Amphetamine derivative, synthetic cathinone, and GHB precursor poisoning: clinical guidelines

List of Abbreviations

Terms and Definitions

Narcotic drugs are natural or synthetic substances and preparations included in the List of Narcotic Drugs, Psychotropic Substances, and Their Precursors Subject to Control in the Russian Federation.

Poisoning is a pathological condition that develops as a result of external (exogenous) exposure of a human or animal body to chemical compounds in amounts that disrupt physiological functions and pose a threat to life [1].

A psychoactive substance is any substance (or mixture of substances) of natural or synthetic origin that affects the functioning of the central nervous system, leading to alterations in mental state.

Stimulants—cathinones and phenethylamines—are two families that together constitute the largest group of new psychoactive substances (more than 270 substances monitored by the EMCDDA since 2005). Both families are linked by structural features based on the phenethylamine core (Fig. 1).

Figure 1. Chemical structure of phenethylamine

Phenylalkylamines are natural substances and their synthetic analogues that are derivatives of phenylethylamine, occurring as psychoactive alkaloids in several plants or obtained synthetically. Psychotropic substances of the phenylalkylamine group remain the most widespread. The best known among them are amphetamine, methamphetamine, ephedrine, mescaline, and MDMA.

Phenylalkylamines:

1. Natural phenylalkylamines:

1) Khat and its primary alkaloids (cathinone, cathine)

2) Mescaline and mescaline-containing plants ("Peyote") and their alkaloids (mescaline)

3) Ephedra and its primary alkaloids (ephedrine, pseudoephedrine, methcathinone, norephedrine)

1. Synthetic phenylalkylamines:

1) Amphetamines and their derivatives (MDA, MMDA)

2) Methamphetamines and their derivatives (MDMA)

3) Phenethylamines (2C-B, diapromide, zipeprol, methylphenidate)

4) Aminoketones (pyrovalerone)

5) Heterocycles

6) Synthetic analogues of ephedroids (pipradrol)

Cathinone is a controlled natural alkaloid of the Khat plant, prohibited from use in the Russian Federation and frequently encountered on the illicit market. Cathinone acts on the same receptors and via the same mechanisms as amphetamine. Essentially, cathinone is a natural amphetamine.

Mescaline is a controlled natural alkaloid obtained synthetically, semi-synthetically, or from the processing products of mescaline-containing cacti. Mescaline is prohibited for use in the Russian Federation and is widely found on the illegal market in the form of "peyote preparations" or active substance (salt form). Both the mescaline base, all its salt forms, and simple derivatives are prohibited. Mescaline is the "oldest" known and most studied "classic" hallucinogen; it has no medical use and is an illegal drug.

Ephedrine is a controlled natural alkaloid of the Ephedra plant, approved for legal use, and widely found on the illegal market in the form of derivatives (hydrochloride and sulfate).

Pseudoephedrine is a controlled natural alkaloid of the Ephedra plant, approved for legal use, and widely found on the illegal market, mainly in the form of derivatives (hydrochloride and sulfate).

Methcathinone (Ephedrone) is a controlled natural alkaloid of the Ephedra plant or, most commonly, a synthetic substance prohibited for legal use and widely found on the illegal market, primarily in the form of hydrochloride. It is a CNS stimulant chemically similar to methamphetamine. It has no medical use. Slang terms: "Jeff", "cosmos", "shirka".

Amphetamine is a controlled synthetic substance prohibited for medical use in the Russian Federation, found in the form of two controlled isomers (dexamfetamine and levamphetamine) and a controlled racemate. Despite the fact that in the Russian Federation amphetamine belongs to Schedule I and cannot be used in legal activities (except for analytical standards), in a number of countries this substance is included in pharmacopoeias in the form of sulfates. First synthesized in 1887 as an ephedrine analogue, it became widespread in medicine as a bronchodilator.

Methamphetamine is a controlled synthetic substance prohibited for legal use, most frequently encountered on the illegal market among other representatives of this class. Its effects are similar to methcathinone. It has approximately twice the potency of amphetamine.

α-Pyrrolidinovalerophenone (α-PVP, α-pyrrolidinopentiophenone) is a synthetic CNS stimulant belonging to the class of pyrrolidinophenones. Starting in 2010–2011, it appeared in illegal sales in the Russian Federation as a stimulant and entactogen [2].

Mephedrone (4-methylmethcathinone, 4-MMC) and its derivative klephedrone (4-chloromethcathinone, 4-CMC) have appeared on the illegal market since 2010 and are used as stimulants and/or MDMA substitutes. Mephedrone and its derivatives are produced in the form of powders, tablets, and capsules, and less commonly as liquids.

Gamma-hydroxybutyric acid (GHB) is a colorless, odorless, salty-tasting substance closely related to the inhibitory neurotransmitter (a chemical compound that transmits signals between nerve cells) GABA.

GHB precursors (1,4-butanediol and gamma-butyrolactone) are used as agents in household chemicals and industry, specifically in certain cleaning and cosmetic products [4].

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Poisoning by narcotic drugs and psychotropic substances is a chemical injury with impaired vital body functions resulting from exposure to a toxic dose of a narcotic drug or psychoactive substance, which include amphetamines, methamphetamines, synthetic cathinones, and GHB precursors.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The main causes of poisoning by drugs and psychodysleptics are recreational use, and less frequently, poisoning occurs as a result of accidental ingestion or criminal poisoning.

1.1.1. Etiology and pathogenesis of acute poisoning with amphetamines, methamphetamines, and their derivatives

The pharmacological effects of amphetamines are complex, but their primary mechanism of action is the release of catecholamines, specifically dopamine, norepinephrine, and serotonin, from presynaptic terminals, leading to a hyperadrenergic state. First and foremost, the mechanism of action of amphetamine is based on its effect on dopaminergic neurons. In presynaptic terminals, there are two pools of dopamine: the vesicular pool and the cytoplasmic pool. The vesicular store of dopamine and other biogenic amines is maintained by the acidic environment inside the vesicles and the maintenance of a stabilizing electrical gradient in the cytoplasm. This environment is maintained by an active adenosine triphosphate (ATP)-dependent proton transport system [5, 6]. Amphetamines enter the nerve cell either by passive diffusion or by exchange diffusion via the reuptake transporter, which is partially dose-dependent. At low concentrations, amphetamines release dopamine from the cytoplasmic pool via exchange diffusion at the site of dopamine reuptake transport in the membrane. At moderate concentrations, amphetamines cross the presynaptic terminal membrane and interact with neurotransmitter transporters on the vesicular membrane, inducing exchange-mediated release of dopamine into the cytoplasm. Subsequently, dopamine is released into the synapse via reverse transport at the site of dopamine reuptake [6, 7]. At high concentrations, an additional mechanism is activated as amphetamines cross cellular and vesicular membranes. Because amphetamines are bases, they alkalinize the vesicles, which allows dopamine to be released from the vesicles and delivered to the synapse via reverse transport [7, 8]. Amphetamines can also block catecholamine reuptake through competitive inhibition [9, 10]. However, this mechanism is considered secondary. Structurally, amphetamines resemble type A and B monoamine oxidase inhibitors (MAO-A and MAO-B inhibitors), making amphetamines weak monoamine oxidase inhibitors.

The selectivity of binding to neurotransmitter transporters largely determines the range of pharmacological effects of a specific amphetamine. The affinity of MDMA for serotonin transporters is 10 times greater than for dopamine and norepinephrine transporters; consequently, it exerts a predominantly serotonergic effect [11].

The most prominent effects of amphetamines are those caused by excessive catecholamine release and subsequent stimulation of numerous receptors, including α-adrenergic receptors, β-adrenergic receptors, dopamine, and serotonin. Most serotonergic neurons of the central nervous system (CNS) are located in the raphe nuclei. Serotonin in the CNS regulates a wide range of functions, including mood, memory, temperature regulation, sleep, and pain [12]. Serotonin is primarily responsible for the hallucinogenic and illusionary properties of amphetamines. Serotonin is also involved in the production of antidiuretic hormone, which can lead to hyponatremia, especially when taking amphetamines with potent serotonergic activity, such as MDMA [13]. Serotonin is also involved in the regulation of fluid secretion and intestinal peristalsis.

Norepinephrine is another important neurotransmitter associated with amphetamine use. Norepinephrine is present in the CNS and is also released from postganglionic sympathetic fibers. The main noradrenergic nucleus in the CNS is the locus coeruleus. Excess release of norepinephrine in the CNS during amphetamine intake leads to reduced fatigue and increased alertness. Excess norepinephrine in the peripheral nervous system leads to many of the symptoms observed with other sympathomimetic drugs, such as cocaine. Norepinephrine acts on adrenergic receptors (α and β), resulting in hypertension and tachycardia.

Dopamine also plays an important role in amphetamine use. Increased dopamine levels in the CNS, particularly in the neostriatum, mediate stereotyped behavior and other forms of motor activity [14, 15, 16, 17]. Dopamine activity in the neostriatum appears to be linked to glutamate release and the inhibition of efferent neurons responsible for gamma-aminobutyric acid (GABA) production [15, 17]. Stimulation of the glutamatergic system in the CNS contributes significantly to stereotyped behavior, motor activity, and the neurotoxicity of amphetamines [17, 18, 19]. The effects of serotonin and dopamine on the mesolimbic system alter perception, and cause psychotic behavior and anorexia [20, 21].

Phenethylamine is a structure with an ethyl group that has an aromatic group and a terminal amine. Specific substitutions made in the phenethylamine chain have led to a wide range of new drugs. Substitutions at various positions of the phenethylamine molecule alter the overall pharmacology and clinical effects of amphetamines, as confirmed by observations in both animals and humans. The addition of an extra methyl group to the terminal amine in amphetamine to yield methamphetamine significantly increases CNS activity. This additional methyl group also makes methamphetamine more lipophilic, providing faster penetration across the blood-brain barrier and increased resistance to degradation by monoamine oxidase. In addition, amphetamines with this methyl group also possess strong stimulant, cardiovascular, and anorectic properties [22]. The addition of a methoxy group at the 2nd or 5th position of the aromatic ring on an amphetamine or methamphetamine compound increases serotonergic activity. Another important substitution of the phenethylamine chain is the addition of a halogen group (such as iodine or bromide), which increases the potency of the compound and leads to it being considered more neurotoxic compared to non-halogenated compounds. This is thought to occur due to a significant decrease in serotonin levels, leading to irreversible neuronal damage. Since amphetamines directly interact with neurotransmitter transporters, minor changes in the molecule can significantly alter the pharmacological profile. The addition of an α-methyl group to amphetamines increases resistance to metabolism by monoamine oxidase. These characteristics provide better oral bioavailability and a longer duration of effect. The methyl group in the amphetamine structure also imparts chirality to the molecule. With the exception of MDMA and certain other amphetamines, d-enantiomers are generally 4 to 10 times more potent than l-forms of amphetamine. Chronic administration of certain amphetamines to animals leads to the depletion of dopamine and serotonin in neuronal synapses and causes the irreversible destruction of these neurons [23, 24, 25, 26, 27, 28]. The etiology of neuronal toxicity may be related to the generation of oxygen free radicals, leading to the formation of toxic dopamine and serotonin metabolites as well as neuronal destruction.

Pharmacokinetics.

Amphetamines can be administered intravenously, orally, intranasally, or by inhalation. All amphetamines are rapidly absorbed, with a bioavailability ranging from 60% to 90% depending on the route of administration. Peak serum concentrations are reached approximately 3 to 6 hours after intake.

Following absorption, amphetamines are distributed to most parts of the body. Amphetamines are relatively lipophilic and easily cross the blood-brain barrier. Amphetamines have large volumes of distribution, ranging from 3 to 5 L/kg for amphetamine, 3 to 4 L/kg for methamphetamine and phentermine, and 11 to 33 L/kg for methylphenidate.

Metabolism. Amphetamines are eliminated from the body via several pathways, including various hepatic transformation pathways and renal excretion. For MDMA and its analogues, N-dealkylation, hydroxylation, and demethylation are the dominant hepatic metabolic pathways. Depending on the specific amphetamine, active metabolites of amphetamines and ephedrine derivatives may be formed. N-demethylation of methamphetamine and MDMA leads to the formation of amphetamine and MDA, respectively. Dealkylation and demethylation are mainly carried out by CYP1A2, CYP2D6, CYP3A4, and flavin-containing monooxygenase. CYP2D6 polymorphism in humans has been identified in relation to differences in p-hydroxylation levels of amphetamines. Increased amphetamine toxicity is a potential concern in patients with reduced CYP2D6 activity. In general, since multiple enzymes and pathways (including renal ones) are involved in amphetamine metabolism, it is less likely that CYP2D6 polymorphism or drug interactions involving CYP3A4 alone will significantly enhance toxicity. However, it remains unclear whether toxicity is enhanced by the simultaneous action of multiple mechanisms affecting drug metabolism and renal impairment.

Excretion. Unchanged amphetamine (30%), methamphetamine (40-50%), MDMA (65%), and phentermine (80%) are excreted by the kidneys.

Amphetamines are bases with a pKa range of 9 to 10, and renal excretion depends on urine pH, with excretion increasing as pH decreases. The half-life of amphetamines varies significantly: amphetamine – 8 to 30 hours; methamphetamine – 12 to 34 hours; MDMA – 5 to 10 hours; methylphenidate – 2.5 to 4 hours; and phentermine – 19 to 24 hours. Repeated administration can lead to drug accumulation and an increase in half-life and duration of effect.

Table 1. Effective doses and duration of effects of amphetamines and their derivatives

Table 2. Toxicokinetic parameters of amphetamine and methamphetamine derivatives [29]

1.1.2. Etiology and pathogenesis of acute synthetic cathinone poisonings

Cathinone is a psychostimulant found in the leaves of the khat plant (Catha edulis). Khat is an evergreen shrub growing in a number of East African countries, the leaves of which contain cathinone and cathine, which exert psychoactive effects. Upon entering the body, cathinone and cathine disrupt the metabolism of norepinephrine, dopamine, and serotonin, leading to an increase in their concentration in the synaptic cleft and consequently exerting psychostimulant and hallucinogenic effects.

Synthetic cathinones were first synthesized in the second half of the 20th century, but only began entering the illegal market in 2012. The most popular ones in the Russian Federation are α-pyrrolidinovalerophenone, mephedrone, and clephedrone.

α-Pyrrolidinovalerophenone (α-PVP, α-pyrrolidinopentiophenone) is the most popular synthetic stimulant used on the illegal market in recent times.

The action of α-PVP is associated with an increase in the extracellular level of monoamines in the brain caused by the inhibition of dopamine and norepinephrine reuptake. In the Russian Federation, the turnover of α-PVP is prohibited as a derivative of N-methylephedrine and is controlled in 16 EU member states [3]. The chemical structure of α-PVP is a derivative of the chemical structure of N-methylephedrine, in which one hydrogen atom at the 3rd position of the side chain is replaced by a monovalent alkyl substituent—an ethyl group, and two hydrogen atoms of the methyl groups (one atom per methyl group) of the dimethylamino fragment are replaced by a divalent ethylene (ethane-1,2-diyl) substituent. Based on this, and in accordance with paragraph 6 of the notes to the List of Narcotic Drugs, Psychotropic Substances, and Their Precursors Subject to Control in the Russian Federation, as well as in accordance with the “Methodological approaches for classifying compounds as 'derivatives of narcotic drugs and psychotropic substances' in accordance with the Decree of the Government of the Russian Federation No. 1178 dated November 19, 2012,” objects of the α-PVP position are derivatives of N-methylephedrine, the turnover of which is under state control as the position “N-methylephedrine and its derivatives, excluding derivatives included as independent entries in the list.”

Synthetic cathinones use intranasal, oral, inhalation, injection (intramuscular or intravenous), and rectal routes of administration.

Synthetic cathinones are potent inhibitors of serotonin reuptake, as well as dopamine and norepinephrine reuptake.

1.1.3. Etiology and pathogenesis of acute GHB precursor poisonings

Gamma-hydroxybutyrate (GHB) is an endogenous compound that acts similarly to the neurotransmitter gamma-aminobutyric acid (GABA), with the highest concentration found in the thalamus, hypothalamus, and substantia nigra. Meanwhile, the cerebellum and certain areas of the cerebral cortex contain the lowest concentrations. Endogenous GHB is also found in the liver, kidneys, heart, bones, and skeletal muscles; nevertheless, its function in peripheral tissues is unknown. It has been observed that the fetal brain contains high concentrations of gamma-hydroxybutyrate, the concentration of which rapidly drops after birth [29].

GHB was first synthesized in 1964 as an analogue and agonist of GABA, in whose structure the amino group is replaced by a hydroxyl group. By chemical structure, gamma-hydroxybutyrate is a 4-carbon fatty acid chain with a carboxyl group at one end and a hydroxyl group in the gamma position (Figure 2).

Figure 2. Chemical structure of gamma-hydroxybutyrate and its precursors

Like GABA, γ-hydroxybutyrate induces excitatory, sedative, and analgesic effects. Nevertheless, GHB consumption poses certain risks due to significant dosing and the potential for adverse interactions with other sedatives and alcohol, and it may also lead to a decrease in GABA synthesis via negative feedback. Upon exogenous administration, GHB is rapidly absorbed, easily crosses the blood-brain barrier into the brain, and exerts a number of psychopharmacological effects; therefore, it was used in medicine as an anesthetic agent, but due to its unpredictable duration of action, it was banned for the treatment of narcolepsy. It may be used in the treatment of ethanol and opioid poisoning. In 1977, it was reported that GHB administration could increase growth hormone secretion during slow-wave sleep, which led to its use as a muscle-building supplement. It is known that γ-hydroxybutyrate has a pronounced antihypoxic effect and potentiates the action of analgesics, narcotics, and alcohol [29].

Recreational use of GHB gained popularity in the 1980s and 1990s, when bodybuilders used it for its purported anabolic effect in stimulating growth hormone. Cases of the substance being used for sexual assault and as a date-rape drug are described [30].

In accordance with the Convention on Psychotropic Substances, GHB was included in Schedule IV in 1971, and its circulation was restricted for use in the treatment of narcolepsy and cataplexy [3].

Due to restrictive measures introduced in the USA, Norway, France, Bulgaria, Italy, Latvia, Norway, Sweden, and Taiwan regarding GHB, a decrease in the number of hospitalizations of individuals with oxybate overdose has been observed over the past decade, yet the number of acute poisonings involving GHB precursors has increased [31].

1,4-Butanediol (1,4-BD) is an organic compound, a typical glycol, which is a colorless, viscous, low-volatility liquid with a sweetish taste. It belongs to non-electrolyte alcohols. Significant amounts of 1,4-butanediol are used in the pharmaceutical, cosmetic, textile, food, and electronic industries, as well as in the production of herbicides, paint solvents, and other organoleptic products. As a moisturizing component, the toxicant is used in the production of polymer film, gelatin, and paper. In everyday life, it is used for cleaning ventilation ducts and chimneys; in industry, it is used as a solvent for varnishes, paints, lubricants, and for paint stripping. Global production of 1,4-butanediol is about one million tons per year. It is also sold in solid form as needle-like crystals [29].

γ-Butyrolactone (GBL) is an organic compound, a hygroscopic, colorless, oily liquid with a faint, specific odor, soluble in water. It is a lactone that undergoes hydrolysis under alkaline conditions—for example, in a sodium hydroxide solution—into sodium γ-hydroxybutyrate, the sodium salt of γ-hydroxybutyric acid. It is used in industry as a solvent, including as a solvent for polyacrylonitrile and cellulose esters, as well as in organic synthesis—specifically in the synthesis of pyrrolidone and its N-alkyl derivatives and GHB—as a chemical solvent and reagent, flavoring agent, stain remover, and paint stripper [29, 31].

According to the World Health Organization (2012), 1,4-BDO and GBL are CNS depressants with euphoric and hypnotic effects. It should be noted that scientists attribute the main toxic effect to the plasma concentration of its primary metabolite, GHB [29, 31].

Mode of use: GHB and its analogs occur in liquid and powder forms with a mildly salty taste, which are dissolved in water or other beverages before use. GHB can enter the body via intravenous, intramuscular, rectal, and oral routes, while GHB precursors are taken orally. Toxicants are often used in combination with alcohol and certain drugs such as amphetamine, cocaine, and marijuana. GHB is rapidly eliminated from the body and can therefore be detected in blood plasma for only up to 4–5 hours after ingestion, and in urine for up to 8–10 hours after ingestion [31].

According to some authors, frequent daily use of GHB over several weeks leads to tolerance and withdrawal syndrome, representing physical dependence [32].

Mechanism of toxic action.

Most clinical manifestations are due to the direct action of GHB or its indirect action (via the conversion of GHB to GABA) at the GABA receptor, specifically the GABAβ receptor. Specific GHB receptors distinct from GABA receptors have also been identified; however, it is believed that action at these receptors does not significantly affect the CNS. In addition, it has been proven that GHB also affects other neurotransmitter systems, specifically dopaminergic, serotonergic, cholinergic, and noradrenergic systems. The greatest effects are manifested upon action on the dopaminergic system [31].

Toxicokinetics.

GHB and its precursors are rapidly absorbed and reach maximum blood concentration within 20 to 45 minutes. Following ingestion, GHB easily crosses the blood-brain barrier and affects the central nervous system (CNS). In the CNS, GHB is synthesized from GABA as a result of a transamination reaction. The catabolism of γ-hydroxybutyrate involves oxidation to succinic semialdehyde, followed by its entry into the Krebs cycle as succinate [31].

Animal studies have shown that GBL is absorbed more rapidly and completely, has a higher maximum concentration, and a shorter time to maximum concentration. At the same time, GBL hydrolyzes to GHB at alkaline pH values, and consequently, pH changes will lead to a shift in the GHB-GBL equilibrium under physiological conditions [31].

Studies in volunteers have shown that there are significant interindividual differences in the rate of 1,4-BD metabolism to GHB, possibly related to differences in alcohol dehydrogenase activity. Following the administration of 1,4-BD to volunteers at a concentration of 25 mg/kg body weight, its half-life was 39.3 ± 11 minutes, and the maximum plasma concentration of GHB was reached in 39.4 ± 11.2 minutes [33, 34].

1.3 Epidemiology of the Disease or Condition

In the 1960s, various amphetamines such as methylenedioxyamphetamine (MDA), paramethoxyamphetamine (PMA), and paramethoxymethamphetamine (PMMA) were widespread as hallucinogens. In the 1980s, methylenedioxy derivatives of amphetamine and methamphetamine appeared, the best known of which were 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyethylamphetamine (MDEA). High-purity methamphetamine hydrochloride was sold in a coarse crystalline form called "ice." Due to the simplicity and low cost of methamphetamine synthesis and local production, methamphetamine is the most common illicit drug produced by clandestine laboratories.

Later, synthetic cathinones sold as "bath salts" became widespread. Between 2005 and 2022, the appearance of more than 900 new psychoactive substances, referred to as "designer drugs," was recorded worldwide. In the early warning system (European Monitoring Centre for Drugs and Drug Addiction), synthetic cannabinoids (39.3%), synthetic cathinones (16.6%), and phenethylamines (14.1%) were the most prevalent. For combined use alongside GHB, patients most frequently use synthetic cathinones—MDVP (57.3%), amphetamine and methamphetamine (18%), and THC (9.8%) [35, 36].

1.4 Features of Coding the Disease or Condition

According to ICD-10:

T40.6 – Poisoning by other and unspecified narcotics

T40.9 – Poisoning by other and unspecified psychodysleptics [hallucinogens]

1.5 Classification of the disease or condition

Depending on the clinical presentation of the disease, acute poisonings vary in severity. When determining severity, only actual clinical symptoms must be taken into account, without assessing risk based on parameters such as the amount of poison ingested and serum drug concentrations. Criteria for assessing the severity of poisonings were proposed by the members of the European Association of Poisons Centres and Clinical Toxicologists (Appendix G1).

1.6 Clinical presentation of the disease or condition

1.5.1. Clinical picture of acute poisonings by amphetamines, methamphetamines, and their derivatives

The clinical picture of poisonings associated with amphetamine intake is the result of a hyperadrenergic state similar to that occurring with other sympathomimetics, such as cocaine, though the duration of the effect may be longer. Most patients with acute amphetamine intoxication exhibit central nervous system and cardiovascular system effects.

Cardiovascular toxicity from acute amphetamine use manifests as arterial hypertension, tachycardia, and rhythm disturbances ranging from premature ventricular contractions to ventricular tachycardia and ventricular fibrillation. Clinically, rhythm disorders, hypertension, myocardial ischemia, tachycardia, and vasospasm are observed.

Central nervous system manifestations include agitation, anorexia, bruxism, choreoathetoid movements, euphoria, headache, hyperreflexia, hallucinations, paranoid psychosis, and seizures.

Other sympathomimetic symptoms include diaphoresis, mydriasis, nausea, tachypnea, and tremor.

Complications may include acute respiratory distress syndrome, ischemic colitis, muscle rigidity, rhabdomyolysis, and intracerebral hemorrhage.

Laboratory abnormalities include elevated creatine phosphokinase, hyperglycemia, hyponatremia, leukocytosis, elevated liver enzymes, and myoglobinuria.

Seizures may be a direct result of amphetamine use or can occur secondarily as a result of hyponatremia, as reported with MDMA and certain synthetic cathinones [37].

1.5.2. Clinical presentation of acute synthetic cathinone poisonings

In acute cathinone poisoning, the clinical presentation is nonspecific. It may manifest as psychomotor agitation and/or hallucinations. In more severe cases, vital organ dysfunction is noted, including cerebral edema, delirious states, coma, cardiovascular and respiratory failure, and renal injury.

Toxic effects occur 10–20 minutes after intranasal administration with an expected duration of approximately 1–2 hours, 15–45 minutes after oral ingestion with a duration of 2–4 hours, and within 10–15 minutes with a 30-minute duration following intravenous administration.

Synthetic cathinones produce stimulant effects similar to those of cocaine, amphetamine, and MDMA: increased alertness, energy, and motivation, euphoria, agitation, mood elevation, openness and ease in communication, sociability and talkativeness, moderate sexual arousal, decreased appetite, and insomnia [38, 39, 40].

Side effects of cathinone use include a wide range of symptoms that can be divided into the following main groups:

Cardiovascular system disorders: tachycardia (over 120 beats per minute), palpitations, chest pain, hypertension (from 160/100 mm Hg), myocarditis, heart failure.

CNS disorders: prolonged cognitive impairment, mental fatigue, disorientation in space and time, irritability, aggression, anxiety, panic attacks, lack of motivation, depression, suicidal ideation and actions, visual and auditory hallucinations. Sleep architecture disruption and nightmares, insomnia, tremor, seizures, hyperthermia, mydriasis, blurred vision, headache, and dizziness. Some users report symptoms similar to Parkinson's disease—prolonged spasm, numbness, and loss of pain sensation [41]. Gait disturbances, hypomimia, and hypotonia have also been observed.

Hematopoietic system disorders: disseminated intravascular coagulation (DIC), thrombocytopenia [42, 43].

Gastrointestinal disorders: nausea, vomiting, anorexia, abdominal pain.

Other: profuse sweating, dry mouth, hyponatremia, hyperkalemia, elevated serum creatinine and creatine kinase, metabolic acidosis, and weight loss following prolonged use.

Of the synthetic cathinone adverse effects listed above, the most common are tachycardia, arterial hypertension, hyperthermia, insomnia, hallucinations, delirium, and confusion.

Psychiatric disorders have been reported primarily following the use of high doses either simultaneously or sequentially [44].

The clinical presentation of acute poisoning includes a wide range of symptoms that can be divided into the following main groups [45]:

• cardiovascular system disorders: tachycardia (over 120 beats per minute), palpitations, chest pain, hypertension (from 160/100 mm Hg), myocarditis, heart failure;

• CNS disorders: disorientation in space and time, motor restlessness, anxiety, visual and auditory sensory illusions, seizure syndrome, hyperthermia, mydriasis, blurred vision, headache and dizziness, prolonged spasm, numbness and loss of pain sensation, gait disturbance;

• hematopoietic system disorders: disseminated intravascular coagulation (DIC), thrombocytopenia, anemia;

• gastrointestinal disorders: nausea, vomiting, abdominal pain;

• other: profuse sweating, dry mouth, hyponatremia, hyperkalemia, elevated serum creatinine and creatine kinase, metabolic acidosis.

Chronic cathinone use can cause various adverse effects such as depression, anorexia, psychosis, memory impairment, cardiovascular complications up to myocardial infarction, gastritis, and liver failure. Similar to the action of amphetamine, cathinones can exacerbate psychiatric symptoms in individuals with pre-existing psychosis [46].

1.5.3. Clinical presentation of acute GHB precursor poisonings

The clinical picture of acute poisoning with GHB precursors depends generally on several factors: the dose of the toxicant, exposure time, and developed complications, primarily involving the CNS, respiratory, and cardiovascular systems. The patient's history of substance use is also of considerable importance in assessing severity, although at the pre-hospital and early hospital stages this factor is usually impossible to determine due to impaired patient consciousness.

Clinical symptoms of GHB intoxication typically include ataxia, confusion, seizures, vomiting, constricted pupils, bradycardia, and hypothermia. Furthermore, agitation, aggressiveness, hallucinations, and delirium are considered dangerous symptoms of acute GHB intoxication. Finally, CNS depression leads to coma and respiratory depression (Table 3) [33].

It should be noted that the clinical presentation of acute poisoning with GHB precursors differs somewhat from comas of other etiologies. The difference lies in the fact that the comatose state can abruptly alternate with periods of pronounced psychomotor agitation, followed by the development of a comatose state, which toxicologists describe as a "sleep and fight" state [47].

Unfortunately, toxicological studies are practically impossible to perform. The rapid metabolism of GHB, as well as its endogenous production in mammals, makes toxicity determination more difficult.

Table 3. – Degree of GHB effects on the body depending on the dose

Clinical manifestations of mild poisoning are similar to ethanol intoxication of a corresponding degree and are characterized by impaired intellectual, motor, and autonomic functions, manifesting as mild dizziness, decreased concentration, elevated mood, overestimation of capabilities, motor activity, and hypersexuality. Internal organ changes are virtually absent. In some cases, slight pupil dilation and reduced pupillary light reflex are observed [47].

Moderate poisonings are characterized by impaired consciousness to the level of sopor, down to 9 points on the Glasgow Coma Scale, hypodynamia, pale and dry skin, miosis, preserved coordinated defensive reactions to painful stimuli, preserved pupillary, corneal, swallowing, and deep reflexes, bradycardia, moderate arterial hypotension, tachypnea/bradypnea, and depressed bowel motility [47].

Severe poisoning is characterized by: encephalopathy of mixed (toxic and hypoxic) genesis, manifesting as coma and neurological disorders; respiratory failure of the aspiration-obstructive type (airway obstruction by tracheobronchial secretions, saliva, vomitus, tongue drop), and in advanced cases also of the central type; cardiovascular pathology (relative hypovolemia with the development of circular collapse); and acute metabolic disorders (metabolic acidosis). Metabolic disorders include hyperglycemia, hypokalemia, and hypernatremia; increased creatine kinase activity / myoglobinuria may be observed. ECG changes are described with U-wave formation, ST-segment shift, QRS complex widening, prolonged QTc interval, right bundle branch block, first-degree atrioventricular block, atrial fibrillation, and asystole in the most severe cases [47, 48, 49].

In GHB-induced coma, 3 degrees can be distinguished: superficial grades I and II, and deep grade III, which may occur with or without complications. Superficial grade I coma is manifested by depressed consciousness, decreased pain sensitivity, and weakened corneal and pupillary reflexes. Tendon reflexes are preserved. Muscle hypotonia, miosis, and periodic floating movements of the eyeballs are noted. Pale skin, bradypnea, tachy- or bradycardia, and hyper- or hypotension are characteristic. In superficial grade II coma, consciousness is completely lost; along with corneal and pupillary reflexes, the swallowing, cough, and tendon reflexes are also depressed; pain sensitivity is reduced. Minor signs of meningeal irritation, involuntary urination, and defecation are possible. Respiration is superficial and weakened. In some cases, mechanical asphyxia (tongue drop, aspiration) develops with stridor phenomena. Hemodynamic parameters: bradycardia, hypotension. It has been proven that the risk of aspiration and apnea is higher in patients with concomitant intake of GHB and other psychoactive substances, particularly alcohol. Deep grade III coma is characterized by further depression of CNS function, sharp suppression of all types of reflex activity, ophthalmoplegia, and the possible appearance of meningeal symptoms and pathological signs. The skin is pale and cold, and body temperature is reduced [47].

Emergence from coma occurs gradually with the restoration of reflexes and muscle tone. In the majority of victims, emergence from coma proceeds without psychomotor agitation and is characterized by drowsiness and adynamia [47].

In a number of cases, spontaneous awakening from coma occurs to a normal level of consciousness, or even hyperactivity. With psychomotor agitation, illusory and hallucinatory symptoms may be observed. Attacks of epileptiform seizures are possible [47, 49, 50].

In uncomplicated coma, positive dynamics with a marked decrease in coma depth are usually observed within 3–4 hours [51].

Complications of the toxicogenic stage of poisoning include the development of acute heart failure, acute respiratory failure, seizure syndrome, aspiration syndrome, and intoxication delirium [47, 52, 53, 54].

Delirium syndrome has a short pre-delirium period, develops with systematic prolonged use of the toxicant in individuals with polysubstance dependence, and has an atypical clinical picture and prolonged course, which distinguishes it from classic alcohol delirium. The average duration of delirium is 9.7 ± 1.3 days. The development of delirium syndrome is observed in the period following the termination of the toxicogenic stage of poisoning, on average 8.6 ± 1.3 hours from the time of the patient's admission to the hospital. In the pre-psychotic stage of delirium, contact with the patient is preserved, expressed as transient disorientation or incomplete orientation to location, animated facial expressions and sweeping movements, increased attention switching, rapid changes of opposite affects, and the anticipation of an "impending threat from the surrounding environment and medical staff." In this stage, fragmentary visual hallucinations of the "calling voices" type may be observed while maintaining a critical attitude toward them. In the full-blown (psychotic) stage of delirium, the clinical picture is characterized by signs of allopsychic disorientation, bewildered, restless, anxious-aggressive behavior with characteristic facial expressions of "terror." Hallucinatory experiences are predominantly visual, scenelike images, more often of "frightening, terrifying content," and auditory illusions of perception of the "conversation behind the wall" type; anthropomorphic "teasing" true visual hallucinations often predominate, either "luring closer to oneself" or "approaching the patient as close as possible." During the psychosis period, patients make repeated attempts to "outshout" imaginary "interlocutors," make defensive actions trying to close themselves with their hands, and "push them away." The patients' speech is characterized by inconsistency, incoherence, and an accelerated pace. Severe disorders of visuospatial orientation are observed. Somatoneurological disorders in delirium syndrome are observed in the form of dry skin, especially in the axillary and inguinal regions, a dry tongue, tachycardia up to 115.6 ± 1.15 beats/min, tachypnea of 23.2 ± 0.2 breaths/min, depression of intestinal peristalsis, and hyperthermia up to 37.1 ± 0.7 °C [47, 52, 53, 54].

2. Diagnostics, medical indications and contraindications for diagnostic methods

2.1 Complaints and Anamnesis

In the diagnosis of acute poisonings with psychotropic substances, one should rely on the following criteria: evidence of recent use of psychotropic substances (anamnesis); presence of symptoms and signs of poisoning (clinical picture of poisoning); and detection of psychotropic substances in biological fluids during chemical and toxicological examination (laboratory confirmation of the diagnosis).

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments. The patient's complaints depend on the type and dose of the narcotic drug. In a number of cases of acute poisonings with amphetamines, methamphetamines, synthetic cathinones, and GHB precursors, complaints are absent due to difficulty or impossibility of contacting the patient.

Comments. At the pre-hospital stage, a careful inspection of the scene of the incident is important, where various material evidence of the cause of poisoning and the type of toxic substance can be found. The obtained information must be reported by the ambulance medical personnel to the hospital physician upon patient hospitalization and reflected in the primary medical documentation.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments. Diagnosis of poisonings must be carried out on the basis of the toxicological situation (discovery of syringes, means for illegal drug manufacture, packaging from psychotropic substances, etc.), toxicological anamnesis aimed at identifying information about the use of narcotic drugs, other psychoactive drugs, dependence on certain substances, and the clinical picture of the poisoning. A feature of narcotic drug poisonings is the absence in most cases of subjective complaints on the part of the patient – medical assistance is usually sought by relatives or acquaintances who have noticed disturbances in their consciousness, behavior, or appearance.

2.2 Physical Examination

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments: Assessment of the skin, mucous membranes, and pupil size is essential for diagnosing adrenergic syndrome—characterized by mydriasis, accommodation disorders, dry skin and mucous membranes, hyperemia, and hyperthermia—as well as for identifying concomitant somatic pathology or injuries.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 4, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

2.3 Laboratory Diagnostics

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments. When using immunochromatographic assay (ICA), it should be taken into account that a negative result always indicates the absence of the target toxic substance in the sample, whereas a positive result, due to potential false positives (cross-reactivity), may lead to a diagnostic error and therefore requires verification by a more precise method such as GC-MS or HPLC-MS.

Currently, qualitative determination using ICA is available for the following narcotic drugs: morphine**, methadone, plant cannabinoids, amphetamine, methamphetamine, α-pyrrolidinovalerophenone, MDMA, cocaine, phenobarbital**, and benzodiazepine derivatives. Rapid diagnostics are performed using test strips to detect drugs in urine and saliva. Both mono-tests (one test per single psychoactive substance) and multi-tests (detection of up to 13 different psychoactive substances in a single test) can be used. ICA with photometric detection allows not only determining the presence of psychoactive substances but also estimating their approximate concentration. As noted earlier, the disadvantages of ICA include the possibility of false-positive results. Therefore, when positive or borderline results are obtained with ICA, confirmatory chemical-toxicological studies using definitive methods, namely GC-MS and/or LC-MS/MS, must be performed.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments: GC-MS is an accurate method for the qualitative and quantitative determination of psychotropic substances in biological media. The method also allows for untargeted analysis, i.e., simultaneously identifying a large number of various psychotropic substances. The HPLC-MS method is less accessible due to its high cost.

To detect and identify narcotic, psychoactive, and other toxic substances, a gas chromatograph coupled with a single-quadrupole mass spectrometer is used. Separation is performed using an HP-5ms capillary column (30 m × 0.25 mm × 0.25 µm). The mass spectrometer is operated under electron ionization conditions (EI, 70 eV) by registering the total ion current (TIC, 40–550 m/z). The injected sample volume is 1 µl.

Data processing is performed using the Automated Mass Spectral Deconvolution and Identification System (AMDIS) and component identification is confirmed using the general-purpose library of the National Institute of Standards and Technology (NIST).

Level of Reliability of Evidence (LRE) – 4, Level of Recommendation Validity (LRV) – C.

Comment. When determining amphetamine, methamphetamine, MDMA, and PVP, samples are analyzed without hydrolysis. For liquid-liquid extraction, a solvent mixture is used: isopropyl alcohol, dichloromethane, dichloroethane, heptane. At low concentrations of stimulants, derivatization with acyl reagents may be performed. A silylating derivatizing reagent is used to determine gamma-hydroxybutyric acid.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Evidence (LoE) – 5, Grade of Recommendation (GoR) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

2.4 Instrumental Diagnostics

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

2.5 Other Procedures

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments. Diagnosing acute poisoning by drugs and psychodysleptics (hallucinogens) is not particularly difficult if there is a clear history and a typical clinical picture. However, such situations are rare, and in practice, differential diagnosis with other pathologies is generally required. In patients admitted in an unconscious state, the following must be ruled out:

• traumatic brain injury;

• cerebrovascular disorders (acute and chronic);

• poisoning by other neurotropic poisons (barbiturates, benzodiazepine derivatives, opioids, etc.);

• infectious brain lesions (viral and bacterial meningitis, encephalitis);

• neoplastic and tuberculous brain lesions;

• metabolic comas (hypoglycemic, diabetic, hepatic, uremic);

• organic mental disorders.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1. Restoration (maintenance) of vital body functions

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments. In cases of aspiration-obstructive respiratory disorders, it is necessary to ensure upper airway patency using a combitube, laryngeal mask, or laryngeal tube, perform oral suction and remove mucus from the upper airways. If acute respiratory failure develops, initiate mechanical ventilation (MV) using various types of mechanical ventilators and manual ventilation bags. To stabilize hemodynamics, securing venous access and intravenous infusion and vasopressor therapy are indicated.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments. When acute respiratory failure develops during mechanical ventilation (in the absence of lung injury), use CMV (VC) or PCV (PC) as initial (starting) ventilation modes according to the following algorithm (against the background of sedation and/or muscle relaxation):

1. During CMV, set the tidal volume (Vt) equal to 6–8 ml/kg of predicted body weight (in PC mode – peak inspiratory pressure 18–20 cm H₂O); F = 8–12 breath/min; I/E ratio = 1:2; inspiratory flow rate 20–25 l/min (constant or sinusoidal flow waveform), PEEP = 3–5 cm H₂O, FiO₃ = 0.6.

2. If, against the background of the parameters specified in cl. 1, chest excursion is satisfactory, lung auscultation reveals breath sounds heard and transmitted on both sides, and oxygenation is adequate (PaO₂ ≥80 mmHg, SaO₂> 95%), the oxygen concentration in the inhaled gas mixture is reduced to the minimum level at which SaO₂ = 96–98%.

3. If chest movements are restricted and respiratory sounds are poorly transmitted, Vt is stepwise increased by 30–50 ml (or PiP by 2–3 cm H₂O) until a "normal" level of chest excursion and transmission of respiratory sounds bilaterally upon lung auscultation are achieved. After that, FiO₂ is decreased as indicated in clause 2.

4. If hyperventilation needs to be established, adjust the number of mechanical breath cycles until mild hyperventilation (PaCO₂ = 32–35 mmHg) or moderate hyperventilation (PaCO₂ = 25–30 mmHg) is achieved.

5. When increasing the I/E ratio to 1:1, it is necessary to increase the inspiratory flow rate until the I/E is reduced to at least 1:1.5.

6. Perform Vt "optimization" using the Vt/Paw curve analysis.

7. Evaluate the Flow/Vt loop and the Flow/Time curve. If the Flow/Vt loop is not closed and/or the expiratory part of the Flow/Time curve does not reach the baseline by the beginning of the next breath, reduce the inspiratory time (it may be necessary to simultaneously increase the inspiratory flow rate) until a fully closed Flow/Vt loop is obtained and the expiratory flow reaches the baseline of the Flow/Time curve by the end of expiration.

8. If necessary, change the oxygen concentration in the inspiratory gas mixture (to maintain oxygenation at a sufficient level) and set an automatic "sigh" (usually 3 times per hour, 1.5 × Vt).

Taking into account the above algorithm, the most commonly used respiratory support parameters in ventilatory acute respiratory failure (ARF) are presented in Table 4.

Table 4 - Most frequently used respiratory support parameters in ventilatory acute respiratory failure

To make a decision on withdrawing respiratory support, use the following main criteria: normalization of neurological status; patient's ability to initiate spontaneous breathing. During the withdrawal of respiratory support, it is necessary to constantly maintain adequate oxygenation (PaO₂ = 85–100 mmHg, SaO₂ = 96–98% at FiO₂ <0.4), PaCO₂ within 35–40 mmHg, and continuously monitor the patient's level of consciousness. After complete discontinuation of mechanical breath cycles, the ventilator is switched to CPAP mode with a positive pressure level of 3–4 cm H₂O.

Particular difficulties at this stage of respiratory support may arise in the following two cases: 1) the duration of mechanical ventilation was 8 days or more; 2) the patient has apallic syndrome (vegetative coma). In such situations, the most optimal option for adapting patients to spontaneous breathing is the use of the BiPAP + MMV protocol according to the following method:

1) The lower positive pressure level (EPAP) is set within 3–4 cm H₂O, and the upper level (IPAP) at 6–8 cm H₂O.

2) The target level of mandatory minute ventilation (MMV) is determined based on 150–200 ml/kg/min of ideal body weight.

3) The IPAP level is gradually decreased (by 1 cm H₂O every 4–5 hours) down to the EPAP value.

4) Switch the ventilator to CPAP mode with a positive pressure level of 2–4 cm H₂O. If necessary, the MMV mode can be continued.

On average, the duration of the BiPAP + MMV protocol is 18–24 hours.

If the condition is stable (no increase in respiratory failure symptoms and/or neurological deficit), the patient can be extubated and completely transferred to spontaneous breathing with humidified oxygen delivery (FiO₂ = 0.3–0.35) for 3–4 hours [8, 18, 38, 41, 51, 56].

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Level of Reliability of Evidence (LRE) – 4, Level of Recommendation Validity (LRV) – C.

3.2. Management of psychomotor agitation

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments. Restraint must be performed with utmost care, using soft, non-traumatic means (sheets, towels, cloth straps, etc.). Every limb and the shoulder girdle must be securely restrained; compression of nerve trunks and blood vessels must be avoided. The restrained patient must remain constantly within the staff's field of vision. Restraint does not replace supervision; on the contrary, it requires continuous monitoring of the patient's condition. The use of patient restraint requires mandatory documentation in medical records.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments. Instead of #diazepam**, patients over 18 years of age may be prescribed bromdihydrochlorphenylbenzodiazepine** solution, 0.5–1 mg IV or IM, maximum daily dose 3–5 ml.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

3.3. Detoxification therapy

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments: The total volume of infusion therapy is 1000–1500 ml per day. In lithium poisoning, it is necessary to restore circulating blood volume due to fluid loss through the gastrointestinal tract. To achieve this, sodium chloride** is administered at a rate 1.5–2 times higher than required for maintenance therapy, which helps increase renal blood flow, urine output, and poison elimination.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comments. In case of deep consciousness depression, tracheal intubation and, if necessary, initiation of mechanical ventilation are indicated prior to gastric lavage. Measures to stabilize hemodynamics and stop seizures are also required. The tube size for adults and adolescents is F36–40, and for children, F22–28. During tube insertion, the patient should be either in a sitting position or lying on the left side with the chin pressed against the chest. The correct placement of the tube is verified by injecting air with a Janet syringe (breath sounds should be audible in the stomach upon auscultation). A single water dose for a child is 10 ml/kg, up to a maximum of 250 ml. A single water dose for an adult is 250 ml. The recommended total volume of water for tube gastric lavage:

- in infants under 1 year – up to 1 L.

- in children aged 2–5 years – up to 3 L.

- in children aged 6–10 years – up to 4 L.

- in children over 10 years – up to 5 L.

- in adults – up to 10 L.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

Comment. Activated charcoal is the most commonly used intestinal adsorbent. Other intestinal adsorbents that may also be used include colloidal silicon dioxide (per instructions), povidone (per instructions), hydrolytic lignin (per instructions), etc. In lithium poisoning, the use of intestinal adsorbents is impractical as they are practically unabsorbed.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

In uncomplicated cases of acute psychoactive substance poisoning (amphetamines, methamphetamines, synthetic cathinones, and GHB precursors), rehabilitation is not required.

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

5. Prevention and Dispensary Observation

Level of Reliability of Evidence (LRE) – 5, Level of Recommendation Validity (LRV) – C.

6. Organization of Medical Care

6.1. Indications for hospitalization

Patients with acute psychoactive substance poisoning (amphetamines, methamphetamines, synthetic cathinones, and GHB precursors) should preferably be hospitalized in a specialized acute poisoning center. In mild cases of acute poisoning, hospitalization in an acute poisoning unit or toxicological beds of a hospital is advisable. Patients with severe poisoning, in the absence of an acute poisoning center and the presence of complications—especially with impaired vital functions—should be hospitalized in an intensive care unit or an emergency hospital intensive care ward, with subsequent transfer to an acute poisoning center or, upon stabilization, to a specialized department.

Criteria for hospital discharge include restoration of consciousness, normalization of spontaneous breathing and hemodynamics, and normalization of homeostasis parameters.

6.2. Indications for patient discharge from the hospital

Treatment in the intensive care unit is carried out until vital function impairments stabilize and detoxification measures are completed, followed by rehabilitation measures in the acute poison treatment center, therapeutic, and pediatric departments.

The duration of hospitalization is determined by the severity of poisoning. Treatment in mild cases lasts on average up to 2 days; in moderate and severe poisonings, the patient is hospitalized in the intensive care unit until detoxification measures are completed and the patient's condition stabilizes. The length of stay in the intensive care unit in severe uncomplicated cases is 3–5 days; in complicated cases, the hospitalization period is up to 10 days or more, followed by rehabilitation in an acute poisoning unit for up to 14 days or more.

7. Additional Information

Factors influencing the disease outcome:

1. General hypothermia below critical levels in individuals with narcotic coma found outside enclosed heated spaces during the cold season.

2. Terminal-stage chronic drug intoxication with signs of multiorgan failure (hepatic, cardiovascular, metabolic disorders), cardiomyopathy, hepatitis B, C, or HIV infection.

Criteria for Evaluating the Quality of Medical Care

Table 5 – Criteria for assessing the quality of medical care

References

Appendix A1. Working Group Composition

1. Lodyagin, Alexey Nikolaevich – MD, PhD, Associate Professor, Chief Freelance Toxicologist of the Northwestern Federal District, Head of the Department of Clinical Toxicology, St. Petersburg I.I. Dzhanelidze Research Institute of Emergency Care.

2. Shikalova, Irina Anatolyevna – PhD in Medicine, Senior Researcher at the Department of Clinical Toxicology, St. Petersburg I.I. Dzhanelidze Research Institute of Emergency Care.

3. Sinenchenko, Andrey Georgievich – PhD in Medicine, Head of the Department of Emergency Psychiatry, Addiction Medicine and Psychorehabilitation, St. Petersburg I.I. Dzhanelidze Research Institute of Emergency Care.

4. Reynyuk, Vladimir Leonidovich – MD, PhD, Associate Professor, Acting Director of the Academician S.N. Golikov Scientific and Clinical Center of Toxicology of the Federal Medical-Biological Agency.

5. Batotsyrenov, Chimit Bairovich – Full-time PhD student at the Academician S.N. Golikov Scientific and Clinical Center of Toxicology of the Federal Medical-Biological Agency, anesthesiologist-intensivist at the St. Petersburg I.I. Dzhanelidze Research Institute of Emergency Care.

6. Balabanova, Olga Leonidovna – PhD in Medicine, Senior Researcher at the Department of Clinical Toxicology, St. Petersburg I.I. Dzhanelidze Research Institute of Emergency Care.

7. Oleg A. Kuznetsov – Candidate of Medical Sciences, Researcher at the Department of Clinical Toxicology, Saint Petersburg Research Institute of Emergency Medicine named after I.I. Джанелидзе.

8. Makarovskaya, Natalia Petrovna – Full-time PhD student at the Department of Emergency Medical Care and Injury Surgery, Academician I.P. Pavlov First St. Petersburg State Medical University, anesthesiologist-intensivist at the St. Petersburg I.I. Dzhanelidze Research Institute of Emergency Care.

9. Narziculov Rustam Abdukhalimovich – Doctor of Medical Sciences, Researcher at the Department of Clinical Toxicology, St. Petersburg Research Institute of Emergency Care named after I.I. Janelidze.

10. Semyon V. Kuznetsov – Ph.D. in Medicine, Associate Professor, Leading Researcher at the Scientific and Clinical Center of Toxicology named after Academician S.N. Golikov of the Federal Medical-Biological Agency (FMBA of Russia), Senior Researcher at the Department of Clinical Toxicology, Saint Petersburg Research Institute of Emergency Medicine named after I.I. Dzhanelidze.

11. Antonova Anna Mikhailovna – Candidate of Medical Sciences, Researcher at the Department of Clinical Toxicology, Saint Petersburg I.I. Dzhanelidze Research Institute of Emergency Medicine.

There is no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines:

1. general practitioner (family physician);

2. psychiatrist-narcologist.

3. emergency and critical care physician;

4. forensic medical expert;

5. functional diagnostics physician;

6. anesthesiologist-intensivist;

7. infectious disease physician;

8. cardiologist;

9. laboratory diagnostic physician;

10. neurologist;

11. neurosurgeon;

12. otorhinolaryngologist;

13. district general practitioner;

14. internist;

15. toxicologist;

16. transfusiologist;

17. surgeon;

18. endoscopist;

Methodology for Developing Clinical Guidelines

The working group members independently performed a systematic search and selection of publications. The search was conducted in the PubMed search engine (http://www.ncbi.nlm.nih.gov/pubmed/), the Cochrane Library (http://www.cochranelibrary.com/), the eLIBRARY.ru scientific electronic library (http://elibrary.ru/defaultx.asp), as well as clinical trial registries: https://clinicaltrials.gov/ and https://www.clinicaltrialsregister.eu/ctr search/search. A total of 220 publications were found, of which 116 were selected. Based on the selected publications, consensus recommendations were formulated and graded using the scales for assessing the levels of evidence and diagnostic methods, the levels of evidence ((LEVEL OF EVIDENCE)) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions), and the grades of recommendation (GRADE OF RECOMMENDATION) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions). (Table 3, Table 4, Table 5) Subsequently, each consensus recommendation was thoroughly discussed at a general meeting of the working group, and a consensus was reached in all cases of disagreement.

Table 1 – Scale for assessing the levels of evidence (LEVEL OF EVIDENCE (LoE)) for diagnostic methods (diagnostic interventions)

Table 2 – Scale for assessing the levels of evidence (LoE) for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

Table 3 – Scale for grading the recommendations (GoR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The clinical guidelines update mechanism provides for their systematic revision—at least once every three years, as well as upon the emergence of new evidence-based data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. Order of the Russian Ministry of Health No. 289 dated October 5, 1998, "On Analytical Diagnostics of Narcotic Drugs, Psychotropic and Other Toxic Substances in the Human Body."

2. Order of the Ministry of Health and Social Development of Russia No. 40 dated January 27, 2006, "On the Organization of Chemical and Toxicological Studies for the Analytical Diagnostics of Alcohol, Narcotic Drugs, Psychotropic and Other Toxic Substances in the Human Body".

3. Order of the Russian Ministry of Health No. 925n dated November 30, 2012, "On Approval of the Procedure for Providing Medical Care for Acute Chemical Poisoning."

4. Order of the Ministry of Health of the Russian Federation No. 203n dated May 10, 2017, "On approval of criteria for assessing the quality of medical care." (In Russ.)

5. Order of the Russian Ministry of Health No. 804n dated October 13, 2017, "On Approval of the Nomenclature of Medical Services".

6. Federal Law No. 489-FZ of December 25, 2018, "On Amendments to Article 40 of the Federal Law 'On Compulsory Medical Insurance in the Russian Federation' and the Federal Law 'The Fundamentals of Healthcare Protection in the Russian Federation' Regarding Clinical Practice Guidelines."

7. Order of the Russian Ministry of Health No. 103n dated February 28, 2019, "On Approval of the Procedure and Deadlines for the Development and Revision of Clinical Guidelines, Their Standard Template, and Requirements for Their Structure, Composition, and Scientific Validity of Information Included in Clinical Guidelines".

8. Order of the Russian Ministry of Health No. 919n dated November 15, 2012, "On Approval of the Procedure for Providing Medical Care to Adult Patients Profiled in 'Anesthesiology and Reanimatology'"

9. Decree of the Government of the Russian Federation No. 2406-r dated October 12, 2019 (as amended on April 16, 2024) "On Approval of the List of Vital and Essential Medicines, as well as Lists of Medicinal Products for Medical Use and the Minimum Assortment of Medicinal Products Required for the Provision of Medical Care"

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

In cases of mild and moderate acute poisoning with psychotropic agents, the patient is informed about the health hazards of these toxic substances, potential complications, long-term consequences of poisoning, planned examinations (chemical-toxicological, clinical-biochemical, instrumental), and treatment (detoxification methods, pathogenetic and specific therapy). The patient (or their legal representative) signs an informed voluntary consent for the proposed scope of examination and treatment.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Poisoning Severity Score

Table specifications:

Russian title: Poisoning severity score

Original title: Poisoning severity score

Source: https://www.who.int/publications/m/item/poisoning-severity-score

Type: Rating scale

Purpose: for quantitative assessment of the severity of acute poisonings.

Contents:

Explanation: The patient's condition, according to the Poisoning Severity Scale, is assessed by the degree of organ and system damage. The occurrence of a specific symptom is checked against a scale that lists vital systems: cardiovascular, respiratory, nervous, circulatory, and gastrointestinal tract, as well as organs involved in the elimination of the toxic agent: liver and kidneys; the muscular system, local toxic effects on the body, and metabolic disorders associated with the toxicant are also evaluated. The severity grade is determined by the dominant symptom.

Appendix G2. Glasgow Coma Scale

Table specifications:

Russian name: Glasgow Coma Scale

Original name: Glasgow Coma Scale

Source: https://www.glasgowcomascale.org

Type: Rating scale

Purpose: For the quantitative assessment of the severity of coma and neuropsychiatric disorders related to impaired consciousness of any etiology.

Contents:

Key:

15 points – clear consciousness

10–14 points – moderate and deep obtundation

8–10 points – stupor

6–7 points – moderate coma

4–5 points – terminal coma

3 points – brain death

Explanation: The patient's condition according to the Glasgow Coma Scale is evaluated based on three parameters, each scored in points. The points are summed. The sum of the three responses ranges from 3 (deep coma) to 15 points (conscious patient).

Appendix G3. Richmond Agitation-Sedation Scale (RASS)

Russian title: Richmond Agitation-Sedation Scale.

Original title: The Richmond Agitation-Sedation Scale (RASS).

Source (official developer website, validation publication): Sessler C.N., Gosnell M.S., Grap M.J., Brophy G.M., O'Neal P.V., Keane K.A., Tesoro E.P., Elswick R.K. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am. J. Respir. Crit. Care Med. 2002; 166 (10): 1338 - 1344.

Type: Rating scale

Purpose: The scale is used to describe the degree of a patient's psychomotor agitation or the depth of sedation. It is widely used in patients on mechanical ventilation to avoid inadequate or excessive sedative effects from medications. The scale allows for assessing the efficacy of ongoing therapy. The scale is easy to use, allowing the patient's condition to be assessed within 30 - 60 seconds using three consecutive steps: observation, response to verbal stimulation, and response to physical stimulation. The use of RASS may be difficult in patients with severe hearing and visual impairments.

Contents:

Key (interpretation):

RASS Assessment Procedure

1. Patient observation

- If the patient is awake, calm, and attentive – 0 points.

- If the patient exhibits behavioral signs characterized by anxiety or agitation – a score from +1 to +4 points using the criteria listed in the description.

2. If the patient is somnolent, ask them in a loud voice, calling them by name, to open their eyes and look at you. Repeat this several times if necessary. Ask the patient to maintain eye contact.

- If eye contact with the patient is possible and maintained for more than 10 seconds – a score of –1 point.

- If eye contact with the patient is possible, but not maintained for 10 seconds – a score of –2 points.

- If the patient makes any movement in response to voice, excluding eye contact – a score of –3 points.

3. If patient does not respond to voice, physically stimulate patient by shaking shoulder and/or rubbing sternum.

- If the patient responds with any movement to physical stimulation – a score of –4 points.

- If the patient does not respond to voice or physical stimulation – a score of –5 points.