricians communicate with mothers and/or patients about CAM. Therefore, we report the studies available in the literature in the pediatric field and summarise what is known about ADRs and risks of CAM, taking into account in particular problems related to interactions between phytotherapy and conventional medicines and to counseling. Conclusion: from the analysis of the literature, some interesting aspects emerge: (1) the extent of CAM use in the pediatric field is increasingly sought by parents of children with chronic illnesses; (2) most parents who choose CAM medicine for their children believe that these therapies are “natural” and thus “safe” and (3) physicians often feel to know too little about CAM and wish to learn more for different reasons including “to dissuade whether the alternative method is unsafe and/or ineffective”. Therefore, pediatricians should be prepared to discuss alternative therapies with parents, since talking about CAM may help to minimize the risks and to restrain parental misconceptions and doubts. Educational interventions for parents should also be performed to bring about a more aware use of traditional and alternative medicines.

Reference: Cuzzolin, Laura, et al. “Patterns and perceptions of complementary/alternative medicine among pediatricians and patients’ mothers: a review of the literature.” European journal of Pediatrics 162.12 (2003): 820-827. DOI 10.1007/s00431-003-1313-9

Effects of row spacing and plant density on quantitative aspects of chamomile flower (Matricaria Chamomilla)* http://www.cabdirect.org/abstracts/20013064910.html


A field experiment was conducted at Zanjan, Iran, in 1998, to study the effects of plant density on the growth and dry weight yield of chamomile flowers (M. chamomilla [Chamomilla recutita]). Rows were spaced at 30, 40 and 50 cm, and plant spacings within the row were at 10, 15 and 20 cm. Decreasing row spacing and increasing plant spacing within the row resulted in an increase in flower dry weight yield. A row spacing of 30 cm and a within row spacing of 10 cm, with a plant density of 333 000 plants/ha, resulted in the highest flower dry weight.

Reference: Jamshidi, K. H. “Effects of row spacing and plant density on quantitative aspects of chamomile flower (Matricaria Chamomilla).” Iranian Journal of Agricultural Sciences 31.1 (2000): 203-210.

Screening of mycotoxin multi contamination in medicinal and aromatic herbs sampled in Spain* http://onlinelibrary.wiley.com/doi/10.1002/jsfa.3647/abstract?userIsAuthenticated=false&deniedAccessCustomisedMessage=


BACKGROUND: The aim of this study was to screen the multi contamination by mycotoxins in a wide variety of aromatic and/or medicinal herb samples collected in Spain. Mycotoxins studied were aflatoxins (AFs), ochratoxin A (OTA), zearalenone (ZEA), deoxynivalenol (DON), T-2 toxin (T-2), citrinin and fumonisins (FBs). Mycotoxins were analyzed by ELISA after a clean-up step with multifunctional columns (AFs, ZEA, DON, FBs, and T-2) or polyamide column (citrinin).

RESULTS: Of the 84 samples analyzed 99% were contaminated with T-2, 98% with ZEA, 96% with AFs, 63% with OTA, 62% with DON, 61% with citrinin and 13% with FBs. Nearly 87% of samples contained four or more mycotoxins simultaneously, being AFs, T-2 and ZEA the mycotoxins co-existing in almost every sample. 100% of the samples in our study were multi contaminated.

CONCLUSION: This study shows that this kind of commodity could be an important source of mycotoxin contamination and, in general, this contamination is not limited to only one group of mycotoxins. Mycotoxin contamination on artichoke immature florets, boldus leaves, burdock leaves, dandelion plant, frangula bark, ginkgo leaves, lemon verbena leaves, olive leaves, red tea leaves, ribgrass leaves, St Mary’s thistle seeds, spearmint leaves, star anise fruit, vervain and white tea leaves has been described for the first time. Finally, this is the first report on DON and T-2 presence in herbs. No study of this kind has been previously developed in Spain. Copyright © 2009 Society of Chemical Industry

Reference: Santos, Liliana, et al. “Screening of mycotoxin multi contamination in medicinal and aromatic herbs sampled in Spain.” Journal of the Science of Food and Agriculture 89.10 (2009): 1802-1807. DOI: 10.1002/jsfa.3647

Growing Conditions and the Essential Oil of Chamomile, Chamomilla Recutita (L.) Rauschert* http://www.tandfonline.com/doi/abs/10.1300/j044v02n02_05


The quantitative and qualitative characteristics of chamomile essential oil were determined for monocultures of a diploid variety under various soil and climatic cultivation conditions of East Slovakia. Both the quantity and the constituents of the essential oil were modified by the growing conditions, but no overall effect on the qualitative composition of the essential oil was noted.

Reference: Salamon, Ivan. “Growing conditions and the essential oil of chamomile, Chamomilla Recutita (L.) Rauschert.” Journal of Herbs, Spices & Medicinal Plants 2.2 (1994): 31-37. DOI:10.1300/J044v02n02_05

Effect of Chemical and Organic Fertilizers on Yield and Essential Oil of Chamomile Flower Heads* https://www.researchgate.net/profile/Saber_Hendawy2/publication/269874380_Medicinal_and_Aromatic_Plant_Science_and_Biotechnology_2011_Global_Science_Books_Effect_of_Chemical_and_Organic_Fertilizers_on_Yield_and_Essential_Oil_of_Chamomile_Flower_Heads/links/54987e120cf2c5a7e342c1f4.pdf


Two experiments were carried out under sandy soil conditions at the experimental station of Sekem Company, Sharkiya region, Egypt during two successive seasons of 2008/2009 and 2009/2010 to study the productivity of chamomile (Matricaria chamomilla L.) flower heads as influenced by different chemical fertilizers, compost rates, and liquid compost. All compost + liquid compost treatments overcame the chemical fertilizers or compost treatments and improved the flower heads growth characters [i.e. fresh or dry weights of flower heads (g plant-1) and flower head diameter (cm)] and essential oil contents [% and g plant-1]. For various essential oil constituents increased, decreased, or did not change in M. chamomilla L. flower heads under chemical and organic fertilizers as compared with unfertilized control plants.

Reference: Hendawy, Saber F., and Khalid A. Khalid. “Effect of chemical and organic fertilizers on yield and essential oil of chamomile flower heads.” Medicinal and Aromatic Plant Science and Biotechnology 5.1 (2011): 43-48.

A plant extract and its modified preparation in functional dyspepsia. Results of a double-blind placebo controlled comparative study* http://europepmc.org/abstract/med/11505331


AIMS: To assess the efficacy and safety of the commercially available herbal preparation (Iberogast, STW-5*) containing extracts from bitter candytuft, chamomile flower, peppermint leaves, caraway fruit, licorice root, lemon balm leaves, angelica root, celandine herbs, milk thistle fruit and its research preparation STW-5-S (without bitter candytuft) in patients with functional dyspepsia. PATIENTS AND METHODS: After a standardized diagnostic workup and at least 7 days free of medication, 60 patients, diagnosed with functional dyspepsia, were recruited in a multicenter trial and randomly assigned to one of 3 treatment groups (STW-5, STW-5-S or placebo). Each patient received the treatment for 4 weeks. The main outcome variables were the improvement of a gastrointestinal symptom score (GIS), a sum score consisted of 10 dyspeptic symptoms rated on a Likert scale. Dyspeptic symptoms were assessed at baseline, 2 and 4 weeks after treatment. RESULTS: 60 patients completed the trial (mean age 46.8 years, range 25-70, female 38 patients). Compared with placebo-group both herbal preparations STW-5 and STW-5-S showed a clinically significant improvement of GIS after 2 and 4 weeks of treatment (p < 0.001). No statistically significant difference could be observed between the efficacy of STW-5 and STW-5 S (p > 0.05), but a solid improvement of gastrointestinal symptoms could be achieved earlier with STW-5 than with its research preparation STW-5-S without bitter candytuft (p = 0.023).

Reference: Madisch, A., et al. “[A plant extract and its modified preparation in functional dyspepsia. Results of a double-blind placebo controlled comparative study].” Zeitschrift fur Gastroenterologie 39.7 (2001): 511-517. DOI: 10.1055/s-2001-16142

Investment rating with a combine harvester acquisition for chamomile flower picking* http://www.actahort.org/books/749/749_33.htm


Our entry concentrates to investment rating with a combine harvester acquisition for chamomile flower picking. We rate investment for combine harvester acquisition through breakpoint. On the basis of the breakpoint, we calculated what area is worth cultivating for a business with its own combine harvester use for chamomile flower harvest. We considered two alternatives at our calculations. An alternative was at breakpoint level and the business used to reach zero economic results with it. The breakpoint was at level 36.9 hectares. B alternative was monitored with 50 hectares area, which would represent 25 hectares of chamomile seeded area at two gatherings. The business would reach 2,095 € profit with B alternative – 50 hectares of gathering area. The calculations started from basic data acquired primarily from School Property at Secondary Agricultural School in Michalovce. Individual cost items were taken from it. The calculated data point to a possibility of effective investment into a combine harvester for chamomile flowers gathering, which would be used for business purposes, eventually for providing services for other businesses. This investment would be effective and it would bring profit to the business.

Reference: Stričík, Michal, and I. Salamon. “Investment rating with a combine harvester acquisition for chamomile flower picking.” I International Symposium on Chamomile Research, Development and Production 749. 2006. DOI:10.17660/ActaHortic.2007.749.33

Binding of STW 5 (Iberogast®) and its components to intestinal 5-HT, muscarinic M3, and opioid receptors* http://www.sciencedirect.com/science/article/pii/S0944711306000717


Clinical studies with the fixed herbal combination product STW 5 (Iberogast®) have indicated an efficacy comparable to metoclopramide (5-HT3 antagonist) and cisapride (5-HT4 agonist) in functional gastrointestinal diseases like functional dyspepsia (FD) and irritable bowel syndrome (IBS). Since serotonin (5-HT3 and 5-HT4) and muscarinic M3 receptors are known to play a central role in the etiology of FD and IBS, the extracts contained in STW 5 and several of their phytochemical components were studied in vitro for binding affinities to these receptors of the intestine. STW 5 inhibited the binding of 3H-GR113808 and 3H-4-DAMP to 5-HT4 and M3 receptors, respectively, about 10 times more potently than the binding of 3H-GR65630 to 5-HT3 receptors. IC50 values for STW 5 did correspond to extract dilutions of 1:1000 (M3 binding) and 1:2000 (5-HT4 binding). In addition, STW 5 also potently inhibited the binding to opioid receptors with an IC50 value of 1:2000. Of the nine herbal extracts contained in STW 5, the fresh plant extract of bitter candytuft (Iberis amara) selectively inhibited binding to M3 receptors, while ethanolic extracts of celandine herb and chamomile flower were selective to 5-HT4, and licorice root to 5-HT3 receptors. Binding affinities to human recombinant 5-HT3, 5-HT4 and M3 receptors were qualitatively similar to those of the corresponding intestinal receptors. The benzylisoquinoline alkaloid berberine had significant inhibitory action on 5-HT4 and M3 binding, showing IC50 values of 40 ng/ml (100 nM) and 200 ng/ml (500 nM), respectively, but is present in the extract of celandine herb only in traces, so that also for the celandine extract a cooperative effect of several phytochemical constituents can be assumed. These in vitro data indicate that 5-HT4 (to a lesser degree 5-HT3), muscarinic M3, and opioid receptors represent target sites for the treatment of FD and IBS with STW 5 (Iberogast®).

Reference: Simmen, U., et al. “Binding of STW 5 (Iberogast®) and its components to intestinal 5-HT, muscarinic M 3, and opioid receptors.” Phytomedicine 13 (2006): 51-55. doi:10.1016/j.phymed.2006.03.012

Reliability of fibers in solid-phase microextraction for routine analysis of the headspace of aromatic and medicinal plants* http://www.sciencedirect.com/science/article/pii/S0021967307002622?np=y


This article evaluates the HS-SPME recovery repeatability, intermediate precision and their performance over time when applied to HS-SPME sampling for quality control of medicinal and aromatic plants. Experiments were carried out on two sets of fibres coated with two different coatings and belonging to different lots (i.e 100 μm polydimethylsiloxane (PDMS) and Carboxen/divinylbenzene/PDMS 50/30 μm, l: 1 cm (CAR/DVB/PDMS)) and on chamomile (Matricaria chamomilla L.), sage (Salvia lavandulifolia Vahl.) and a standard solution containing 3-hexanol, isoamyl acetate, 1,8-cineole and menthol in diisobutyl phthalate. The performance of each set of fibres was evaluated by determining a group of complementary statistical parameters including: (i) repeatability of the absolute areas of each marker from each matrix with each fibre; (ii) intra-fibre repeatability of the total absolute areas of the markers of each matrix obtained with each fibre of each set; (iii) inter-fibre intermediate precision of the total absolute areas of the markers of each matrix obtained with all fibres of each set; and (iv) analysis of variance by one-way ANOVA with Fisher and Tukey tests. The influence of the number of analyses on fiber effectiveness (fiber lifetime) was studied by linear regression analysis (LRA). The results proved that HS-SPME can successfully be used for routine control analysis of aromatic and medicinal plants since both types of fibers showed good repeatability and intermediate precision of analytes recovery and consistency over time. Unlike data previously reported by other authors, CAR/DVB/PDMS coated fibers gave better results than those coated with PDMS. The fiber-life seemed mainly to be influenced by the number and conditions of samplings and nature of the matrix investigated.

Reference: Bicchi, Carlo, et al. “Reliability of fibers in solid-phase microextraction for routine analysis of the headspace of aromatic and medicinal plants.” Journal of Chromatography A 1152.1 (2007): 138-149. doi:10.1016/j.chroma.2007.02.011

Region-specific effects of STW 5 (Iberogast®) and its components in gastric fundus, corpus, and antrum* http://www.sciencedirect.com/science/article/pii/S0944711306000754


Functional dyspepsia (FD) is a disorder that involves impaired gastric accommodation, antral hypomotility, and upper abdominal pain. The herbal drug STW 5 (Iberogast®) is used to successfully treat FD patients. Here, we report in vitro data revealing the mode of action of STW 5 and its individual herbal extracts on gastric motility. STW 5 evoked a relaxation of the proximal stomach but increased antral motility. Both effects are myogenic. The extracts of Angelica root, chamomile flower, and licorice root mimicked the inhibitory effects in the proximal stomach whereas the extracts of greater celandine herb, Melissa leaf, caraway fruit, and bitter candytuft increased motility of the proximal stomach. All extracts increased motility in the antrum comparable to the effects of STW 5. We conclude that the differential effects of STW 5 on proximal and distal stomach motor activity are not caused by solely spasmolytic or anti-spasmolytic effects of the individual components. It is suggested that the individual extracts target transduction mechanisms that are specifically expressed in the proximal vs. distal stomach. We present a rationale for the differential effect of STW 5 which is a result of the combined actions of its individual components and reason that the inhibitory effects in the proximal and the excitatory effects in the distal stomach may contribute to symptom relief in FD patients treated with STW 5 (Iberogast®).

Reference: Schemann, M., et al. “Region-specific effects of STW 5 (Iberogast®) and its components in gastric fundus, corpus, and antrum.” Phytomedicine 13 (2006): 90-99. doi:10.1016/j.phymed.2006.03.020

Passionflower 4:1 extract

The role of nectar production, flower pigments, and odor in the pollination of four species of Passiflora (Passifloraceae) in south-eastern Brazil* http://onlinelibrary.wiley.com/doi/10.1111/j.1095-8339.2001.tb00563.x/abstract


The pollination biology of four species of passionflower was studied in south-eastern Brazil, specifically the importance of chemical features of floral nectar, pigments, and odors. All species required pollinators to produce fruits: P. alata was pollinated by bees, P. speciosa by hummingbirds, and P. galbana and P. mucronata by bats. Pollinators consumed nectar as a food source. The activity of vertebrate pollinators reflected resource availability: they foraged when large amounts of nectar were available and when quantitative resource predictability was greater. The nectar of the vertebrate-pollinated species was richer in cholesterol and phospholipids and had a potassium-sodium ratio higher than 1.0. For all species, the light absorption of flowers was paralleled by the pollinators’ visual spectral sensitivity. This first report on Passiflora floral volatile compounds showed that there was a greater chemical class diversity among the species pollinated by animals with an acute olfactory sense, such as bees and bats. Benzenoid alcohols were the most represented compounds. The fragrances contained compounds that occur in other plant species and in the exocrine secretions of bees. This study shows a strong association between pollinators and the attracting and rewarding features of flowers.

Reference: Varassin, Isabela Galarda, Jose Roberto Trigo, and Marlies Sazima. “The role of nectar production, flower pigments, and odor in the pollination of four species of Passiflora (Passifloraceae) in south‐eastern Brazil.” Botanical Journal of the Linnean Society 136.2 (2001): 139-152. DOI: 10.1111/j.1095-8339.2001.tb00563.x

Passifloricins, polyketides α-pyrones from Passiflora foetida resin* http://www.sciencedirect.com/science/article/pii/S0031942200004787


Three polyketides α-pyrones, named passiflorine, were isolated from Passiflora foetida resin; their structures and relative configurations were assigned through 2D NMR spectroscopic analyses. These types of compounds were not detected in other passion flowers.

Reference: Echeverri, Fernando, et al. “Passifloricins, polyketides α-pyrones from Passiflora foetida resin.” Phytochemistry 56.8 (2001): 881-885. doi:10.1016/S0031-9422(00)00478-7

Honeybees mark with scent and reject recently visited flowers* http://link.springer.com/article/10.1007/BF00319022


Experimental evidence is reported for flower-marking by honeybees (Apis mellifera ligustica) while they were foraging on an artificial patch of flowers yielding a continuous and equal flow of sucrose solution. Honeybees marked with scent and rejected all recently visited and nectar-depleted flowers. The short fade-out time of this scent allowed discrimination of flowers that temporarily provided no food. The repellent nature of this scent mark was demonstrated by the use of an air extractor connected to the patch; when the apparatus was turned on, the rejection behavior disappeared. The movement pattern of foraging bees also contributed to foraging efficiency, as the probability of an immediate return to the flower just abandoned was very low. However, when a quick repeat visit took place, the presence of the repellent scent-mark promoted rapid rejection.

Reference: Giurfa, Martin, and Josué A. Núñez. “Honeybees mark with scent and reject recently visited flowers.” Oecologia 89.1 (1992): 113-117. DOI 10.1007/BF00319022

Breast-enhancing, herbal compositions, and methods of using the same* https://www.google.com/patents/US6200594


Topical and oral compositions containing unique blends of certain herbs effectively enhance breasts in human females by strengthening connective tissues and encouraging the growth of new cells. The topical composition contains Saw Palmetto berry extract, Chaste Tree berry extract, Fenugreek seed extract, Fennel seed extract, Comfrey extract, White Willow Bark extract, Ma Huang extract, Black Cohosh extract, Guarana extract, Passion Flower extract, Bilberry extract, Horsetail extract, and Cayenne extract. The oral composition is a dietary supplement system containing two diet supplement compositions. The first composition contains extracts of Blessed Thistle, Hops, Wild Yam, Fenugreek seed, Saw Palmetto Berry, Chaste Tree berry, Fennel seed, Black Cohosh, Damiana, Dong Quai, Lycium Chinese Herb, Scullcap Concentrate, and Curcubita Pepo Pumpkin seed, as well as Methyl Sulfonyl Methane and Royal Jelly. The second composition contains extracts of Saw Palmetto Berry, Chaste Tree Berry, Black Cohosh, Fennel seed, Fenugreek seed, Lycium Chinese Herb, Scullcap Concentrate, and Curcubita Pepo Pumpkin seed, as well as Methyl Sulfonyl Methane and Royal Jelly. The topical composition, which is preferably in cream form, is topically applied to the breast area daily for a sufficient period of time. The oral system, preferably in the form of a plurality of capsules taken separately, is orally administered on a daily basis for a sufficient period, wherein capsules of the first composition are taken for the first period and capsules of the second composition are taken for a subsequent second period. Most preferably, the topical and oral compositions are administered concurrently in a treatment regimen. The latter regimen provides a synergistic breast enhancement relative to the individual topical and oral treatments.

Reference: Ernest, Joseph Michael, and Allen Smith. “Breast-enhancing, herbal compositions, and methods of using same.” U.S. Patent No. 6,200,594. 13 Mar. 2001.

Screening of Argentine plant extracts: Impact on growth parameters and aflatoxin B1 accumulation by Aspergillus section Flavi* http://www.sciencedirect.com/science/article/pii/S016816050700637X


The effect of essential oils, ethanolic and aqueous extract of 41 vegetable species on Aspergillus section Flavi growth was evaluated. The in vitro screen was a two-stage process. A wide-spectrum initial screen which identified promising antifungal plant extracts was carried out first. After that, identified extracts were studied in more detail by in vitro assays.

A total of 96 plant extracts were screened. Essential oils were found to be the most effective extract controlling aflatoxigenic strains. Clove, mountain thyme, poleo, and eucalyptus essential oils were selected to study their antifungal effect. Studies on the percentage of germination, germ-tube elongation rate, growth rate, and aflatoxin B1 accumulation were carried out. Clove, mountain thyme, and poleo essential oils showed the most antifungal effect under all growth parameters analyzed as well as aflatoxin B1 accumulation. Our results suggest that mountain thyme and poleo, which are native vegetal species of Argentina, and clove essential oils could be used alone or in conjunction with other substances to control the presence of aflatoxigenic fungi in stored maize.

Reference: Bluma, R., M. R. Amaiden, and M. Etcheverry. “Screening of Argentine plant extracts: impact on growth parameters and aflatoxin B 1 accumulation by Aspergillus section Flavi.” International journal of food microbiology 122.1 (2008): 114-125. doi:10.1016/j.ijfoodmicro.2007.11.050

Somatic hybridization of the Passiflora species, P. edulisf. flavicarpa Degener. and P. incarnata L.* http://jxb.oxfordjournals.org/content/46/7/777.short


Somatic hybrid plants have been produced following electrofusion of mesophyll protoplasts of P. edulis. f. flavicarpa and P. incarnata. These hybrids exhibited morphological characteristics intermediate between those of the two parental species. Further evidence of hybridity has been provided by isozyme analysis, ploidy determinations and molecular characterization (RAPD analysis). These somatic hybrid plants have been used in first generation backcrossing experiments with both P. edulis f. flavicarpa and P. incarnata; descriptions are provided of the floral and fruit characteristics, as well as seed production.

Reference: Otoni, W. C., et al. “Somatic hybridization of the Passiflora species, P. edulisf. flavicarpa Degener. and P. incarnata L.” Journal of experimental botany 46.7 (1995): 777-785. doi: 10.1093/jxb/46.7.777

Vacuum Headspace Method in Aroma Research: Flavor Chemistry of Yellow Passion Fruits* http://pubs.acs.org/doi/abs/10.1021/jf970655s


The volatile flavor components of yellow passion fruits have been isolated using four different isolation techniques. The most representative and typical extract was obtained by vacuum headspace sampling and subsequent liquid− extraction of the aqueous phase. This vacuum headspace concentrate was pre-fractionated by medium-pressure adsorption chromatography on silica gel. Approximately 180 components were identified in the LC fractions of yellow passion fruit flavor for the first time. Of these compounds, 14 components have not previously been reported as naturally occurring flavor ingredients. Moreover, 47 sulfur-containing volatiles were identified in yellow passion fruits after enrichment by preparative multidimensional capillary gas chromatography; 35 of these components are reported to be present in the tropical fruit flavor for the first time, and 23 of these sulfur-bearing compounds have not been previously reported as constituents of food flavors and are therefore new natural components. In addition, the enantiomeric distributions of several chiral flavor substances were determined by enantioselective multidimensional gas chromatography.

Reference: Werkhoff, P., et al. “Vacuum headspace method in aroma research: flavor chemistry of yellow passion fruits.” Journal of Agricultural and Food Chemistry 46.3 (1998): 1076-1093. DOI: 10.1021/jf970655s

A stable reddish-purple anthocyanin in the leaf ofGynura aurantiaca cv. ‘Purple Passion’* http://link.springer.com/article/10.1007/BF02344246


The anthocyanin (GAA) in the epidermis and hair of the leaf ofGynura aurantiaca cv. ‘Purple Passion’ was isolated and identified as cyanidin tetra-glucoside acylated by three molecules of caffeic acid and one molecule of malonic acid. GAA was also isolated from the lower epidermis of the leaf ofG. bicolor DC. GAA showed a very stable reddish purple color from weakly acid to neutral pH region, but the color of the deacylated compound disappeared rapidly in the same region. This indicated that the attached organic acids must play an essential role in the stabilization of the color.

Comparison of the profiles of the visible absorption spectra of the intact epidermal peels and cells ofG. aurantiaca andG. bicolor with those of GAA dissolved in various pH solutions suggested that the pH of the epidermal vacuole containing GAA was nearly 4.3.

GAA was indistinguishable from the anthocyanin (rubrocinerarin) which we had previously isolated from the purplish red flowers of Senecio cruentus DC. by means of UV-Vis, NMR and Mass spectra.

Reference: Yoshitama, Kunijiro, et al. “A stable reddish-purple anthocyanin in the leaf ofGynura aurantiaca cv.‘Purple Passion’.” Journal of plant research 107.3 (1994): 209-214. DOI


Salicylic Acid Levels in Thermogenic and Non-Thermogenic Plants* http://aob.oxfordjournals.org/content/66/4/369.short


The natural trigger for heat production in the thermogenic inflorescences of Sauromatum guttatum Schott (voodoo lily) was recently identified as salicylic acid (SA), which induced heat production at levels as low as 13 ng g f. wt−1. Since then the levels of SA were determined in other thermogenic and non-thermogenic plant species. In thermogenic inflorescences of five aroid species, and in male cones of at least four thermogenic cycads SA levels during heat production exceeded 1 μg g f. wt−1. SA was not detected in the thermogenic flowers of a water lily, Victoria Regia Lindl. (Nymphaeaceae), and Bactris major Jacq. (Palmae). Levels of salicylic acid varied substantially in the floral parts of seven non-thermogenic species and in the leaves of 27 non-thermogenic species.

Reference: RASKIN, ILYA, et al. “Salicylic acid levels in thermogenic and non-thermogenic plants.” Annals of Botany 66.4 (1990): 369-373.

Resource Partitioning* http://link.springer.com/chapter/10.1007/978-1-4899-3368-3_11


At some point during their lifetime, individuals of most insects are probably involved in a competition for an essential resource, be it for food, mating territories, egg-laying sites, or refugia. Should the density of competing individuals exceed the carrying capacity of a unit of resource, the result may be detrimental to fitness. Therefore, selection should favor avoidance of overcrowding. In some species, however, too low a density of individuals on a unit of a resource may have equally detrimental consequences to fitness. Here, selection should favor some degree of aggregation, short of overcrowding. Thus, we may consider the concept of an optical density range of individuals per unit of the resource as valid (Peters and Barbosa, 1977; Prokopy, 1981a

Reference: Prokopy, Ronald J., Bernard D. Roitberg, and Anne L. Averill. “Resource partitioning.” Chemical ecology of insects. Springer US, 1984. 301-330. DOI



Human microglia convert l-tryptophan into the neurotoxin quinolinic acid* http://www.biochemj.org/content/320/2/595.abstract


Immune activation leads to accumulations of the neurotoxin and kynurenine pathway metabolite quinolinic acid within the central nervous system of human patients. Whereas macrophages can convert l-tryptophan to quinolinic acid, it is not known whether human brain microglia can synthesize quinolinic acid. Human microglia, peripheral blood macrophages, and cultures of human fetal brain cells (astrocytes and neurons) were incubated with [13C6]l-tryptophan in the absence or presence of interferon γ. [13C6]Quinolinic acid was identified and quantified by gas chromatography and electron-capture negative-chemical ionization mass spectrometry. Both l-kynurenine and [13C6]quinolinic acid was produced by unstimulated cultures of microglia and macrophages. Interferon γ, an inducer of indoleamine 2,3-dioxygenase, increased the accumulation of l-kynurenine by all three cell types (to more than 40 µM). Whereas large quantities of [13C6]quinolinic acid were produced by microglia and macrophages (to 438 and 1410 nM respectively), minute quantities of [13C6]quinolinic acid were produced in human fetal brain cultures (not more than 2 nM). Activated microglia and macrophage infiltrate into the brain might be an important source of accelerated conversion of l-tryptophan into quinolinic acid within the central nervous system in inflammatory diseases.

Reference: HEYES, Melvyn P., et al. “Human microglia convert l-tryptophan into the neurotoxin quinolinic acid.” Biochemical Journal 320.2 (1996): 595-597. DOI: 10.1042/bj3200595

L-Tryptophan in Mania Contribution to a Permissive Hypothesis of Affective Disorders* http://archpsyc.jamanetwork.com/article.aspx?articleid=491056



Five manic patients were treated with chlorpromazine hydrochloride (CPZ), then with L-tryptophan (LTP), and five with LTP first, then CPZ, in a double-blind, placebo-controlled crossover study. LTP was slightly superior to CPZ in all regards. Mania and depression may be linked by a central indoleamine deficit.

Reference: Prange Jr, Arthur J., et al. “L-tryptophan in mania: contribution to a permissive hypothesis of affective disorders.” Archives of General Psychiatry 30.1 (1974): 56. doi:10.1001/archpsyc.1974.01760070040006

Determination of the tryptophan content of feedingstuffs with particular reference to cereals* http://onlinelibrary.wiley.com/doi/10.1002/jsfa.2740180901/abstract


Three procedures, commonly used for the determination of tryptophan, were found to be unsatisfactory for the assay of cereals. A method using p-dimethylaminobenzaldehyde was unsatisfactory because cereals dissolved slowly in the sulphuric acid reagent produced turbid solutions and gave high blank values. Racemisation of L-tryptophan was found to be incomplete on hydrolysis with barium hydroxide; therefore, microbiological assays are invalidated. Neutralization of the barium hydroxide with sulphuric acid or carbon dioxide resulted in considerable loss of tryptophan.

A method is described based on hydrolysis with barium hydroxide, precipitation of barium sulfate from an acid solution and colorimetric analysis using p-dimethylaminobenzaldehyde. The procedure has proved useful for the routine analysis of cereals and other feedingstuffs.

Reference: Miller, E. L. “Determination of the tryptophan content of feedingstuffs with particular reference to cereals.” Journal of the Science of Food and Agriculture 18.9 (1967): 381-386. DOI: 10.1002/jsfa.2740180901

Eosinophilia-Myalgia Syndrome Associated With Exposure to Tryptophan From a Single Manufacturer* http://jama.jamanetwork.com/article.aspx?articleid=382499


Although eosinophilia-myalgia syndrome has been linked to the use of tryptophan, it has been unclear whether tryptophan itself or a contaminant causes illness. In Oregon, we compared the brand and source of tryptophan used by 58 patients with eosinophilia-myalgia syndrome with the brand and source of tryptophan used by 30 asymptomatic controls identified through a random telephone survey and 63 asymptomatic controls who contacted the Oregon Health Division voluntarily. Although a single brand/retail lot of tryptophan was statistically associated with the development of eosinophilia-myalgia syndrome, there was no common importer, wholesaler, tablet maker, encapsulator, or distributor. However, 45 (98%) of 46 cases had taken a product made by one manufacturer, compared with three (30%) of 10 telephone survey controls and 15 (48%) of 31 volunteer controls. Retail lots of tryptophan from this manufacturer that were associated with cases were significantly more likely to have been produced from January through June 1989 than lots from this manufacturer that were taken by controls. These findings indicate that the recent epidemic of eosinophilia-myalgia syndrome was caused by a contaminant or an alteration in a subset of tryptophan manufactured by a single company in Japan shortly before the outbreak began.

Reference: Slutsker, Laurence, et al. “Eosinophilia-myalgia syndrome associated with exposure to tryptophan from a single manufacturer.” Jama 264.2 (1990): 213-217. doi:10.1001/jama.1990.03450020065028.

Slutsker, Laurence, et al. “Eosinophilia-myalgia syndrome associated with exposure to tryptophan from a single manufacturer.” Jama 264.2 (1990): 213-217. doi:10.1001/jama.1990.03450020065028.

Studies of Alpha-methyl-para-tyrosine, L-dopa, and L-tryptophan in Depression and Mania* http://ajp.psychiatryonline.org/doi/abs/10.1176/ajp.127.7.872?journalCode=ajphttp://ajp.psychiatryonline.org/doi/abs/10.1176/ajp.127.7.872?journalCode=ajp


L-dopa and L-tryptophan, metabolic precursors of norepinephrine and serotonin respectively, and αMPT, a blocker of catecholamine synthesis, were administered to depressed and manic patients in an attempt to decrease their psychopathology and to test the monoamine theory of affective disorders. L-dopa and αMPT clearly altered mood and thought patterns in some patients, while L-tryptophan was less active. Analysis of urinary and cerebrospinal fluid amine metabolites documented the metabolic effects of the compounds during periods of behavioral change.

Reference: BUNNEY JR, WILLIAM E., et al. “Studies of alpha-methyl-para-tyrosine, L-dopa, and L-tryptophan in depression and mania.” American Journal of Psychiatry 127.7 (1971): 872-881.

Human macrophages convert l-tryptophan into the neurotoxin quinolinic acid* http://www.biochemj.org/content/283/3/633.abstract


Substantial increases in the concentrations of the excitotoxin and N-methyl-D-aspartate-receptor agonist quinolinic acid (QUIN) occur in human patients and non-human primates with inflammatory diseases. Such increases were postulated to be secondary to induction of indoleamine 2,3-dioxygenase in inflammatory cells, particularly macrophages, by interferon-gamma. To test this hypothesis, human peripheral-blood macrophages were incubated with L-[13C6]tryptophan in the absence or presence of interferon-gamma. [13C6]QUIN was quantified by gas chromatography and electron-capture negative-chemical-ionization mass spectrometry. [13C6]QUIN was detected in the incubation medium of both unstimulated and stimulated cultures. Exposure to interferon-gamma substantially increased the accumulation of [13C6]QUIN in a dose- and time-dependent manner. The QUIN concentrations achieved exceeded those reported in both cerebrospinal fluid and blood of patients and of non-human primates with inflammatory diseases. Macrophages stimulated with interferon-gamma may be an important source of accelerated L-tryptophan conversion into QUIN in inflammatory diseases.

Reference: Heyes, Melvyn P., Kuniaki Saito, and Sanford P. Markey. “Human macrophages convert L-tryptophan into the neurotoxin quinolinic acid.” Biochemical Journal 283.3 (1992): 633-635. DOI: 10.1042/bj2830633

l-Tryptophan in affective disorders: Indoleamine changes and differential clinical effects* http://link.springer.com/article/10.1007/BF00421216


Large oral doses of l-tryptophan yielded negligible antidepressant effects in unipolar depressed patients, but partial antidepressant and antimanic effects in some patients with bipolar affective disorder. Marked changes in cerebrospinal fluid, platelet and urinary levels of serotonin and 5-hydroxyindoleacetic acid in these patients during l-tryptophan administration suggest that the low response rate of severely depressed patients is probably not attributable to impaired l-tryptophan metabolism during a depression.

Reference: Murphy, Dennis L., et al. “L-tryptophan in affective disorders: indoleamine changes and differential clinical effects.” Psychopharmacologia 34.1 (1974): 11-20. DOI 10.1007/BF00421216

Eosinophilia-Myalgia Syndrome in L-Tryptophan—Exposed Patients* http://jama.jamanetwork.com/article.aspx?articleid=394240


Objectives.  —To study the incidence of eosinophilia-myalgia syndrome, the risk factors associated with the syndrome, and the clinical spectrum of illness associated with L-tryptophan use in an exposed population.

Design.  —Retrospective cohort and nested case-control studies of risk factors for eosinophilia-myalgia syndrome using inpatient and outpatient chart reviews, telephone interviews, and in-person patient interviews. A descriptive study of the clinical course of L-tryptophan users.

Setting.  —Office practice of one psychiatrist based in a small city (population 43467) in South Carolina.

Patients.  —Eligible subjects were all patients from the practice who used L-tryptophan during the 1989 study interval. Of these, 418 (87%) were interviewed.

Main Outcome Measures.  —Clinical spectrum of illness associated with L-tryptophan use, including definite and possible cases of eosinophilia-myalgia syndrome.

Results.  —Among the 418 interviewed L-tryptophan users, we identified 47 definite cases (11%) and 68 possible cases (16%) of eosinophilia-myalgia syndrome, most of which involved patients who were using one retail brand of L-tryptophan (brand A). Among the 157 brand A users, we identified 45 definite cases (29%) and 36 possible cases (23%) of eosinophilia-myalgia syndrome, and the risk for the syndrome increased as the brand A dose increased. Fifty percent (19 of 38) of those using more than 4000 mg/day developed definite eosinophilia-myalgia syndrome, and 84% (32 of 38) developed either definite or possible eosinophilia-myalgia syndrome. On multivariate analysis, the risk for definite eosinophilia-myalgia syndrome was associated with brand A dose and age of the patient; however, gender, race, and use of other medications were not associated with the syndrome.

Conclusions.  —These results suggest that many people exposed to the agent causing eosinophilia-myalgia syndrome may develop an illness, and a dose of presumably contaminated L-tryptophan is the single most important predictor of eosinophilia-myalgia syndrome. The broad range of signs and symptoms reported by patients using L-tryptophan illustrates that a strict case definition may identify only about half of those affected. (JAMA. 1992;267:77-82)

Reference: Kamb, Mary L., et al. “Eosinophilia-myalgia syndrome in L-tryptophan—exposed patients.” Jama 267.1 (1992): 77-82. doi:10.1001/jama.1992.03480010085029.

Studies on the regulation of tryptophan biosynthesis in Escherichia coli* http://www.sciencedirect.com/science/article/pii/S0022283665800328


Two types of mutation within the anthranilate synthetase gene affect the capacity of Escherichia coli K12 to regulate the rate of tryptophan synthetase formation. The first category consists of certain anthranilate-responding auxotrophs in which a pleiotropic mutational lesion strongly interferes with the capacity of the cell to de-repress when grown on limiting supplement. The second category (MTR)‡ includes mutants which are able to grow at high concentrations of 5-methyltryptophan. These mutants de-repress normally, but cannot be repressed in the presence of usually effective levels of L-tryptophan. Mutations of the MTR type arise directly in wild type E. coli as well as concomitantly with a reversion of regulatory anthranilate auxotrophs to tryptophan independence. MTR mutations at the anthranilate locus display decreased sensitivity to feedback inhibition, suggesting that repression of tryptophan biosynthesis may be mechanistically connected to feedback inhibition. In heterogeneous, regulatory anthranilate alleles are recessive in trans position to wild type in terms of ability to grow in the absence of supplement. However, these mutant alleles appear to be cis-dominant. The MTR mutation is dominant over both the wild type and auxotrophic alleles; diploids bearing an MTR allele grow well at levels of 5-methyltryptophan sufficient to inhibit wild type cells, even when an essential function must be carried out by a gene in cis position to an MTs allele.

Reference: Somerville, R. L., and C. Yanofsky. “Studies on the regulation of tryptophan biosynthesis in Escherichia coli.” Journal of molecular biology 11.4 (1965): 747-759. doi:10.1016/S0022-2836(65)80032-8

BRIEF COMMUNICATION: Sleep Induced by L-Tryptophan: Effect of Dosages within the Normal Dietary Intake* http://journals.lww.com/jonmd/Abstract/1979/08000/BRIEF_COMMUNICATION__Sleep_Induced_by.8.aspx


Previous results have demonstrated the sleep-inducing effects of L-tryptophan in doses of 1 to 15 g at bedtime. The present laboratory study extends the dose-response curve downward, comparing doses of 1/4 g, 1/2 g, and 1 g of L-tryptophan with placebo, in 15 mild insomniacs (subjects who reported sleep latencies of over 30 minutes). One gram of L-tryptophan significantly reduced sleep latency: the lower doses produced a trend in the same direction. Stage IV sleep was significantly increased by 1/4 g of L-tryptophan. These results at low doses have interesting implications since the normal dietary intake of L-tryptophan is 1/2 g to 2 g per day.

Reference: HARTMANN, ERNEST, and CHERYL L. SPINWEBER. “BRIEF COMMUNICATION: Sleep Induced by L-Tryptophan: Effect of Dosages within the Normal Dietary Intake.” The Journal of nervous and mental disease 167.8 (1979): 497-499.

Neuroendocrine and Mood Responses to Intravenous L-Tryptophan in 3,4-Methylenedioxymethamphetamine (MDMA) Users* http://archpsyc.jamanetwork.com/article.aspx?articleid=494454

Preliminary Observations


3,4-Methylenedioxymethamphetamine (MDMA; “ecstasy”) is a selective serotonin (5-HT) neurotoxin in laboratory animals. To assess its effects on 5-HT function in humans, serum prolactin (PRL) and mood responses to intravenous L-tryptophan were measured in nine recreational users of MDMA and compared with findings from nine matched healthy controls. L-Tryptophan induced a rise in the PRL concentration in controls, but not in MDMA users. Peak change and the area under the curve of the PRL response appeared to be blunted in MDMA users, but the difference from controls did not reach statistical significance. This study provides suggestive evidence of altered 5-HT function in MDMA users, but more definitive studies clearly are needed.

Reference: Price, Lawrence H., et al. “Neuroendocrine and mood responses to intravenous L-tryptophan in 3, 4-Methylenedioxymethamphetamine (MDMA) users: preliminary observations.” Archives of General Psychiatry 46.1 (1989): 20. doi:10.1001/archpsyc.1989.01810010022003

Increased neopterin and interferon-gamma secretion and lower availability of L-tryptophan in major depression: Further evidence for an immune response* http://www.sciencedirect.com/science/article/pii/0165178194900035


There is now some evidence that major depression may be accompanied by an immune response. The latter condition is suggested by elevated secretion of neopterin and interferon-γ (IFNγ) and by lower L-tryptophan (L-TRP) plasma levels. This study investigated the plasma levels of neopterin, L-TRP, and the L-TRP/competing amino acids (CAA) ratio in 30 normal control subjects and 47 depressed subjects (16 minor depressed, 13 simple major depressed, and 18 melancholic subjects), and IFNγ secretion by mitogen-stimulated peripheral blood mononuclear cells in 7 normal control subjects and 13 major depressed subjects. Plasma neopterin levels were significantly higher in depressed subjects than in normal controls; 61% of melancholic patients had increased neopterin levels (⩾ 7 nmol/1) with a specificity of 90%. Patients with major depression had significantly lower L-TRP and L-TRP/CAA values compared with normal control subjects. The amino acid values were significantly and negatively correlated with plasma neopterin levels. Major depressed subjects exhibited significantly higher IFNγ secretion than did normal control subjects. The results further support the hypothesis that major depression is accompanied by an immune response and that the lower L-TRP availability in that illness may be an epiphenomenon of immune activation.

Reference: Maes, Michael, et al. “Increased neopterin and interferon-gamma secretion and lower availability of L-tryptophan in major depression: further evidence for an immune response.” Psychiatry Research 54.2 (1994): 143-160. doi:10.1016/0165-1781(94)90003-5

The Comparative Antidepressant Value of L-Tryptophan and Imipramine With and Without Attempted Potentiation by Liothyronine* http://archpsyc.jamanetwork.com/article.aspx?articleid=490611



In a trial lasting four weeks, patients responded equally well to imipramine (150 mg daily) or to L-tryptophan (9 gm daily). Patients who received a small dose of L-triiodothyronine (T3, liothyronine sodium (25μg daily for the first two weeks of treatment) in addition to imipramine showed a significantly better therapeutic response than patients who received either imipramine or tryptophan alone. Liothyronine did not enhance the therapeutic response to L-tryptophan. None of the treatments tested seemed to benefit any particular symptom of depression differentially. In particular, L-tryptophan had no specific effect on the sleep deficit of the syndrome. Liothyronine appeared to diminish the side effects of both imipramine and L-tryptophan in both men and women.

Reference: Coppen, Alec, et al. “The comparative antidepressant value of L-tryptophan and imipramine with and without attempted potentiation by liothyronine.” Archives of General Psychiatry 26.3 (1972): 234-241. doi:10.1001/archpsyc.1972.01750210042009


Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses* http://www.sciencedirect.com/science/article/pii/0896627394900558


The pineal hormone melatonin regulates seasonal reproductive function and modulates circadian rhythms in mammals. We now report the cloning and characterization of a high-affinity receptor for melatonin from the sheep and human. The receptor cDNAs encode proteins that are members of a newly discovered group within the G protein-coupled receptor family. Expression of the sheep and human receptors in COS-7 cells results in high-affinity 2-[125I]iodomelatonin binding and pharmacological characteristics similar to endogenous high-affinity receptors. Functional studies of NIH 3T3 cells stably expressing the sheep receptor show that the mammalian melatonin receptor is coupled to inhibition of adenylyl cyclase through a pertussis toxin-sensitive mechanism. In situ hybridization studies of melatonin receptor mRNA in several mammals reveal hybridization signals in the hypophyseal pars tuberalis and hypothalamic suprachiasmatic nucleus. The cloned high-affinity receptor likely mediates the reproductive and circadian actions of melatonin in mammals.

Reference: Reppert, Steven M., David R. Weaver, and Takashi Ebisawa. “Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses.” Neuron 13.5 (1994): 1177-1185. doi:10.1016/0896-6273(94)90055-8

Melatonin: A peroxyl radical scavenger more effective than vitamin E* http://www.sciencedirect.com/science/article/pii/0024320594006660?np=y


We have compared the peroxyl radical scavenger ability of melatonin with that of vitamin E, vitamin C and reduced glutathione (GSH). In the assay system, β-phycoerythrin (β-PE) was used as fluorescent indicator protein, 2-2′-azo-bis(2-amidinopropane)dihydrochloride as a peroxyl radical generator and the water-soluble vitamin E analog, Trolox, as a reference standard. Results are expressed as oxygen radical absorbing capacity (ORACperox) units, where 1 ORAC unit equals the net protection produced by 1 μM Trolox. A linear correlation of ORAC values with concentration (0.5–4 μM) of all the substances tested has been observed. However, on a molar basis, the relative ORACperox of Trolox, vitamin C, GSH and melatonin was 1: 1.12: 0.68: 2.04, respectively. Thus, melatonin, which is a lipid-soluble compound, was twice more active than vitamin E, believed to be the most effective lipophilic antioxidant.

Reference: Pieri, Carlo, et al. “Melatonin: a peroxyl radical scavenger more effective than vitamin E.” Life sciences 55.15 (1994): PL271-PL276. doi:10.1016/0024-3205(94)00666-0

Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebrates.* http://europepmc.org/abstract/med/7773197


Twenty-four edible plants were investigated for the presence of melatonin, heretofore considered to be a molecule found only in the animal kingdom. The amount of melatonin in different plants varied greatly with the highest melatonin being present in plants of the rice family. Melatonin was identified by radioimmunoassay and verified by high-performance liquid chromatography with fluorescence detection. Feeding a diet containing plant products rich in melatonin to chicks increased radioimmunoassayable levels of melatonin in their blood. Likewise, melatonin extracted from plants inhibited binding of [125I]iodomelatonin to rabbit brain. Thus, melatonin ingested in foodstuffs enters the blood and is capable of binding to melatonin binding sites in the brain of mammals.

Reference: Hattori, Atsuhiko, et al. “Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebrates.” Biochemistry and molecular biology international 35.3 (1995): 627-634.

Melatonin replacement therapy of elderly insomniacs* http://europepmc.org/abstract/med/8552931


Changes in sleep-wake patterns are among the hallmarks of biological aging. Previously, we reported that impaired melatonin secretion is associated with sleep disorders in old age. In this study, we investigated the effects of melatonin replacement therapy on melatonin-deficient elderly insomniacs. The study comprised a running-in, no-treatment period and four experimental periods. During the second, third and fourth periods, subjects were administered tablets for 7 consecutive days, 2 hours before the desired bedtime. The tablets were either 2 mg melatonin administered as sustained-release or fast-release formulations or an identical-looking placebo. The fifth period, which concluded the study, was a 2-month period of daily administration of 1 mg sustained-release melatonin 2 hours before the desired bedtime. During each of these five experimental periods, sleep-wake patterns were monitored by wrist-worn actigraphs. Analysis of the first three 1-week periods revealed that a 1-week treatment with 2 mg sustained-release melatonin was effective for sleep maintenance (i.e. sleep efficiency and activity level) of elderly insomniacs, while sleep initiation was improved by the fast-release melatonin treatment. Sleep maintenance and initiation were further improved following the 2-month 1-mg sustained-release melatonin treatment, indicating that tolerance had not developed. After cessation of treatment, sleep quality deteriorated. Our findings suggest that for melatonin-deficient elderly insomniacs, melatonin replacement therapy may be beneficial in the initiation and maintenance of sleep.

Reference: Haimov, Iris, et al. “Melatonin replacement therapy of elderly insomniacs.” Sleep 18.7 (1995): 598-603.

Improvement of sleep quality in elderly people by controlled-release melatonin* http://www.sciencedirect.com/science/article/pii/S0140673695913823


Melatonin, produced by the pineal gland at night, has a role in the regulation of the sleep-wake cycle. Among elderly people, even those who are healthy, the frequency of sleep disorders is high and there is an association with impairment of melatonin production. We investigated the effect of a controlled-release formulation of melatonin on sleep quality in 12 elderly subjects (aged 76 [SD 8] years) who were receiving various medications for chronic illnesses and who complained of insomnia.

In all 12 subjects, the peak excretion of the main melatonin metabolite 6-sulphatoxymelatonin during the night was lower than normal and/or delayed in comparison with non-insomniac elderly people. In a randomized, double-blind, crossover study the subjects were treated for 3 weeks with 2 mg per night of controlled-release melatonin and for 3 weeks with placebo, with a week’s washout period. Sleep quality was objectively monitored by wrist actigraphy. Sleep efficiency was significantly greater after melatonin than after placebo (83 [SE 4] vs 75 [3]%, p<0·001) and wake time after sleep onset was significantly shorter (49 [14] vs 73 [13] min, p<0·001). Sleep latency decreased, but not significantly (19 [5] vs 33 [7] min, p=0·088). Total sleep time was not affected. The only adverse effects reported were two cases of pruritus, one during melatonin and one during placebo treatment; both resolved spontaneously.

Melatonin deficiency may have an important role in the high frequency of insomnia among elderly people. Controlled-release melatonin replacement therapy effectively improves sleep quality in this population.

Reference: Garfinkel, D., et al. “Improvement of sleep quality in elderly people by controlled-release melatonin.” The Lancet 346.8974 (1995): 541-544. doi:10.1016/S0140-6736(95)91382-3

Melatonin receptors: Are there multiple subtypes?* http://www.sciencedirect.com/science/article/pii/S0165614700889786


There is no evidence for more than one site of action for the hormone melatonin (N-acetyl-5-methoxytryptamine). Recent pharmacological and molecular advances are providing the tools to address the characterization of melatonin receptor subtypes. The development of novel melatonin receptor agonists and antagonists, high-affinity radioligands, quantitative bioassays, and the recent cloning of melatonin receptors are furthering our understanding of native and recombinant melatonin receptors. In this article, Margarita Dubocovich discusses the properties of melatonin receptors, and the basis for their classification into at least two subtypes, the ML1 and ML2.

Reference: Dubocovich, Margarita L. “Melatonin receptors: are there multiple subtypes?.” Trends in pharmacological sciences 16.2 (1995): 50-56. doi:10.1016/S0165-6147(00)88978-6

Pineal Melatonin: Cell Biology of Its Synthesis and of Its Physiological Interactions* http://press.endocrine.org/doi/abs/10.1210/edrv-12-2-151



UNTIL 35 yr ago, most scientists did not take research on the pineal gland seriously. The decade beginning in 1956, however, provided several discoveries that laid the foundation for what has become a very active area of investigation. These important early observations included the findings that, 1), the physiological activity of the pineal is influenced by the photoperiodic environment (1–5); 2), the gland contains a substance, N-acetyl-5-methoxytryptamine or melatonin, which has obvious endocrine capabilities (6, 7); 3), the function of the reproductive system in photoperiodically dependent rodents is inextricably linked to the physiology of the pineal gland (5, 8, 9); 4), the sympathetic innervation to the pineal is required for the gland to maintain its biosynthetic and endocrine activities (10, 11); and 5), the pineal gland can be rapidly removed from rodents with minimal damage to adjacent neural structures using a specially designed trephine (12).

Since the mid-1960s, research on the pineal gland has increased exponentially, and its association with a wide variety of physiological systems has been documented (13–18). Proof that melatonin is the hormone of pineal origin that accounts for many of the endocrine manifestations of the gland, however, came somewhat later. Thus, whereas some early studies certainly suggested that melatonin had modulatory effects on the neuroendocrine- reproductive axis (19, 20), these actions were questioned when it was observed that in hamsters bearing sc placed melatonin pellets, which release the indole continuously, the ability of short day exposure and the pineal to suppress reproductive physiology was unexpectedly negated (21–23). These observations were, however, followed closely by studies showing that melatonin, administered as a single daily injection at a precise time with regard to the light-dark cycle, induced quiescence of the neuroendocrine-reproductive axis just as did short day exposure (24, 25).

– See more at http://press.endocrine.org/doi/abs/10.1210/edrv-12-2-151#sthash.Yf6ZfxN6.dpuf

Reference: Reiter, Russel J. “Pineal Melatonin: Cell Biology of Its Synthesis and of Its Physiological Interactions*.” Endocrine reviews 12.2 (1991): 151-180. DOI: http://dx.doi.org/10.1210/edrv-12-2-151

Melatonin stimulates brain glutathione peroxidase activity* http://www.sciencedirect.com/science/article/pii/019701869400154M


Exogenously administered melatonin causes a 2-fold rise in glutathione peroxidase activity within 30 min in the brain of the rat. Furthermore, brain glutathione peroxidase activity is higher at night than during the day and is correlated with high night-time tissue melatonin levels. Glutathione peroxidase is thought to be the principal enzyme eliminating peroxides in the brain. This antioxidative enzyme reduces the formation of hydroxyl radicals formed via iron-catalyzed Fenton-type reactions from hydrogen peroxide by reducing this oxidant to water. Since the hydroxyl radical is the most noxious oxygen radical known, induction of brain glutathione peroxidase might be an important mechanism by which melatonin exerts its potent neuroprotective effects.

Reference: Barlow-Walden, L. R., et al. “Melatonin stimulates brain glutathione peroxidase activity.” Neurochemistry international 26.5 (1995): 497-502. doi:10.1016/0197-0186(94)00154-M

Melatonin in humans physiological and clinical studies.* http://europepmc.org/abstract/med/381589


Studies are reported of the variation of melatonin in serum, plasma urine and cerebrospinal fluid in normal subjects and in patients with various diseases. The diurnal variation of plasma and urine melatonin found in healthy controls on a regular dark-sleep pattern persisted when the subjects slept in the light. The effect of sleep deprivation and of rapid light exposure at night is reported. There was a correlation between melatonin in morning urine and plasma at 2 a.m. Four hours of extended darkness in the morning, as well as a 9-hour shift of sleep and activity cycles following travel, affected the melatonin rhythm. The night increase in plasma melatonin preceded both the cortisol and prolactin rise. A single oral dose of 4.3 X 10(5) nmol of melatonin given to a 44-year-old healthy male gave a peak plasma value of 624 nmol/l after 30 min. Plasma melatonin was not affected by electroconvulsive therapy, TRH-injection, L-Dopa or bromoergocryptine orally. Patients with alcoholism, migraine, postoperative pinealoma, panhypopituitarism, hereditary dystonia and schizophrenics on propranolol exhibited a decreased amplitude of their diurnal rhythm of melatonin. Two patients with pituitary tumors had occasional high levels of plasma melatonin. The change in melatonin secretion in human is apparently controlled by a mechanism which is at least partly influenced by environmental lighting conditions, drugs, and different disease states.

Reference: Wetterberg, L. “Melatonin in humans physiological and clinical studies.” Journal of neural transmission. Supplementum 13 (1977): 289-310.

Regulation of antioxidant enzymes: a significant role for melatonin* http://onlinelibrary.wiley.com/doi/10.1046/j.1600-079X.2003.00092.x/full


Antioxidant enzymes form the first line of defense against free radicals in organisms. Their regulation depends mainly on the oxidant status of the cell, given that oxidants are their principal modulators. However, other factors have been reported to increase antioxidant enzyme activity and/or gene expression. During the last decade, the antioxidant melatonin has been shown to possess genomic actions, regulating the expression of several genes. Melatonin also influences both antioxidant enzyme activity and cellular mRNA levels for these enzymes. In the present report, we review the studies which document the influence of melatonin on the activity and expression of the antioxidative enzymes glutathione peroxidase, superoxide dismutases and catalase both under physiological and under conditions of elevated oxidative stress. We also analyze the possible mechanisms by which melatonin regulates these enzymes.

Reference: Rodriguez, Carmen, et al. “Regulation of antioxidant enzymes: a significant role for melatonin.” Journal of pineal research 36.1 (2004): 1-9. DOI: 10.1046/j.1600-079X.2003.00092.x

Enzymatic O-Methylation of N-Acetylserotonin to Melatonin* http://science.sciencemag.org/content/131/3409/1312


An enzyme, hydroxyindole-O-methyltransferase, that can transfer the methyl group of S-adenosylmethionine to the hydroxy group of N-acetylserotonin to form the hormone melatonin is described. This enzyme, which is highly localized in the pineal gland, also O-methylates serotonin.

Reference: Axelrod, Julius, and Herbert Weissbach. “Enzymatic O-methylation of N-acetylserotonin to melatonin.” Science 131.3409 (1960): 1312-1312. DOI: 10.1126/science.131.3409.1312

Action Spectrum for Melatonin Regulation in Humans: Evidence for a Novel Circadian Photoreceptor* http://www.jneurosci.org/content/21/16/6405.short


The photopigment in the human eye that transduces light for circadian and neuroendocrine regulation, is unknown. The aim of this study was to establish an action spectrum for light-induced melatonin suppression that could help elucidate the ocular photoreceptor system for regulating the human pineal gland. Subjects (37 females, 35 males, mean age of 24.5 ± 0.3 years) were healthy and had normal color vision. Full-field, monochromatic light exposures took place between 2:00 and 3:30 A.M. while subjects’ pupils were dilated. Blood samples collected before and after light exposures were quantified for melatonin. Each subject was tested with at least seven different irradiances of one wavelength with a minimum of 1 week between each nighttime exposure. Nighttime melatonin suppression tests (n = 627) were completed with wavelengths from 420 to 600 nm. The data were fit to eight univariant, sigmoidal fluence-response curves (R 2 = 0.81–0.95). The action spectrum constructed from these data fit an opsin template (R 2 = 0.91), which identifies 446–477 nm as the most potent wavelength region providing circadian input for regulating melatonin secretion. The results suggest that, in humans, a single photopigment may be primarily responsible for melatonin suppression, and its peak absorbance appears to be distinct from that of rod and cone cell photopigments for vision. The data also suggest that this new photopigment is retinaldehyde based. These findings suggest that there is a novel opsin photopigment in the human eye that mediates circadian photoreception.

Reference: Brainard, George C., et al. “Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor.” The Journal of Neuroscience 21.16 (2001): 6405-6412.

Melatonin is a scavenger of peroxynitrite* http://www.sciencedirect.com/science/article/pii/S0024320597000088


Peroxynitrite is a toxic oxidant formed from the reaction of Superoxide and nitric oxide under conditions of inflammation and oxidant stress. Here we demonstrate that the pineal neurohormone melatonin inhibits peroxynitrite-mediated oxidant processes. Melatonin caused a dose-dependent inhibition of the oxidation of dihydrorhodamine 123 to rhodamine in vitro. Moreover, in cultured J774 macrophages, melatonin inhibited the development of DNA single-strand breakage in response to peroxynitrite and reduced the suppression of mitochondrial respiration. Thus, melatonin appears to be a scavenger of peroxynitrite. This action may contribute to the antioxidant and anti-inflammatory effects of melatonin in various pathophysiological conditions.

Reference: Gilad, Eli, et al. “Melatonin is a scavenger of peroxynitrite.” Life sciences 60.10 (1997): PL169-PL174. doi:10.1016/S0024-3205(97)00008-8

Molecular characterization of a second melatonin receptor expressed in human retina and brain: the Mel1b melatonin receptor* http://www.pnas.org/content/92/19/8734.short


A G protein-coupled receptor for the pineal hormone melatonin was recently cloned from mammals and designated the Mel1a melatonin receptor. We now report the cloning of a second G protein-coupled melatonin receptor from humans and designate it the Mel1b melatonin receptor. The Mel1b receptor cDNA encodes a protein of 362 amino acids that is 60% identical at the amino acid level to the human Mel1a receptor. Transient expression of the Mel1b receptor in COS-1 cells results in high-affinity 2-[125I]iodomelatonin binding (Kd = 160 +/- 30 pM). In addition, the rank order of inhibition of specific 2-[125I]iodomelatonin binding by eight ligands is similar to that exhibited by the Mel1a melatonin receptor. Functional studies of NIH 3T3 cells stably expressing the Mel1b melatonin receptor indicate that it is coupled to inhibition of adenylyl cyclase. Comparative reverse transcription PCR shows that the Mel1b melatonin receptor is expressed in retina and, to a lesser extent, brain. PCR analysis of human-rodent somatic cell hybrids maps the Mel1b receptor gene (MTNR1B) to human chromosome 11q21-22. The Mel1b melatonin receptor may mediate the reported actions of melatonin in the retina and participate in some of the neurobiological effects of melatonin in mammals.

Reference: Reppert, Steven M., et al. “Molecular characterization of a second melatonin receptor expressed in human retina and brain: the Mel1b melatonin receptor.” Proceedings of the National Academy of Sciences 92.19 (1995): 8734-8738.