Synthetic analogs of drugs such as methamphetamine and cocaine were legally sold as “bath salts” between 2010 and 2013. Synthetic cathinones are β-ketophenethylamines, which are structurally similar to amphetamines and are therefore abused. Cathinone, and to a lesser extent its metabolite—cathine—are responsible for the amphetamine-like euphoric effects, which are achieved by chewing the leaves and twigs of the khat plant (Catha edulis). Many psychoactive substances, including mephedrone, methylenedioxypyrovalerone (MDPV), methylone, butylone, and naphirone, have been identified in the newer products, so-called bath salts. Cathinone, mephedrone, methcathinone, and methylone have been shown to strongly inhibit the reuptake of dopamine, serotonin, and noradrenaline. These substances also increase the presynaptic release of the same monoamines, but to a lesser extent (6, 7). The literature offers limited data on the pharmacokinetics and pharmacodynamics of synthetic cathinones in humans.

Penders and Gestring (8) describe the case of three people who consumed bath salts. The patients suffered from hallucinations, were hyperactive and aggressive, and had insomnia. Two of them were treated with risperidone orally at a dosage of 0.5 mg twice daily. One of the men was given 1 mg of haloperidol. After 2–3 days of therapy, the symptoms of paranoia subsided (8).

Antonowicz et al. (6) describe the case of a 27-year-old girl and her 32-year-old boyfriend who were brought to a hospital after reporting to the police that they were under attack. Police officers found them barricaded in the bedroom, claiming that there was a corpse in the hallway and that they had been killed. Upon reaching the emergency room, they had tachycardia, were scared, and were perspiring profusely. Blood and urine counts were normal. They were transferred to a psychiatric ward where they were monitored. The woman was given 0.5 mg of risperidone; the man was not administered any antipsychotic drugs during his hospital stay. The patients admitted that they had been consuming an illegally obtained drug, Suboxone. Then they started taking a product called “Powdered Rush.” They were ingesting it by inhalation for 5–6 days before being admitted to the hospital. The substance ingested by the couple contained MDPV and was marketed as “bath salts” (6).

Mangewala et al. (9) cite the case of a 15-year-old boy with no prior psychiatric history. He reported to the emergency room complaining of agitation and psychotic symptoms. The patient had reportedly smoked marijuana laced with bath salts. Soon afterwards, the patient became paranoid and barricaded himself in his father's house. The police were called to forcibly enter the house and the patient was taken to the emergency room. The patient's agitation continued to worsen and laboratory tests revealed an elevated level of creatine phosphokinase (CPK). The urine toxicology report was negative. The patient was treated in a hospital intensive care unit (ICU) where he continued to exhibit psychotic and agitated behavior, at one point attacking a staff member. He returned home a few days later once his health had stabilized, although at home he was still showing signs of paranoia. When the patient presented again with symptoms of paranoia a month later, his father took him back to the hospital, where he was referred for psychiatric hospitalization. During the first interview, during which he was non-verbal, the patient was diagnosed with periods of extreme psychomotor impairment. In another situation, he seemed confused, and kept repeating questions to himself. He made paranoid statements such as, “Don't let them take me!” and “How do I get out of this?” The patient reported that nothing around him was real. He claimed that his father had been replaced by an impostor, and that his sister had been hurt by unknown parties. During the interview, he was able to admit that some part of his paranoia was not real. He reported fear but denied any thoughts, intentions, or plans that were suicidal or homicidal in nature. The patient's family was also interviewed and denied that the patient had any history of psychiatric problems or similar behavior. In addition, they reported no history of head injuries or epileptic seizures and no family history of psychiatric illness. However, they declared that the patient had used marijuana in the past without any negative side effects. As mentioned earlier, the patient stated that, to his belief, he was smoking marijuana mixed with “bath salts.” While hospitalized, the patient was treated with a combination of 5 mg of olanzapine once daily and 0.5 mg of lorazepam twice daily. The dose of olanzapine was increased to 7.5 mg per day, which combined with the lorazepam reduced the symptoms of psychosis and agitation. He began to interact with his peers. The symptoms of paranoia resolved within 3 days of treatment and the patient was discharged with a prescription for 7.5 mg of olanzapine once daily, 0.5 mg of lorazepam twice daily, and outpatient follow-up. He had no recurrence of symptoms during the 8-week follow-up period. He denied continued use of the substance. No further adjustments in dosage were required (9).

Lenz et al. (10) report the story of a 22-year-old man who found himself in the Emergency Department (ED) after ingesting 1 g of a substance which he called Cristalius the previous night. Mephedrone and a synthetic cathinone derivatives were presumed as the main ingredients.

That morning, after running three miles to start his intense physical exercise, he felt dizzy and light-headed. He was transported to his military aid station and had a brief syncopal episode on the way. He woke up at the aid station confused and belligerent, and therefore had to be handcuffed. Eventually, he calmed down enough to be taken to the hospital, but had a tachycardia of up to 173 beats per minute during the transport. After arriving at the ED, he was given 2 mg of lorazepam for sedation. He remained confused. His heart rate slowly returned to normal, and within 3 h it had dropped to 100 beats per minute with a blood pressure of 129/50 mmHg. He was aware of people, his surroundings, and the time and was less anxious, though he complained of fatigue. The clinically significant laboratory results at that time were a creatine kinase level of 668 U/l (norm: 25–200), a creatinine level of 1.35 mg/dl (norm: 0.66–1.25), and a troponin level of 0.516 ng/ml (norm: 0.0–0.034). One week prior to his admission to the hospital, the patient's urine screening test was positive for amphetamines. He claimed it was because he had borrowed Adderall from a friend, but tested negative for the drug while hospitalized. Intravenous hydration was also initiated; his creatinine levels dropped to 0.97 and his creatine kinase levels rose to 1544. The patient, however, remained asymptomatic with no muscle pain. He only confessed to using marijuana in high school and denied taking any other illegal substances before using Cristalius twice. He denied any past or current symptoms of mood disorders or post-traumatic stress. He refused a positive drug test on his ward and stated that he consumed his last alcoholic drink 6–7 months earlier. At the time of discharge, the patient was stable and asymptomatic (10).

Nervous system stimulants, including methamphetamine and cocaine, are responsible for permanent changes in the dopaminergic reward system in the brain. This causes persistent dysphoria after drug withdrawal (11). There are also psychoactive substances that produce a psychotic syndrome similar to schizophrenia. Usually, these symptoms disappear with treatment, but a few cases of persistent hallucinations have been reported after stopping amphetamine use. Electroshock has been shown to alleviate these types of hallucinations. Synthetic cathinones, which are also stimulants, cause similar symptoms as the above-mentioned products. The case of a patient who was abusing MDPV for several months has been described. He suffered from persistent symptoms of psychosis, visual hallucinations, suspicion, and social withdrawal. After unsuccessful attempts at antipsychotic treatment, electroconvulsive therapy was performed (12).

Penders et al. (12) report the case of a 26-year-old woman who suffered from severe hallucinations and social withdrawal. These symptoms had appeared 8 months earlier, after she had taken bath salts, and persisted even after the substance was no longer being consumed. The patient had been using these substances for 13 months before being admitted to the hospital, but the first hallucinations began 5 months later. There were no serious mental disorders in her family medical history. No improvement was observed under prior treatment with haloperidol and risperidone; minimal improvement was noted only after the administration of 120 mg of lurasidone nightly. The patient was also prescribed 40 mg of citalopram and 300 mg of trazodone for sleep. Before commencing a modified bilateral electroconvulsive therapy, the patient was subjected to general anesthesia consisting of intravenous injection of 100 mg of methohexital and 100 mg of succinylcholine. The Somatic Thymatron IV device was used at the short heart rate setting, the stimulus being 15% (75.6 milicouloms or 15 J). The initial dosage of 120 mg of lurasidone was still being administered at nighttime. After two treatments with a seizure time of 31 and 44 s, the patient reported a reduction in visual hallucinations. Lurasidone was then discontinued. After two more treatments with a seizure time of 19 and 25 s, the hallucinations decreased again. The patient noticed an improvement in mood and a reduction in social anxiety, after which she was discharged from the hospital. Eight months after the end of treatment, the woman continued to experience occasional hallucinations, fewer psychotic symptoms with improved social functions, and a complete disappearance of the previous suspicions. This was the first case to be described in which the symptoms of depression and hallucinations persisted after cessation of synthetic cathinone use (bath salts). In this case, the patient's condition did not improve on antipsychotics and antidepressants. A significant yet incomplete improvement was achieved after a short cycle of four standard electroconvulsive therapy sessions. During the abuse of stimulants, including synthetic cathinones, the level of dopamine changes. Some evidence suggests that generalized seizures lead to the release of monoamines, which confirms the beneficial effects of electroconvulsive shock therapy in schizophrenia. Electroshock therapy and antipsychotics have also been shown to work synergistically. Electroconvulsive therapy may be beneficial in patients with persistent psychotic symptoms following drug abuse, including synthetic cathinones (12).

Another patient with depressive disorders due to cathinone dependence was prescribed bupropion with a gradual increase in dosage to 450 mg per day, which along with the therapy sessions, helped to end these symptoms (13).

Lev-Ran et al. (13) present the case of a 23-year-old man. As a child, he was diagnosed with ADHD and was treated with methylphenidate for 3 years. Two years before the event in question, he started having depressive states and suicidal thoughts. During this time, he occasionally used cannabis and MDMA. Then he started taking cathinone daily. He claims that he was initially euphoric after consuming the substance, but within a few weeks the level of euphoria it caused decreased despite higher dosages. He gradually increased the daily intake, and swallowed up to 15 capsules (200 mg/capsule) per day. He worked during this time and was not intoxicated during working hours. His regimen of use was to consume cathinone continuously after returning home in the afternoon until late at night, when he fell asleep exhausted. He reported regular effects of withdrawal-like dysphoria and agitation during working hours that resolved after returning home and consuming cathinone. After a few months, the effect of cathinone weakened and he began to inhale the contents of the capsules. In the following year, his cathinone use increased and his level of functioning gradually worsened. He reported a severe, constant dysphoric mood that would improve for a very short time after consuming cathinone. He took cathinone almost exclusively when he was alone and gradually withdrew from social activities. Eventually, he underwent a psychiatric evaluation. His symptoms and complaints met the DSM-IV criteria for substance (amphetamine) addiction and major depression. After the initial evaluation, the patient agreed to weekly treatment sessions and was prescribed bupropion, with the dose gradually increasing to 300 mg/day. At the end of the meeting, the patient rated his motivation to stop cathinone treatment as “five out of ten” and confidence in abstaining from cathinone as “one in ten.” After 4 weeks of bupropion treatment, he reported a partial improvement in his mood as well as a significant reduction in cathinone cravings. He also reported reducing the frequency of cathinone use to twice a week and decreasing the amount to 5–10 capsules each time. At that time, he rated his confidence level of abstaining from cathinone as “five out of ten” and decided to return to ingesting (instead of inhaling) cathinone as part of a harm reduction strategy. The bupropion was increased to 450 mg/day and the weekly therapy continued for an additional 4 weeks. At the end of this period, the patient reported complete cathinone abstinence and markedly improved mood, and rated his confidence level in cathinone abstention as “nine out of ten.” He continued to abstain from cathinone and since remained in remission from depression for 12 months (13).

Garrett et al. (14) write about a 22-year-old man who presented to the ED. During the examination, the patient suffered from tachycardia and was sweating profusely. His pupils were dilated and he had a tremor at rest. The patient was unable to stand on his own. He had no drug allergies that he was aware of. He was taking fluoxetine (40 mg) and olanzapine (10 mg). He was also administered zopiclone at night. The patient had suffered from depression, mania, and self-harm for 2 years. Two bags were found on his person: a plastic bag labeled “Vegetable Food” and a brown paper bag labeled “Red Doves.” The patient admitted to taking approximately 40 capsules from these bag within a 4-h span; the main substance ingested was mephedrone. Adequate treatment of his serotonin syndrome (general supportive measures, IV fluids, and oral diazepam) led to the neurological symptoms resolving and the patient being discharged after 15 h (14).

Kasick et al. (15) report the case of a 38-year-old white male with no prior history of psychosis who claimed to have seen snakes and was acting oddly. He was given 2 mg of naloxone twice at the scene, but no improvement was observed. After 45 min of verbal de-escalation by the doctors, the patient was confined to an emergency bed and taken to an external hospital. While in the ED, he had tachycardia (the ECG revealed a pulse of 144, sporadic premature ventricular contractions (PVCs), and a QTc of 430 ms) and his temperature was 38.2°C. He was restrained on the bed, but he did not want to be covered with a blanket for fear of being bitten by “scorpions.” The patient had ingested bath salts packaged under the name “Arctic Blast” (a street name for synthetic cathinone) twice in the previous 2 days. He remained agitated in the emergency room and received 3 mg of intravenous lorazepam over 4 h with 2 L of IV fluids. Laboratory assays showed elevated levels of hemoglobin and hematocrit, consistent with his history of polycythemia. The white blood cell and platelet counts were normal. His first urine drug test was ostensibly only positive for phencyclidine (PCP); his serum ethanol level was zero. He remained very agitated and oversensitive and was given 4 mg of intravenous lorazepam on account of his attempts to leave the hospital. He was anxious and paranoid: he believed that people were stealing his possessions. He fought physically with security guards. Owing to his physical aggression, he was given a total of 6 mg of intravenous lorazepam and 5 mg of haloperidol. His creatine kinase (CK) level was elevated, at 1,468 IU/L. He was given IV fluids at 200 ml/ hour for 24 h. The additional drug screening done 9 h after the initial screening was positive for benzodiazepines, but negative for PCP or other substances. As time went on, the patient became calmer, but still had difficulties with awareness, orientation, cognitive speed, and attention. The next morning, 35 h after the patient's first exposure to emergency services, he remained alert and irritable, but his awareness had improved significantly. The patient clearly described how he had bought the “bath salts” from the local “head shop” and how he had drunk about half a spoonful of the bath salts in a carbonated cola drink twice in the 2 days prior to admission. He still vehemently denied ever using phencyclidine, although he did describe a more distant history of alcohol and cannabis use. He denied any history of psychosis or previous psychiatric treatment. His vital signs and increased CK levels returned to normal. Over the next 24 h, the patient showed a lasting improvement in attention, awareness, focus, concentration, and speed of thought. He had no residual psychotic symptoms and behaved normally on further cognitive screening. The next day, he was discharged (15).

Benzer et al. (16) report the case of a 36-year-old man with a history of alcohol and drug abuse who was admitted to hospital because of severe agitation and paranoia. The patient's girlfriend reported that the patient had been sober for ~20 months until he lost his job. Three days prior to admission, the patient began drinking alcohol and taking bath salts intranasally after sleepless nights. The night before taking the psychoactive substance, agitation, and auditory and visual hallucinations occurred; as a consequence, the patient believed that people were trying to harm him. On the morning of admission, shortly after taking more bath salts, he ran outside without any clothes on, shouting that someone was trying to strangle him. His girlfriend called the police, who found the patient running naked in the street. When the paramedics arrived, they found him being restrained by police officers, belligerent and confused, with illogical, paranoid, and rambling speech. His pulse was 157 beats per minute, with limited radial pulses, and his respiratory rate was 24 breaths per minute. His pupils were 5 mm in diameter. The patient was transported to the emergency room. On the way, he suddenly fell silent, and the paramedics suspected a seizure. They tried to administer midazolam but the patient removed the intravenous catheter. After arriving at the hospital, it was impossible to communicate with the patient. His history was obtained from his girlfriend. He had a history of depression and alcohol and drug abuse (including heroin, cocaine, and prescription opiates). His only medication was fluoxetine, which he reportedly had not taken for 2 weeks. During the examination, the patient was agitated, flailing his arms and legs, jerking his head, and making loud, incomprehensible sounds. He was unable to cooperate during the investigation and had to be restrained by several security officers. His pupils were equal and reactive to light; his gaze was focused upwards with slow, horizontal movements of the eyes. The patient's speech was quick and mostly incomprehensible, but he mentioned attacking and being attacked by animals, humans, and monsters. The rest of the examination proceeded normally. The patient was immobilized and administered intravenous midazolam followed by lorazepam, but his condition did not improve. Then, etomidate and rocuronium were administered, the trachea was intubated, and mechanical ventilation was begun, followed by sedation with propofol. A urinary catheter and an esophagus tube were inserted. In the next stage, fomepizole, sodium thiosulfate, sodium bicarbonate, saline solution, and potassium chloride were administered intravenously, after which he was admitted to the ICU and his condition improved (16).

Adamowicz et al. (21) describe the diazepam and midazolam treatment of a 20-year-old man with a history of addiction to psychoactive substances. The patient consumed substances that he purchased online, which he combined with 250 ml of 40% alcohol. A few minutes after consumption, he developed severe psychomotor agitation, as a result of which an ambulance was called. The patient was given 10 mg of diazepam and 5 mg of midazolam on site. On admission to the hospital, the man was conscious, cardiovascularly and respiratorily stable, severely agitated, and non-verbal. The patient screamed and fought; he was uncooperative and a threat to his own health. He presented with convulsions and an elevated temperature. His electrocardiogram showed a sinus rhythm. After 2 h, he suffered from cardiac arrest; intubation, ventilation, defibrillation, and cardiac massage were performed and adrenaline and atropine were administered, but this did not have much effect. Death occurred <4 h after the consumption of the psychoactive substance. Postmortem blood tests showed that the young man was intoxicated with 3-MMC, 5-APB, and ethyl alcohol (21).

Midazolam was also used in a case described by Hall et al. (22), in which a 21-year-old man who had snorted “bath salts” (research showed that the product was a mixture of synthetic cathinones) was described by police officers as having “superhuman strength” and being seemingly immune to pain. He was sweating heavily, making growling noises, and hallucinating. Help was called and paramedics immediately administered 10 mg of midazolam intramuscularly. The patient was immobilized and transported to the emergency room. The patient's condition normalized after sedation and intravenous rehydration with saline solution (22). Propofol was cited as an alternative to benzodiazepines in studies done from 2010 to 2013, but more recent research has also demonstrated the effectiveness of dexmedetomidine (23).

Pichini et al. (24) in their article, report the case of a male infant who, 20 h after delivery, began to display increased irritability, high-pitched crying, increased muscle tone of the limbs and increased tendon reflexes. The mother confessed to smoking mephedrone daily during her pregnancy. The newborn was diagnosed with neonatal withdrawal syndrome (NWS). The following treatment was applied: phenobarbital once as an intramuscular bolus at a dosage of 20 mg/kg, and then 10 mg/kg per day orally. The dose was gradually reduced over the following days as the Finnegan score (the neonatal withdrawal symptom score) was above eight. After 12 days of phenobarbital treatment, the symptoms improved. HPLC analysis showed the presence of methadone, its metabolite EDDP (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine) and 4-MMC (4-methylmethcathinone; mephedrone) in the blood of the newborn. After 15 days, he was discharged from the hospital (24).

Pierluigi et al. (25) describe a case illustrating the use of risperidone in a 28-year-old man in 2014. The patient was admitted to the clinic due to symptoms suggestive of a depressive episode that had occurred within the previous 4 weeks. When he was hospitalized, his assessment of reality was not marked by hallucinations or delusions. The patient complained of a general “lack of energy.” He was medicated with antipsychotics and antidepressants, i.e., risperidone (4 mg/day), venlafaxine (75 mg/day), biperide (4 mg/day), and delorazepam (2 mg/day). During the course of therapy, the patient explained that most of the experimental substance use in his life had taken place over several years, but in the last 8 months prior to admission to the ward, his frequency of taking the psychoactive substance Alpha-PVP (synthetic cathinone) had increased. At the same time, he experienced a worsening of his depression symptoms until the last episode, in which he experienced visual hallucinations, leading to a referral for treatment. The stay in the ward lasted 40 days, during which he participated in a rehabilitation program including individual (every 2 weeks) and group (two or three times a day) psychotherapy sessions as well as psychopharmacological assessment and psychomotor rehabilitation. A significant change in his health status occurred after administration of bupropion (150 mg/day). This drug helped reduce the depressive symptoms caused by the consumption of the psychoactive substance (25). This antidepressant was chosen because of its chemical structure. Bupropion, a substituted cathinone, α-aminocetone, is a dopamine and norepinephrine reuptake inhibitor and an antagonist of the nicotinic acetylcholine receptor. It has also been shown to modulate the levels of certain cytokines associated with inflammatory diseases. Numerous studies have also been conducted to investigate the effectiveness of bupropion in smoking cessation therapy (26).

Oppek et al. (27), however, describe a case of a 29-year-old woman with a history of polysubstance addiction who used significant amounts of bupropion (up to 2.4 g) intravenously to intoxicate herself. Although it is widely believed that bupropion is not addictive, this situation shows us that people prone to addiction can consume it in very large doses daily. Based on this case, Oppek and other authors conclude that administration of bupropion in subjects prone to addiction should be carried out with caution, as its possible impact raises doubts (27).

Literature from 2014 to 2015 contains guidelines—for the first time—on how to counteract serotoninergic syndrome. Apart from intensive cooling of the body and the benzodiazepines mentioned in the studies done from 2010 to 2013, 5-HT2A receptor antagonists should be administered, i.e., cyproheptadine or chlorpromazine (28).

According to the literature, it is still very difficult to define a universal method of treating intoxication with cathinones due to the large differences in action and the immense number of NPS's. As there is no specific treatment plan, therapy is symptomatic and supportive. Taking into account the similarity of cathinones to other stimulants, it is recommended to take similar steps in reducing the side effects. When cathinone-induced delirium is suspected, clinicians focus on controlling agitation and complications such as metabolic acidosis. If serotonin syndrome occurs, benzodiazepines and/or cyproheptadine are recommended, just like in the studies published from 2014 to 2015.

As it follows from the publications released between 2010 and 2015, benzodiazepines are still administered orally or intravenously, e.g., diazepam (0.1–0.3 mg/kg body weight), in the case of over-excitation, hyperthermia, aggression, hallucinations or bradycardia and hypertension. Occasionally, higher doses of the drug can be used to achieve and/or maintain a sedative effect. Heart attacks and arrhythmias should be excluded with the use of electrocardiogram (12). Therapy aimed at controlling aggression and agitation still relies on the intranasal or intramuscular administration of midazolam or the intramuscular administration of lorazepam, which can also prevent seizures. As reported in previous years, if there are contraindications to the use of benzodiazepines (e.g., alcohol consumption), administration of propofol or antipsychotics (haloperidol, olanzapine, ziprasidone) should be considered, which may additionally prevent seizures and dysrhythmia. Furthermore, the literature shows that olanzapine is effective in controlling attacks of aggression. Clinicians do not recommend the use of antipsychotics for acute psychosis, owing to the reduction of the seizure threshold and the risk of extrapyramidal symptoms. As medical data show, there are currently no effective pharmacological treatments for synthetic cathinone addiction and withdrawal syndrome. For patients who regularly take synthetic cathinones, symptomatic treatment should be combined with psychotherapy and behavioral therapy (46–48).