Anxiolytics

Anxiolytics (from lat. anxietas – anxiety, fear + Greek. lytikos – capable of dissolving, weakening), or tranquilizers (from lat.tranquillo – soothe), or ataractics (from the Greek. ataraxia – equanimity) – psychotropic drugs that reduce the severity or suppress anxiety, fear, anxiety, emotional stress.
The appearance of the first tranquilizers dates back to the 50s of the XX century. Prior to this, alcohol, opium, bromides (from the beginning of the 19th century), barbiturates (from the beginning of the 20th century) and other drugs were used to correct anxiety states.
In 1952, during the search for central muscle relaxants, meprobamate (Meprotan) was synthesized. In the 60s, in a number of clinical studies, anxiolytic properties (when taken in high doses – 100-400 mg / day) were found in hydroxyzine (Atarax), one of the first antihistamines, an antagonist of Hone-histamine receptors, which have been used in dermatology since 1955.The first generation of anxiolytics also includes trimethosine (Trioxazine, canceled in 1996), the central anticholinergic benactisin (Amisil), atypical anxiolytics mebicar and benzoclidine (Oksylidine).
Medicines of the anxiolytic group have been widely used in medical practice since the 1960s, when the first tranquilizers appeared – benzodiazepine derivatives: chlordiazepoxide (Librium, 1960) and diazepam (Valium, 1962).
The sedative (calming) effect is manifested by a decrease in psychomotor excitability, daytime activity, a decrease in concentration, a decrease in the reaction rate, etc.
The hypnotic (hypnotic) effect is expressed in facilitating the onset of sleep and increasing its duration. The depressing effect of tranquilizers on the central nervous system contributes to the mutual enhancement of the effects of hypnotics, anesthetic and analgesics.
Muscle relaxant activity (relaxation of skeletal muscles) is mainly due to inhibition of polysynaptic spinal reflexes. Benzodiazepines can also directly inhibit motor nerves and muscle function. The muscle relaxant effect when using tranquilizers is often a positive factor for relieving tension, arousal, incl. motor, but may also limit the use of drugs in patients whose work requires a quick mental and physical response. It should be borne in mind that the muscle relaxant effect can be manifested by a feeling of lethargy, weakness, etc.
The anticonvulsant effect is manifested in the suppression of the spread of epileptogenic activity that occurs in epileptogenic foci in the cortex, thalamus and limbic structures. Anticonvulsant effects are not only related to effects on GABABUT-receptor complex, but also due to the effect on voltage-gated sodium channels.
The amnestic effect (the ability to induce amnesia) is manifested mainly with parenteral administration (diazepam, midazolam *, etc.). The mechanism of this effect is not yet clear.
In the spectrum of action of some tranquilizers, additional effects are sometimes distinguished, incl. vegetative stabilizing. The vegetative stabilizing effect is associated with the normalization of the functional activity of the autonomic nervous system. Clinically, this effect can be expressed in a decrease in autonomic manifestations of anxiety (instability of blood pressure, tachycardia, sweating, dysfunction of the gastrointestinal tract, etc.). Tofisopam, diazepam, gidazepam, etc. have a pronounced vegetotropic effect.
Benzodiazepine derivatives can exhibit all pharmacological properties characteristic of this group, however, the severity and ratio of effects in different benzodiazepines may be different, which determines the peculiarities of the clinical use of individual drugs.
According to the characteristics of the clinical action, benzodiazepine anxiolytics can be divided into 3 groups:
one). Benzodiazepines with anxiolytic predominance.
2). Benzodiazepines with a predominance of hypnotic effects.
3). Benzodiazepines with predominantly anticonvulsant action.
Phenazepam has a pronounced anxiolytic effect (it surpasses many benzodiazepines in terms of anxiolytic activity, including diazepam), diazepam, lorazepam, alprazolam, etc. Moderately expressed anxiolytic effect in chlordiazepoxide, bromazepam, gidazepamaz, clobazam and dr.
The sedative-hypnotic effect is especially pronounced in nitrazepam *, flunitrazepam *, flurazepam *, temazepam *, triazolam *, midazolam *, estazolam *, etc. and they are used mainly as hypnotics.
Anticonvulsant properties are typical for clonazepam, diazepam, and (to a lesser extent) for nitrazepam *, etc.
Muscle relaxant activity is characteristic of diazepam, chlordiazepoxide, lorazepam, tetrazepam, etc.
For some anxiolytics, a pronounced anxiolytic effect is characteristic with a relatively weak muscle relaxant and hypnotic (tofisopam, medazepam, etc.), and therefore they are more convenient for use in the daytime (the so-called daytime tranquilizers).
Benzodiazepine derivatives differ in their pharmacokinetics, which is also taken into account when prescribing these drugs. According to the duration of action (taking into account the effect of active metabolites), benzodiazepines can be classified as follows:
– long-acting (T1/2 – 24–48 h): diazepam, chlordiazepoxide, etc .;
– average duration of action (T1/2 – 6-24 hours): alprazolam, oxazepam, lorazepam, etc .;
– short-acting (T1/2 – less than 6 hours): midazolam * and others.
All benzodiazepines are lipophilic compounds. The lipophilicity of different substances of this group varies by more than 50 times, the most lipophilic of the benzodiazepines are diazepam and midazolam *.
When taken orally, benzodiazepines are well absorbed from the gastrointestinal tract, mainly from the duodenum (absorption depends on several factors, including lipophilicity). Diazepam and triazolam * are absorbed most rapidly, oxazepam and lorazepam are the least rapidly absorbed. Antacids can decrease the rate (but not the degree of absorption) of some benzodiazepines, incl. diazepam and chlordiazepoxide. After intramuscular administration, benzodiazepines are absorbed more slowly than when taken orally (with the exception of lorazepam and midazolam *, which are rapidly absorbed when administered intramuscularly).
The time to reach the maximum plasma concentration after a single dose for different drugs varies from 30 minutes to several hours. The equilibrium concentration in the blood during the course of benzodiazepine administration is usually achieved within a few days after the initiation of therapy (for benzodiazepines with a short and medium half-life) or within 5 days – 2 weeks (for drugs with a long half-life). Benzodiazepines and their metabolites are characterized by a high degree of binding to blood proteins, ranging from 70% (alprazolam) to 98% (diazepam).
High lipophilicity determines the penetration of these drugs through the BBB and other biological barriers, as well as a significant rate of redistribution from the central nervous system to tissues (adipose tissue, muscles). The volume of distribution of benzodiazepines is quite high.
The primary metabolism of benzodiazepines occurs in the liver. The exceptions are dipotassium clorazepate and flurazepam *, which are rapidly metabolized in the gastrointestinal tract and do not enter the systemic circulation in clinically significant amounts. The action is exerted by their active metabolites, which subsequently undergo biotransformation in the liver. Most benzodiazepines undergo microsomal oxidation in the liver, mainly by N-demethylation or hydroxylation to active or inactive metabolites. Then the metabolites undergo conjugation or further biotransformation.
In the process of metabolism, many benzodiazepines form the same active metabolites, some of them are used as independent drugs (oxazepam, etc.). The duration of the therapeutic effect for benzodiazepines with active metabolites is not determined by T1/2 initial substance, and T1/2 active metabolites. For example, T1/2 desmethyldiazepam (nordiazepam), which is an active metabolite of chlordiazepoxide, diazepam and dipotassium clorazepate, is, according to some data, more than 30-100 hours, according to others – 40-200 hours, which significantly exceeds the half-life of the starting substances.
Some benzodiazepines do not form active metabolites – lorazepam, oxazepam, temazepam *, etc. and undergo only the process of conjugation under the action of glucuronyl transferase with the formation of glucuronides.
Benzodiazepines (and their metabolites) are excreted mainly through the kidneys in the form of conjugates, less than 2% – unchanged, a small part – through the intestines.
Several pharmacokinetic parameters of benzodiazepines are age dependent. So, in elderly patients, the volume of distribution may increase. In addition, in elderly patients and children, the half-life may be lengthened.
The time of onset and the duration of the effects for benzodiazepine anxiolytics are not always associated with their half-life, but with the course of administration, these parameters are largely correlated. When taking repeated doses of benzodiazepines with prolonged T1/2 cumulation of the drug itself and / or its active metabolites occurs. This is associated with the aftereffect of drugs (diazepam, etc.). The accumulation of benzodiazepines with a short to medium half-life is usually minimal, and they are rapidly cleared from the body after the end of therapy.
The spectrum of clinical use of anxiolytics is mainly associated with their anti-anxiety action. Benzodiazepines are used for all types of anxiety disorders (they may be indicated for the treatment of anxiety conditions or for the short-term relief of symptoms of anxiety).
In psychiatric and neurological practice, anxiolytics are used in the treatment of neuroses, psychopathies, neurosis-like and psychopathic conditions, accompanied by anxiety, fear, increased irritability, emotional stress. For the relief of anxiety-phobic disorders (panic attacks, etc.), drugs with the most pronounced anxiolytic and anti-phobic effect are effective – alprazolam, lorazepam, phenazepam. Some benzodiazepine anxiolytics are used to relieve anxiety syndrome in endogenous mental illness, incl. with schizophrenia (as an adjuvant in the complex therapy) – diazepam, phenazepam, etc.
In acute conditions, for example, in order to relieve pronounced psychomotor agitation, parenteral administration of benzodiazepines (diazepam, phenazepam, etc.).
In acute alcohol withdrawal, anxiolytics (diazepam, oxazepam, phenazepam, chlordiazepoxide, etc.) are used as part of complex therapy to alleviate symptoms such as agitation, nervous tension, anxiety, anxiety, tremor, as well as to reduce the likelihood of development or signs, incl. h hallucinations, acute delirium.
For sleep disorders, benzodiazepines are used, which, along with anxiolytic, pronounced hypnotic effects (nitrazepam *, flunitrazepam *, triazolam *, temazepam *, etc.). They relieve emotional stress, reduce anxiety, anxiety and promote sleep. The use of benzodiazepines such as diazepam or phenazepam for sleep disorders is advisable in cases where insomnia is combined with daytime anxiety and it is desirable that the anxiolytic effect continues throughout the day.
Benzodiazepines with a pronounced anticonvulsant effect can be effective in the treatment of epilepsy, status epilepticus (clonazepam, diazepam, etc.), nitrazepam * – in some forms of seizures, especially in children.
Benzodiazepines, like other anxiolytics, are widely used in many areas of medicine: cardiology, anesthesiology and surgery, dermatology, etc.
Some benzodiazepines with a pronounced muscle relaxant effect (diazepam, chlordiazepoxide, etc.) are indicated for spastic conditions associated with damage to the brain or spinal cord, etc.
Benzodiazepines are used for sedation on the eve and immediately before surgical interventions and endoscopic procedures, for induction of anesthesia, for ataralgesia in combination with analgesics (flunitrazepam *, midazolam *, diazepam, etc.).
The use of some anxiolytics in healthy people can be justified in acute reactive stress conditions in extreme situations (fire, industrial disaster, earthquake, etc.). It should be borne in mind that anxiety or tension associated with everyday stress is not an indication for the appointment of anxiolytics, therefore, they should not be prescribed for any stressful conditions, in particular for grief reactions or somatic diseases.
The main contraindications for the appointment of benzodiazepines are individual hypersensitivity, severe hepatic failure, severe myasthenia gravis, glaucoma, severe respiratory failure, ataxia, suicidal tendencies, drug or alcohol dependence (except for the treatment of acute withdrawal symptoms).
Avoid taking benzodiazepines during pregnancy (especially in the first trimester) and during lactation.
Benzodiazepines cross the placenta easily. There is evidence that chlordiazepoxide and diazepam increase the risk of congenital malformations when administered in the first trimester of pregnancy. Other drugs in this group can also increase this risk, therefore, the prescription of benzodiazepine drugs during pregnancy should be approached very carefully and used only in the absence of an alternative, comparing the possible risk to the fetus and the benefits to the mother.
When prescribing benzodiazepines (clonazepam, diazepam, etc.) during pregnancy for women with epilepsy, it should be borne in mind that there are reports of an increase in the incidence of congenital malformations in children whose mothers have taken anticonvulsants during pregnancy, but there is a causal relationship between these facts have not yet been established. On the other hand, in women taking anticonvulsants (such as clonazepam), withdrawal before or during pregnancy is possible only in cases where seizures are mild and rare if untreated, and if the likelihood of an epileptic condition and withdrawal symptoms is assessed as low.
The use of benzodiazepine derivatives in the third trimester of pregnancy (especially in the last weeks) can lead to the accumulation of the drug in the tissues of the fetus, and as a result, to the depression of the central nervous system in newborns. At the same time, in newborns, muscle weakness, hypothermia, respiratory depression, and impaired sucking reflex may be noted.
Long-term use of benzodiazepines during pregnancy, incl. in advanced stages, may lead to physical dependence and withdrawal symptoms in the newborn.
Benzodiazepines are used with caution (only for strict indications) during labor, for example, parenteral administration of diazepam in preterm labor or premature placental abruption. Diazepam in low doses, as a rule, does not have an adverse effect on the fetus, however, the use of high doses can cause an irregular heart rhythm in newborns, a decrease in blood pressure, asthma attacks, muscle weakness, hypothermia, and other symptoms.
Since benzodiazepines pass into breast milk in significant quantities, drugs in this group should not be used by nursing mothers. In newborns, the metabolism of benzodiazepines is slower than in adults, as a result of which these drugs and their metabolites can accumulate in the body and cause sedation. However, feeding difficulties and weight loss in newborns are possible.
In therapeutic doses, benzodiazepines usually do not affect respiratory function, do not change blood pressure. However, in patients with obstructive pulmonary diseases, with sleep apnea syndrome, etc., while taking these drugs, the condition may worsen.
Parenteral administration of benzodiazepines, especially to elderly and senile patients, can lead to respiratory disorders (apnea) and cardiovascular function (hypotension, bradycardia, up to cardiac arrest).
It is not recommended to use benzodiazepines as the only treatment for anxiety in combination with depression or severe depression. suicidal attempts are possible (benzodiazepines can increase the manifestation of depression). However, some of the benzodiazepine anxiolytics (alprazolam, lorazepam, oxazepam) are effective in treating anxiety associated with depressive conditions of various origins (usually in combination with antidepressants).
Since most benzodiazepines undergo biotransformation in the liver, if its function is impaired, the duration of the therapeutic effect of these drugs may change, and serious side effects may occur. In this regard, special care should be taken when prescribing benzodiazepines to patients with impaired liver function.
The use of anxiolytics in children and adolescents under 18 is justified only in exceptional cases, with clearly justified indications, while the duration of treatment should be minimal.
Elderly and senile patients, debilitated patients, children (especially small ones) are usually more sensitive to the neurotropic effect of benzodiazepines. In particular, patients over 65 years of age should avoid the systematic use of benzodiazepines (especially long-acting), because taking these drugs can lead to undesirable consequences in the form of excessive sedation, dizziness, disorientation and coordination of movements. This can be the cause of falls of patients and related fractures.
Adverse side effects when taking benzodiazepines are signs of CNS depression, incl. daytime sleepiness, lethargy, muscle weakness, dullness of emotions, headache, dizziness, ataxia, etc. Cognitive impairment is possible (for example, with prolonged use of diazepam, phenazepam).
In connection with a decrease in the speed of psychomotor reactions, a weakening of concentration of attention, anxiolytics should be prescribed with caution on an outpatient basis, incl. patients whose work requires a quick mental and physical reaction, and is also associated with increased concentration of attention (vehicle drivers, etc.).
When taking benzodiazepine anxiolytics, paradoxical reactions are possible (acute agitation, anxiety, hallucinations, nightmares, bouts of rage, inappropriate behavior), which are more often manifested in children, elderly patients and mentally ill patients. If paradoxical reactions occur, the drug should be discontinued immediately.
After taking some, mainly long-acting drugs (for example, diazepam), aftereffect syndrome is possible (muscle weakness, decreased performance, etc.).
The use of anxiolytics can lead to the development of addiction (a decrease in the effect with prolonged use), as well as to the formation of drug dependence (physical and / or mental) and the occurrence of a withdrawal syndrome. The risk of dependence increases with long-term use (over 6 months), especially in high doses, as well as in patients with a history of drug and alcohol dependence.
With a sharp withdrawal of the drug against the background of drug dependence, a withdrawal syndrome may occur (tremor, convulsions, vomiting, excessive sweating), in severe cases – depersonalization, hallucinations, epileptic seizures (abrupt withdrawal in epilepsy).
It should be remembered that treatment with anxiolytics can only be carried out under the supervision of a physician. When prescribing benzodiazepines for the treatment of anxiety disorders, the principle of gradually increasing the dose should be observed – from the lowest effective to the optimal one for obtaining a therapeutic effect (except for acute conditions). The course of treatment should be as short as possible, after which a re-assessment of the patient’s condition is required to decide whether to continue therapy. Due to the possibility of the development of addiction and the emergence of drug dependence, the WHO Conciliation Commission (1996) does not recommend the use of benzodiazepine drugs continuously for more than 2-3 weeks. If long-term treatment is necessary (several months), the course should be carried out according to the method of intermittent therapy, stopping the intake for several days, followed by the appointment of the same individually selected dose. Withdrawal should be carried out by gradual dose reduction to reduce the risk of withdrawal.
When treating with anxiolytics, it is necessary to take into account the possible interaction of drugs of this group with other drugs. Anxiolytics potentiate the effects of other drugs that depress the central nervous system (narcotic analgesics, anesthetic drugs, hypnotics, antipsychotics with a pronounced sedative effect, antihistamines with a pronounced sedative effect), muscle relaxants, etc.
When taking anxiolytics, the use of alcoholic beverages is unacceptable, since alcohol enhances the depressing effect of drugs of this group on the central nervous system (which can be accompanied by severe side effects, including loss of consciousness, respiratory depression), in turn, tranquilizers increase the toxic effect of alcohol on the central nervous system. When used simultaneously with alcohol, in addition to increasing the depressing effect on the central nervous system, paradoxical reactions are possible (psychomotor agitation, aggressive behavior, a state of pathological intoxication).
The simultaneous use of benzodiazepines with other drugs that depress the central nervous system, as well as alcohol, can lead to overdose and life-threatening consequences (in case of a serious overdose, medical attention is required).
Symptoms of anxiolytic overdose can be depression of the central nervous system of varying severity (from drowsiness to coma), incl. severe drowsiness, lethargy, weakness, decreased muscle tone, ataxia, in more severe cases – prolonged confusion, inhibition of reflexes, coma, hypotension, respiratory depression are also possible. In case of intoxication with benzodiazepines, vomiting should be induced, it is possible to use activated charcoal, gastric lavage through a tube (if the patient is unconscious), symptomatic therapy, monitoring of vital functions is necessary, intravenous administration of fluids (to enhance urine output), if necessary – mechanical ventilation. Hemodialysis with benzodiazepine overdose is ineffective.
A specific antagonist of benzodiazepine receptors is flumazenil, a 1,4-benzodiazepine derivative with high affinity for benzodiazepine receptors. It competitively blocks benzodiazepine receptors and eliminates or reduces the severity of the central effects of substances that excite these receptors, but does not prevent the action of other drugs with a depressing effect on the central nervous system (barbiturates, opioids, etc.). The use of flumazenil as a specific antidote for benzodiazepine overdose is possible only in a hospital setting. It should be borne in mind that flumazenil is used as an additional, and not as the only agent. When administered intravenously, flumazenil acts quickly, but not for a long time (the effect of all benzodiazepines lasts longer), therefore, overdose symptoms may return. In addition, the development of epileptic seizures is possible (especially in patients taking benzodiazepines together with tricyclic antidepressants, in patients with epilepsy).
Despite the fact that benzodiazepines occupy a leading position in terms of the degree of study and breadth of application, other anxiolytics are also used in medical practice.
Until now, benzoclidine has not lost its value. Benzoclidine reduces the activity of cortical neurons and inhibits the activity of the reticular formation of the brainstem, lowers the excitability of the vasomotor center, and improves cerebral circulation. It is used in the treatment of anxiety disorders, incl. anxiety-depressive states (especially mild and associated with cerebral circulation failure). Especially indicated for elderly patients with atherosclerosis with cerebral disorders, arterial hypertension, paroxysmal tachycardia.
The return of interest in hydroxyzine is associated with the peculiarities of its pharmacological action. Hydroxyzine is an antagonist of central m-choline and Hone-histamine receptors. A pronounced sedative and moderate anxiolytic effect is manifested by inhibition of the activity of some subcortical structures of the central nervous system. Hydroxyzine is characterized by a fairly rapid development of anxiolytic action (during the first week of treatment), the absence of an amnestic effect. Unlike benzodiazepines, with prolonged use, hydroxyzine does not cause addiction and dependence, and there are no withdrawal or rebound syndromes. In addition to being used in the treatment of anxiety disorders, incl. with psychosomatic diseases, it is used for premedication, relief of alcohol withdrawal syndrome, as well as for itchy dermatoses.
Benactisin (a derivative of diphenylmethane) significantly differs from other anxiolytics, the anxiolytic effect of which is due to the reversible blockade of central m-cholinergic receptors. Due to the pronounced effect on the central cholinergic structures, benactisin is referred to the group of central anticholinergics. Its effect on the central nervous system is manifested by a sedative effect, inhibition of the convulsive and toxic effects of anticholinesterase and cholinomimetic substances, an increase in the action of barbiturates and other hypnotics, analgesics, etc. Currently, due to the presence of effective tranquilizers, as well as in connection with undesirable side effects, associated with atropine-like action (dry mouth, tachycardia, mydriasis, etc.), benactisin is practically not used as an anxiolytic.
A propanediol derivative (meprobamate) has no effect on benzodiazepine and cholinergic receptors. Its anxiolytic effect is associated with a depressing effect on various parts of the central nervous system, including the thalamus and the limbic system; the muscle relaxant effect is due to inhibition of the transmission of excitation in the region of the interneurons of the lateral horns of the spinal cord, thalamus and hypothalamus. In addition to the treatment of anxiety disorders, meprobamate is used for menopausal and premenstrual syndromes. It is less effective than benzodiazepines and has limited use at this time.
Representatives of the third generation anxiolytics are buspirone, oxymethylethylpyridine succinate (Mexidol), etc. The anxiolytic effect of Mexidol is associated with its modulating effect on membranes, incl. GABABUT-receptor complex, and is manifested by an improvement in synaptic transmission.
The mechanism of action of buspirone is not fully understood. Buspirone is a partial agonist of serotonin receptors, has a high affinity for serotonin receptors of the 5-HT subtype1A. Reduces the synthesis and release of serotonin, the activity of serotonergic neurons, incl. in the dorsal nucleus of the suture. In addition, it selectively blocks (antagonist) pre- and postsynaptic D2-dopamine receptors (has a moderate affinity) and increases the rate of excitation of dopamine neurons in the midbrain. Some data indicate that buspirone has an effect on other neurotransmitter systems. Buspirone is effective in the treatment of mixed anxiety-depressive states, panic disorders, etc. The anxiolytic effect develops gradually, manifests itself after 7-14 days and reaches a maximum after 4 weeks. Unlike benzodiazepines, buspirone does not have a sedative effect, does not adversely affect psychomotor functions, does not cause tolerance, drug dependence and withdrawal symptoms, does not potentiate the effect of alcohol.
In addition to drugs belonging to the group of anxiolytics, drugs from other pharmacological groups have an anti-anxiety effect to some extent: some beta-blockers (propranolol, oxprenolol, acebutolol, timolol, etc.), alpha-adrenergic agonists (clonidine). Thus, propranolol is effective in the treatment of anxiety states associated with hyperreactivity of the sympathetic nervous system and accompanied by a significant severity of somatic and autonomic symptoms, clonidine has the ability to reduce somatovegetative manifestations in withdrawal symptoms of opium addiction.
In the treatment of anxiety disorders, incl. with obsession, panic disorder, some antidepressants are indicated. In severe anxiety disorders, individual drugs from the group of antipsychotics give a pronounced effect.
At present, an intensive search continues for new drugs with anxiolytic effect and, at the same time, safer and more effective than existing drugs. Screening of benzodiazepine derivatives is aimed at identifying more selective drugs with the most pronounced anxiolytic effect with a minimum of side effects. The search is also carried out among substances that affect serotonergic transmission, antagonists of excitatory amino acids (glutamate, aspartate), etc.
Below is a list of anxiolytics:

  • Tetramethyltetraazabicyclooctandione
  • Alprazolam
  • Aminophenylbutyric acid (Acidum aminophenylbutyricum)
  • Diazepam
  • Dipotassium clorazepate
  • Lorazepam
  • Hydroxyzine
  • Morpholinoethylthioethoxybenzimidazole (Morpholinoethylthioethoxybenzimidazole)
  • Fabomotizol
  • Bromazepam
  • Bromdihydrochlorophenylbenzodiazepine (Bromdihydrochlorphenylbenzodiazepinum)
  • Tofisopam
  • Proxybarbal
  • Medazepam
  • Ethylmethylhydroxypyridine succinate (Aethylmethylhydroxypyridini succinas)
  • Tetrazepam
  • Chlordiazepoxide
  • Oxazepam
  • Benzoclidine
  • Buspirone
  • Etifoxine
  • Antibodies to brain-specific protein S-100 (Anticorpora ad proteino S-100 cerebrospecifico)