New research out of Murdoch University has shown that saffron can enhance the quality of sleep in adults who have been experiencing poor sleep.
Lead researcher Dr Adrian Lopresti, whose earlier research found saffron to be an effective natural agent for the treatment of mild-to-moderate depression, said one of the features of that research showed improvements in sleep.
“This new research used volunteers who were not being treated for depression, were physically-healthy, had been medication free for at least four weeks – apart from the contraceptive pill – and had self-reported symptoms of poor sleep.”
“Research indicates that between 10 to 45% of adults report regular difficulty either falling or staying asleep.”
“This is a serious issue as poor sleep quality can have a negative impact on both mental and physical health and can interfere with daily function,” Dr Lopresti said.
“Our previous research showed saffron was an effective add-on to pharmaceutical antidepressants in patients experiencing mild-to-moderate depression.
Because many of these people reported improvements in their sleep, in this study we focused on healthy adults who were generally medication free but had experienced poor sleep lasting greater than four weeks.”
Dr Lopresti said the results from the Murdoch University study indicate a standardised saffron extract (affron®) at a dose of 14mg, twice daily for 28 days improved sleep quality in adults with self-reported poor sleep, with most of these changes occurring in the first 7-days of treatment.
“Our previous research showed saffron was an effective add-on to pharmaceutical antidepressants in patients experiencing mild-to-moderate depression.”
“In addition to the improved sleep, the study showed that saffron was well tolerated with no reported adverse effects,” Dr Lopresti said.
However, the researchers reported that even though the results were positive, the findings require replication using larger sample size and differing populations.
“Our early research is indeed positive and there is evidence that taking a standardised saffron extract is associated with improvements in sleep quality,” Dr Lopresti said.
“However, to verify these findings, further studies using larger sample sizes, treatment periods and volunteers with varying characteristics is required.”
Sleep disorders, characterised by a frequent difficulty to fall asleep or maintain sleep, are the most prevalent health conditions amongst adults. In Europe, prevalence rates vary between countries from 16.5% in Denmark and Italy to 31.2% in Poland , with adults between 45 and 64 years old being the most affected by sleep disorders .
Long-term effects of sleep deprivation may not only cause fatigue and decrease cognitive performance, but even increase the risk of type 2 diabetes [5, 6], hypertension , cardiovascular disease , depression  and early mortality . Therefore, getting enough sleep of good quality is important for human health.
Apart from lifestyle changes such as improving sleep habits and creating a sleep-friendly environment, prescription drugs such as benzodiazepines and the “z drugs”, particularly zolpidem, zopiclone and zaleplon are frequently used for sleep disturbances.
Both groups enhance the effects of the gamma-aminobutyric acid (GABA) at a site on the GABAAreceptor. However, for both benzodiazepines and the “z drugs”, extensive evidence for harmful side effects and drug interactions can be found in the literature.
Reported side effects include morning drowsiness, impairment of cognition and psychomotor performance, amnesia, hallucinations, and even suicidality [11–14]. Furthermore, the use of these hypnotic drugs may lead to dependency, further limiting their usefulness . For all these reasons, most people prefer to turn to safer treatment options such as herbal products.
The history of plant-derived sleep aids goes back as far as ancient times. Plants such as valerian (Valeriana officinalis L.), hops (Humulus lupulus L.), passion flower (Passiflora incarnata L.), lavender (Lavandula officinalis L.) or lemon balm (Melissa officinalis L.) have been used by healers to reduce anxiety, induce calmness, and promote sleep.
Since medicinal plants are made up of a variety of constituents that exert different beneficial properties that may help to combat sleep problems, different herbs are often combined to achieve synergistic effects.
However, solid evidence of their efficacy is lacking for many natural products available on the market. To date, clinical trials in humans provide preliminary evidence for only a few herbal sleep aids, such as valerian, passion flower or lemon balm [15–19].
IQP-AO-101 (Night Coach™, InQpharm) is a proprietary formulation that contains asparagus extract, saffron extract, lemon balm extract, vitamin C, vitamin E and zinc.
The formulation is designed to improve restorative sleep and rejuvenate body cells for optimal physical and mental performance. A range of studies support the efficacy of individual ingredients used in the formulation to promote sleep.
In clinical trials, asparagus extract was found to decrease fatigue and improve quality of life, stress resistance, and the ability to sleep [20, 21], an effect which may be attributed to its ability to stabilize serum and salivary cortisol levels .
A 4-week treatment with saffron extract significantly ameliorated mood, reduced anxiety, and improved stress management in healthy adults . Saffron extract and its constituents, safranal and crocins (crocin and its hydrolysis product crocetin), were shown to affect various neuronal pathways relevant to sleep promotion.
In a mouse study, saffron aqueous extract and safranal demonstrated muscle relaxant, anxiolytic, and hypnotic effects that were similar to diazepam, suggesting a mechanism of action mediated by GABA-benzodiazepine receptor complex .
Crocins demonstrated anxiolytic effects in a rat study  and increased the total time of non-rapid eye movement sleep in mice [26, 27]. They were shown to have an antagonistic effect at the 5-HT receptor site , thus improving mood, and activating the opioid sigma (1) receptors , which ameliorate anxiety-like behavior in rats .
For lemon balm, three clinical trials support its potential use for sleep disorders by reducing stress, depression and anxiety [17–19]. It was shown to decrease serum corticosterone levels in mice  and its active constituents, namely, rosmarinic acid and the triterpenoids oleanolic acid and ursolic acid were shown to inhibit gamma-aminobutyric acid catabolism, thus increasing GABA levels .
The rationale for the use of vitamins C and E in this formulation is based on their antioxidant properties that may prevent short- and long-term memory impairment induced by sleep deprivation, as reported in animal studies by Mhaidat et al. 2015 and Alzoubi et al. 2012, respectively [33, 34]. Vitamin C has been demonstrated to lower cortisol and products of lipid peroxidation caused by sleep deprivation in rats , whereas zinc was reported to inhibit N-methyl-D-aspartate (NMDA) receptor and restore glutamatergic transmission for its antidepressant effects [36, 37]. Additionally, zinc seems to be important for sleep in humans as serum concentration of zinc correlates with the quality and amount of sleep .
Therefore, the aim of our study was to investigate the potential of IQP-AO-101 to promote sleep in subjects with sleep disturbances and to evaluate its tolerability.
IQP-AO-101 is a product containing asparagus extract, saffron extract, lemon balm extract, vitamin C, vitamin E and zinc that could potentially alleviate sleep disturbances. It has been developed based on the current scientific literature evidence.
The primary objective of this randomized, double-blind, placebo-controlled clinical study was to evaluate safety and efficacy of IQP-AO-101 on sleep parameters over a period of 6 weeks in healthy subjects experiencing sleep disturbances.
In the present trial, it was demonstrated that subjects who consumed IQP-AO-101 showed a statistically significant improvement in the mean mAIS total score after 6 weeks. All individual mAIS night parameters related to sleep (sleep induction, night awakening, final awakening and overall quality of sleep) and all parameters related to daytime performance that may be affected by sleep quality (sense of well-being, extent of impact of the sleep problems on daytime sleepiness and functioning and feeling refreshed upon awakening) showed a statistically significant improvement after consumption of IQP-AO-101 for 6 weeks. These findings indicate that IQP-AO-101 may improve nighttime sleep and, hence, as a result improve daytime performance.
The assessment of the sleep data obtained with the activity tracker did not show any significant difference between the IQP-AO-101 or placebo group with regard to tracked total time in bed, sleep time, wake time and number of night awakenings.
Similarly, no significant differences between both study groups were observed in total time in bed as reported by subjects in a sleep diary. One explanation for the discrepancy between the findings is the different underlying approach of the mAIS questionnaire and activity tracker to assessing sleep parameters.
An activity tracker is a wearable device worn on the wrist that measures every motion caused by wrist or arm. It works based on the assumption that people move most during wake states with a progressive reduction in motion as they approach the deepest stages of sleep, such that sleep/wake states may be discriminated by measuring and analyzing these movements to quantify the sleep patterns .
Comparing to polysomnography, the gold standard for measuring sleep, which measures other dimensions of sleep such as brain waves, eye movements, muscle activity, heart physiology and respiratory function in a laboratory setting, activity tracker measured sleep data may suffer in accuracy .
On the other hand, mAIS is a subjective assessment which depends on the subjects’ retrospective recall on any perceived change in the sleep parameters during the past week. As previously reported, findings for subjective measures do not always agree with objective measures .
Nevertheless, subject reported outcomes per questionnaires like mAIS are considered valuable in obtaining the subjects’ perspective regarding their treatment experiences.
We investigated the potential effect of IQP-AO-101 on mood states by administering the POMS-65 questionnaire which measures six different dimensions of mood swing, including tension, depression, anger, fatigue, confusion and vigor. However, our results revealed that IQP-AO-101 had not significantly impacted the mood states of the subjects in the current study. This could have been due to a small sample size, large individual variability, and/or generally low level of mood disturbances reported by the subjects at baseline thereby making significant changes difficult to detect.
One important part of this study is that IQP-AO-101 showed an excellent tolerability profile as per evaluation by both participants and investigator. There were no clinically significant changes in subjects’ safety parameters and no investigational product-related adverse effects were reported, indicating that the administration of IQP-AO-101 is tolerable for short-term use.
IQP-AO-101 contains ingredients that have previously been shown to alleviate sleep disturbances in animal or human clinical trials. Possible mechanisms of action for this effect may relate to modulation of the hypothalamus-pituitary-adrenal axis, interaction between neurohormonal systems of the brain and protection of neuronal cells from oxidative stress [22, 23, 25, 26, 29, 30, 32, 33, 36–38].
In a study by Ito et al. 2014, asparagus extract was shown to stabilize serum and salivary cortisol levels in humans . Crocin, a saffron extract constituent, was shown to reduce corticosterone level in frontal cortex of stressed rats  and in plasma levels of rats exposed to chronic restraint stress .
Lemon balm was also observed to decrease serum corticosterone levels in mice . Furthermore, Olayaki et al. 2015 demonstrated recently that vitamin C prevented sleep deprivation-induced elevation in cortisol in the rat plasma . IQP-AO-101 ingredients also seem to be able to modulate several neurohormonal pathways in the brain.
Saffron extract and its constituents, safranal and crocins (crocin and its hydrolysis product crocetin), were previously reported to trigger and increase the production of dopamine and glutamate in the brain [50, 51].
In addition, water extract of Melissa officinalis L. was reported to modulate serotonergic pathways in rats in a forced swimming test . Furthermore, saffron aqueous extract and safranal showed in a mouse study muscle relaxant, anxiolytic, and hypnotic effects similar to diazepam, suggesting a mechanism of action mediated by GABA-benzodiazepine receptor complex .
Active constituents of lemon balm, rosmarinic acid, oleanolic acid and ursolic acid, were shown to inhibit gamma-aminobutyric acid catabolism in an in vitro study, thus possibly increasing GABA levels . Yoo et al. 2011 also observed increase in GABA after treatment with lemon balm extract .
Zinc might also be involved in the mode of action of IQP-AO-101 as it was observed to inhibit N-methyl-D-aspartate (NMDA) receptor and restore glutamatergic transmission [36, 37]. Neuroprotection due to antioxidative effects could be another mechanism contributing to results observed in this clinical trial.
In an in vitro cell study by Ogasawara et al. 2014, asparagus extract was shown to scavenge the negative effect of free radicals at the cellular level . In another study, asparagus extract was demonstrated to enhance expression of cytoprotective factors such as heat shock transcription factor 1 (HSF1) and Nrf2 protein .
There is also evidence that saffron and its constituents, crocin, crocetin, and safranal can mitigate oxidative stress.
In a study on hyperlipidemic rats, both saffron and crocin decreased elevated levels of MDA, glutathione peroxidase enzyme activity (GSHPx), total glutathione (GSH) and oxidized glutathione (GSSG) in serum and increased SOD, CAT, ferric reducing/antioxidant power (FRAP), and total sulfhydryl values in liver tissue with a reduction in thiobarbituric acid reactive species (TBARS) .
Moreover, crocin was shown to be a potent antioxidant that combats ischemic stress-induced neuron death by increasing GSH synthesis and thus inhibiting neutral sphingomyelinase activity and ceramide formation.
It increased the GSH synthesis via promoting mRNA expression of γ-glutamylcysteine synthetase (γ-GCS) .
In addition, vitamin C was demonstrated to lower products of lipid peroxidation caused by sleep deprivation in a rat model .
Further research is needed to elucidate the mechanism of action of IQP-AO-101.
A limitation of this study is that the evaluation of safety and efficacy was performed over a relatively short period of 6 weeks, and no follow-up assessment was performed after IQP-AO-101 had been discontinued. Hence, no information about the benefits on sleep and safety of long-term use is currently available.
Furthermore, the study was conducted as a pilot clinical trial without prior estimation of sample size and statistical power, thus it may be difficult to draw firm conclusions from its results. Lastly, it is unknown if the use of IQP-AO-101 would produce similar results in individuals with more pronounced sleep difficulties. Future studies should validate the efficacy of IQP-AO-101 for alleviating sleep problems in a sufficiently powered study with morelarger subject numbers. Its safety and tolerability should also be evaluated over a longer period of time.