A key to a healthy life is getting a good night’s sleep. It is during sleep when our body performs its main restorative functions, such as tissue regeneration, muscle growth and protein synthesis. During this time, it is possible to replenish energy and regulate metabolism, essential factors for maintaining a healthy body and mind and preventing the onset of chronic diseases. Sleep is also important for appetite regulation, as it regulates stress-related hormones (cortisol), which helps control weight and blood glucose levels.

How many hours of sleep are enough for good health?

Table 1: Recommended hours of sleep according to age (1).

Unfortunately, at various times in our lives, sleeping this many hours and with the necessary quality is almost impossible and, especially depressing, when suffering from insomnia. Day-to-day stress and worries can negatively affect biological rhythms, making it difficult to sleep and decreasing its quality.

Benzodiazepines

A widely used resource for the treatment of severe sleep disorders and anxiety are psychoactive drugs based on benzodiazepines, such as Diazepam (Valium), Alprazolan (Xanax), Lorazepam (Ativan) or Estazolam (Prosom). These drugs must be used rationally and under strict medical prescription, since they generate dependency very easily. In fact, the use of benzodiazepines for a period of time of approximately 3 to 6 weeks, even using therapeutic doses, easily leads to a state of dependence (2).

Structurally (figure 1), benzodiazepines are the result of the fusion of a benzene ring (ring A) with a 1,4-diazepine ring (ring B). Benzodiazepines that express anesthetic effects more markedly also have an aryl ring in position 5 (ring C), which increases their potency at the pharmacological level. The different benzodiazepines available on the market have different chemical groups in positions 1, 2, 5 or 7 and additionally in 2 ′, which modulate the pharmacological properties, the potency of the effect and the pharmacokinetic conditions (duration of effect, distribution, etc.) .

Figure 1: General structure of a benzodiazepine.

The mechanism of action of benzodiazepines.

GABA (γ-Aminobutyric acid) is the most important inhibitory neurotransmitter in the central nervous system. The function of GABA is to inhibit or reduce neuronal activity through its action on specific receptors called GABA-A receptors. These receptors are proteins located on the membranes of neurons in synaptic spaces (the space between a presynaptic and a postsynaptic neuron), where chemical synapse occurs. As a consequence, the inhibition of neuronal activity produces a feeling of calm, muscle relaxation and sedation, which plays an important role in behavior, cognition and the body’s response to stress (3). Due to their ability to bind to certain sites (alpha subunits) located on GABA-A receptors, benzodiazepines modulate the effect of GABA by acting as enhancers of its suppressive effect on neuronal activity. For this reason, benzodiazepines are responsible for causing anxiolytic (anxiety reducing), hypnotic (sleep inducing), sedative, anticonvulsant and muscle relaxant effects.

The public health problem generated by the use of benzodiazepines

The main problem associated with the use of benzodiazepines is their ability to generate addiction. One of the typical signs of the establishment of addiction in many patients is the appearance of withdrawal syndrome, caused after a sudden interruption of the chronic and prolonged intake of these substances. Typical withdrawal symptoms are: anxiety, panic attacks, hyperventilation, tremors, sleep disturbances, muscle spasms, anorexia, weight loss, visual disturbances, sweating, dysphoria, hypersensitivity to noise, seizures, hallucinations, and delusions. To further complicate the situation, in many European countries (4,5), benzodiazepines are often used in an uncontrolled manner by the population, giving rise to a serious public health problem that worries the authorities, since that addiction to this substance is difficult to manage therapeutically.

The pleasurable sensations that addictive drugs normally generate, and which are disastrously attractive to vulnerable people, occur when dopamine levels in the reward (or pleasure) area of the brain rise abruptly. These types of drugs interfere with the body’s natural mechanisms to control the flow of dopamine. More specifically, benzodiazepines weaken the action of a group of neurons called interneurons, which are found in the ventral tegmental area of the brain (VTA). Interneurons normally help prevent excessive dopamine levels by regulating the firing rates of dopamine-producing neurons. Therefore, when benzodiazepines limit the restrictive influence of interneurons, dopamine-producing neurons release more dopamine than normal (6).

Dopamine is the chemical that mediates pleasure in the brain. Its production takes place in pleasant situations and aims to stimulate the performance of pleasant activities, important for survival, such as food or sex. Some drugs such as opioids and benzodiazepines have the ability to artificially stimulate dopamine production in the brain, leading to imbalances in the natural reward/survival process.

Natural alternatives to benzodiazepines

Since the factors responsible for anxiety and insomnia are not expected to decrease, it is essential for the patient’s quality of life to find anxiolytic alternatives with less potential to induce adverse reactions. In this sense, there has been great interest on the part of the scientific community in the study of medicinal plants (7). Since ancient times, some plants have been used to treat insomnia and anxiety, and today the use of their extracts has gained increasing acceptance by the medical community (7). However, most medicinal plants lack chemical and pharmacological data and, in many cases, their active principles have not yet been identified or chemically studied. It is expected that with the advancement of scientific studies in the area of phytochemistry and phytomedicine, we will have a greater amount of natural resources to help in the treatment of this type of disorder.

Among the various medicinal plants known for their anxiolytic, sedative and relaxing properties, we can highlight kava-kava (Piper methysticum), passionflower (Passiflora incarnata), grifonia (Griffonia simpliciflia), valerian (Valeriana officinalis), chamomile (Matricaria recutita) and arnica (Galphimia glauca). These plants have been extensively studied and their most important active ingredients have been identified. Among those examples, kava-kava was no longer authorized as an ingredient in food supplements in Europe after 2002, due to suspected hepatotoxicity (8).

4Sleep: 4 powerful ingredients to help you sleep better

Aware of the need to offer safe alternatives to help people who suffer from insomnia and have difficulties falling asleep, Nutribiolite has developed 4Sleep, a food supplement that combines melatonin and the concentrated extracts of griffonia, valerian and chamomile. Each of these ingredients demonstrated, in various scientific research articles, important anxiolytic properties that help promote the biological processes associated with relaxation and falling asleep. The combination of these ingredients aims to obtain an additive effect that provides a progressive and long-lasting sleep-inducing effect. In the following chapters, we provide a brief summary of the properties of each of these 4Sleep ingredients.