Substances Included Synonyms

Therapeutic Toxic Class

A)

B)

Specific Substances

A)

1) Ethcathinone (synonym)
2) N-Et Cat (synonym)
3) 2-ethylamino-1-phenyl-propan-1-one (synonym)
4) C(11)H(15)NO

1) Cat (synonym)
2) Bubbles (synonym)
3) Ephedrone (synonym)
4) Jeff (synonym)
5) Goob (synonym)
6) Mulka (synonym)
7) Meow (synonym)
8) Methylcathinone (synonym)
9) Monomethylpropion (synonym)
10) C(10)H(13)NO
11) CAS 5650- 44-2
12) 2-(methylamino)-1-phenyl-1-propan-1-one (synonym)

1) 4-M (synonym)
2) 4-MMC (synonym)
3) MCAT (synonym)
4) M-CAT (synonym)
5) 4-MMC (synonym)
6) 4-MEC (synonym)
7) Mephedrone (synonym)
8) Meow (synonym)
9) Meow-Meow (synonym)
10) Meph (synonym)
11) Miaow (synonym)
12) Miaow-Miaow (synonym)
13) Plant food (synonym)
14) Top Cat (synonym)

1) 4-FMC (synonym)
2) Flephedrone (synonym)

1) alpha-Pyrrolidinobutiophenone (Alpha-PBP) (synonym)
2) alpha-Pyrrolidinopentiophenone (Alpha-PDP) (synonym)
3) alpha-Pyrrolidinopropiophenone (Alpha-PPP) (synonym)
4) alpha-Pyrrolidinovalerophenone (Alpha-PVP) (synonym)
5) Buphedrone
6) Butylone (3,4-benzodioxolylbutanamine) (synonym)
7) Ethylone (synonym)
8) Methylone (4-methylenedioxy-N-methylcathinone) (synonym)
9) 1-(4-methylphenyl)-2-(pyrrolidinyl)-1-propanone (MPPP) (synonym)
10) 3,4-Methylenedioxypyrovalerone (MDPV) (synonym)
11) Methedrone (4-methoxymethcathinone) (synonym)
12) Pentedrone (synonym)
13) Pentylone (synonym)

1) Blue silk (synonym)
2) Bliss (synonym)
3) Bloom (synonym)
4) Charge (synonym)
5) Cloud 9 (synonym)
6) Cloud Nine (synonym)
7) Cotton cloud (synonym)
8) Drone (synonym)
9) Dynamite (synonym)
10) Flakka (synonym)
11) Gravel (synonym)
12) Hurricane Charlie (synonym)
13) Ivory Snow (synonym)
14) Ivory wave (synonym)
15) Lunar Wave (synonym)
16) Moon dust (synonym)
17) Ocean Burst (synonym)
18) Ocean Snow (synonym)
19) Purple Ivory (synonym)
20) Purple Wave (synonym)
21) Red Dove (synonym)
22) Scarface (synonym)
23) Subcoca (synonym)
24) Snow Leopard (synonym)
25) Stardust (synonym)
26) Toot (synonym)
27) Vanilla Sky (synonym)
28) White dove (synonym)
29) White Knight (synonym)
30) White Lightning (synonym)
31) Zoom (synonym)

Available Forms Sources

A)

1) These products are typically sold in 50 mg to 500 mg packets marked "not for human consumption". They are often purchased at convenience stores, tobacco outlets, gas stations, tatoo parlors, truck stops or pawn shops. They may be advertised as plant food, bath crystals or herbal incense. Most commonly used by nasal insufflation ("snorting"), these products are also frequently ingested and less often injected (Fass et al, 2012).
2) Synthetic cathinones can also be administered by IV injection. Overall, clinical events appeared similar to previously reported cases of synthetic cathinone abuse (Batisse et al, 2014).
3) CATHINONE

a) Cathinone is chemically similar to amphetamine, with the only exception that the carbonyl group has been changed to a methylene group in the alpha position of the amphetamine chain (Kalix, 1992).
b) Cathinone has been included in Schedule I, and cathine in Schedule III, of the UN Convention on Psychotropic Substances following a recommendation of the World Health Organization (Elme et al, 1987).
c) HAGIGAT: An illicit capsule containing 200 mg cathinone and sold in Israel as a substitute for Khat. It can be purchased at convenience stores as a natural stimulant and aphrodisiac for men and women. In Hebrew, the translation of Hagigat is "Gat/Khat" party. Of note, chewing Khat leaves is a tradition followed by many immigrants to Israel, and has been adopted by many others; its use is considered legal (Bentur et al, 2008).

4) METHCATHINONE

a) Methcathinone, a synthetic derivative of cathinone, is a psychostimulant drug of abuse (Gygi et al, 1996). In 1993, it was designated as a Schedule 1 drug under the US Federal Controlled Substances Act (Calkins et al, 1995). Historically, it was produced as a potential appetite suppressant in the early 1950s and 1960s, but was never marketed because of its addictive potential. Abuse of methcathinone has occurred in the former Soviet Union since the 1980s and is referred to as "ephedrone" (Gygi et al, 1996).

1) Methcathinone is simple to produce and all the ingredients are legal and inexpensive (Gygi et al, 1996). It is distributed as a white to off-white, chunky, powder material; it may have tinges of blue or yellow (Calkins et al, 1995). It is usually administered by inhalation(O'Dea et al, 1997); it can also be injected and absorbed by the oral or dermal route (Rosen, 1993).
2) In a survey of 19 methcathinone users, the most common route of administration was inhalation or oral. For those oral users, it was usually added to a caffeine beverage. Other routes of exposure included: intravenous, dissolving in a nasal spray, or smoking it with marijuana (Calkins et al, 1995).

B)

1) Methcathinone can be produced from pseudoephedrine (eg, Sudafed(R)) along with potassium permanganate to produce an oxidant reaction (de Bie et al, 2007). Potassium permanganate is the preferred oxidizing agent (Selikhova et al, 2008).

C)

1) SUMMARY

a) Synthetic cathinone derivatives act similar to other stimulants, in particular, amphetamine. These agents can promote the release of neurotransmitters, dopamine, noradrenalin and serotonin (Independent Scientific Committee on Drugs, 2010). Methcathinone is structurally similar to amphetamine and produces some of the same clinical effects (Rosen, 1993). Clinical events frequently reported with these agents include: tachycardia, dysrhythmias, agitation, hypertension, hyperthermia, diaphoresis, palpitations, chest pain, confusion, paranoia, hallucinations, violent behavior and seizure (Slomski, 2012; Spiller et al, 2011).

2) Cathine (d-norpseudoephedrine) is widely used in certain countries as the active principle of pharmaceutical preparations inducing anorexia (Eisenberg et al, 1987).
3) Recreational use of 4-methylcathinone (ie, mephedrone) has become increasingly popular worldwide. In the United Kingdom, it is estimated that it is the fourth leading drug of abuse (excluding alcohol and tobacco) behind cannabis, ecstasy and cocaine (Independent Scientific Committee on Drugs, 2010).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Methcathinone (ephedrone) and 4-methylmethcathinone (mephedrone) are the 2 most well known synthetic cathinone derivatives. Other agents include: 3,4-methylenedioxypyrovalerone (MDPV), methylone and butylone. Methcathinone was originally produced as an appetite suppressant, but was never marketed. These agents are primarily used as psychostimulant drugs of abuse. Behavioral effects are similar to amphetamine and methamphetamine.
B) EPIDEMIOLOGY: These agents are popular among young adults; mephedrone appears to be the most popular. These agents have been widely used in Russia and across Europe and mostly recently in the United Kingdom. Methcathinone has been found in the United States. Fatalities have been reported in the media; however, these cases have been poorly documented. Exposure usually occurs via inhalation or oral administration, and less frequently the parenteral route. Coingestants (ie, alcohol, marijuana, depressants, other stimulants) may play a significant role in fatal cases.
C) PHARMACOLOGY: Synthetic cathinone derivatives are chemically similar to cathinone, a psychoactive stimulant found in the khat plant. Methcathinone is structurally related to amphetamine, while mephedrone is thought to act similar to cocaine, amphetamine and MDMA. These agents likely promote the release of neurotransmitters dopamine, noradrenalin and serotonin.
D) TOXICOLOGY: Toxicity results primarily from excess sympathomimetic activity. These agents are highly addictive; psychological and perhaps physical dependence can develop. MDPV is reportedly more potent than other cathinone derivatives. The health risks of butylone and methylone are unknown, but anticipated to be similar to other synthetic cathinone derivatives. A young woman died after ingesting 2 capsules containing butylone and methylone; symptoms were initially characteristic of serotonin syndrome followed by progressive multiorgan failure.
E) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Clinical events associated with exposure may include features of sympathomimetic toxicity (eg, agitation, tachycardia, hypertension, mydriasis). Other acute effects include: insomnia, anorexia, hallucinations, paranoia, and palpitations. Brief episodes of drug-induced psychosis have developed. These agents may be used alone or together with other stimulants or alcohol to help moderate or enhance the effects of the drug.
2) SEVERE TOXICITY: Severe agitated delirium, aggressive violent behavior, hallucinations and paranoia have been reported following repeated or chronic use of these agents. Hyperthermia, hypotension, rhabdomyolysis complicated by acute renal failure, hyperkalemia, acidosis and cardiac dysrhythmias may develop. Elevated hepatic enzymes and coagulopathy may also develop. Coma has been observed. Seizures may develop following a significant exposure. Fatal dysrhythmias have occurred.
3) CHRONIC use may lead to physical and/or psychological dependence. Withdrawal may occur.

0.2.3)

A) WITH POISONING/EXPOSURE

1) Life threatening hyperthermia can develop in patients with severe agitation. Hypertension and mild to moderate tachycardia have also occurred.

0.2.4)

A) WITH POISONING/EXPOSURE

1) Mydriasis has been frequently observed. Blurred vision has also been reported.

0.2.5)

A) Mild hypertension and tachycardia with palpitations can occur. Dysrhythmias and myocardial ischemia have been reported infrequently.

Laboratory Monitoring

A)

B)

C)

D)

E)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Treatment is symptomatic and supportive; patients may only require observation. Benzodiazepines should be given for sedation as needed. Reassure the patient. Intravenous fluids may be indicated.

B) MANAGEMENT OF SEVERE TOXICITY

1) Goal of therapy is to control agitation, reverse or prevent hyperthermia, and support the paranoid or delirious patient. Liberal use of benzodiazepines are the mainstay of therapy. Administer intravenous fluids. Orotracheal intubation is indicated for airway protection in cases of severe agitation, coma or recurrent seizure activity. Treatment is symptomatic and supportive. Benzodiazepines should be given to treat delirium, seizures and moderate hypertension or tachycardia.

C) DECONTAMINATION

1) PREHOSPITAL: Prehospital decontamination is not recommended because of the risk of aspiration (delirium, seizures) potentially outweighs any potential benefit.
2) HOSPITAL: Decontamination may not be indicated based on the route of exposure. Activated charcoal may be considered if a recent oral exposure and the patient is able to protect their airway or the airway is protected.

D) AIRWAY MANAGEMENT

1) Airway management should be performed early in a patient with signs of severe poisoning (ie, severe agitation, coma, seizures).

E) ANTIDOTE

1) There is no specific antidote.

F) DELIRIUM

1) Liberal use of benzodiazepines is recommended for agitation/delirium (Diazepam: Dose: 5 to 10 mg IV every 5 to 10 minutes; titrated to effect). Large doses may be required until the patient is adequately sedated.

G) SEIZURE

1) Treat with benzodiazepines. Add barbiturates or propofol if seizures persist. These amphetamine-like agents may produce CNS stimulation; seizures have been rarely reported.

H) HYPERTENSION

1) Treat initially with IV benzodiazepine to control agitation/delirium. Hypertension usually resolves once the patient is less agitated.

I) TACHYCARDIA

1) Mild tachycardia does not require intervention. Treat moderate to severe tachycardia with benzodiazepines and intravenous fluids.

J) HYPERTHERMIA

1) Hyperthermia is a marker of severe toxicity and must be treated rapidly and aggressively to avoid complications. Administer benzodiazepines to control agitation, large doses or the addition of a second agent such as propofol may be required. Neuromuscular paralysis and endotracheal intubation may be necessary in severe cases. Monitor rectal temperature continuously. Cooling measures include keeping the skin moist and encouraging evaporation with fans. Ice packs at the groin and axilla, cooled IV fluids, a cooling blanket, and ventilation with cool air can also be used. For severe hyperthermia, place the patient in an ice water bath for rapid cooling.

K) MONITORING OF PATIENT

1) Monitor vital signs, including core temperature, and mental status. Measurement of plasma concentrations are available for some of these agents, but are not clinically useful or readily available. Monitor serum electrolytes, renal function, CK, liver enzymes and coagulation profile in patients with severe toxicity. Obtain cardiac enzymes and chest x-ray in a patient with chest pain. A metabolic panel may be useful if the diagnosis is uncertain. Obtain an ECG and institute continuous cardiac monitoring in a patient with moderate to severe toxicity. Consider a head CT and lumbar puncture to rule out intracranial mass, bleeding, or infection. A CPK should be obtained if rhabdomyolysis is suspected in a patient with severe agitation, seizure activity, or hyperthermia.

L) ENHANCED ELIMINATION

1) Hemodialysis and hemoperfusion are of no value.

M) PATIENT DISPOSITION

1) HOME CRITERIA: Asymptomatic adults may be monitored at home. However, it is unlikely that a patient will be asymptomatic if a binge user.
2) OBSERVATION CRITERIA: Patients with deliberate self-harm ingestions or children with any ingestion and symptomatic patients should be sent to a healthcare facility for observation for 6 to 8 hours.
3) ADMISSION CRITERIA: Patients with significant persistent central nervous system stimulation (i.e., hallucinations, delirium, seizures), or persistent hypertension and tachycardia should be admitted. Patients with coma, seizures, dysrhythmias, or delirium should be admitted to an intensive care setting.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (i.e., seizures, dysrhythmias, severe delirium, coma), or in whom the diagnosis is not clear. Patients with a history of chronic abuse should be referred for rehabilitation.

N) PITFALLS

1) Failure to control agitation may result in other complications (ie, rhabdomyolysis, severe hyperthermia). Failure to monitor temperature and treat hyperthermia aggressively. Failure to recognize that polydrug use is likely with these agents. Clandestine manufacturer of these agents has produced significant toxicity (eg, manganism due to potassium permanganate exposure) following chronic use.

O) PHARMACOKINETICS

1) Based on limited data with cathinone, these agents are likely to be quickly absorbed following oral exposure.

P) TOXICOKINETICS

1) Physical and psychological dependence can develop. These agents are highly addictive. Chronic abusers will often have periods of binge use where the drug is used multiple times throughout a 24-hour period for several days, resulting in prolonged clinical effects.

Q) DIFFERENTIAL DIAGNOSIS

1) Hypoglycemia, central nervous system infection, other sympathomimetic poisoning (ie, amphetamine, cocaine), anticholinergic toxicity, mental illness presenting with mania or hallucinations, or ethanol/benzodiazepine/barbiturate withdrawal.

Range Of Toxicity

A)

B)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

E)

1) MILD TO MODERATE TOXICITY: Clinical events associated with exposure may include features of sympathomimetic toxicity (eg, agitation, tachycardia, hypertension, mydriasis). Other acute effects include: insomnia, anorexia, hallucinations, paranoia, and palpitations. Brief episodes of drug-induced psychosis have developed. These agents may be used alone or together with other stimulants or alcohol to help moderate or enhance the effects of the drug.
2) SEVERE TOXICITY: Severe agitated delirium, aggressive violent behavior, hallucinations and paranoia have been reported following repeated or chronic use of these agents. Hyperthermia, hypotension, rhabdomyolysis complicated by acute renal failure, hyperkalemia, acidosis and cardiac dysrhythmias may develop. Elevated hepatic enzymes and coagulopathy may also develop. Coma has been observed. Seizures may develop following a significant exposure. Fatal dysrhythmias have occurred.
3) CHRONIC use may lead to physical and/or psychological dependence. Withdrawal may occur.

Vital Signs

3.3.1)

A) WITH POISONING/EXPOSURE

1) Life threatening hyperthermia can develop in patients with severe agitation. Hypertension and mild to moderate tachycardia have also occurred.

3.3.3)

A) Life threatening hyperthermia can develop in patients who develop severe agitation or serotonin syndrome. If not treated aggressively complications can include rhabdomyolysis, hyperkalemia, acute renal failure, metabolic acidosis, acute hepatic failure, severe coagulopathy and death (Kesha et al, 2013; Mugele et al, 2012; Borek & Holstege, 2012; Murray et al, 2012; Warrick et al, 2012).
B) Severe hyperthermia (rectal temperature of 106.3 degrees F) and multiogran failure developed in an adult with severe agitation following injection of MDPV. The patient recovered following aggressive care (Borek & Holstege, 2012). In another case, a man admitting to bath salt use was found delusional and developed agitation, ventricular tachycardia and severe hyperthermia (peaked at 107.1 F) soon after admission. He rapidly developed asystole that was unresponsive to resuscitation efforts. The patient died 12 hours after presentation to the emergency department; postmortem biological testing was positive for MDPV (Kesha et al, 2013).
C) In one case, a patient developed a fever along with an elevated white blood cell count after repeated injections of methcathinone over a 6-hour period (Emerson & Cisek, 1993). CNS stimulation may produce an increase in body temperature; cathinone has produced body temperature elevations in animals (Kalix, 1992).

3.3.4)

A) WITH POISONING/EXPOSURE

1) Hypertension has been observed following exposure (Wood et al, 2010) and should likely be anticipated because of its amphetamine-like effects (Kalix, 1992).
2) In a limited number of cases, moderate hypotension has been reported following methcathinone toxicity (Emerson & Cisek, 1993). Coingestion of other agents (ie, alcohol or benzodiazepines) may alter the typical presentation of these agents (Belhadj-Tahar & Sadeg, 2005).

3.3.5)

A) WITH POISONING/EXPOSURE

1) Mild to moderate tachycardia has been reported following acute exposure to synthetic cathinone derivatives (Wood et al, 2010; Belhadj-Tahar & Sadeg, 2005; Emerson & Cisek, 1993), which is consistent with sympathomimetic toxicity (Wood et al, 2010).

Heent

3.4.1)

A) WITH POISONING/EXPOSURE

1) Mydriasis has been frequently observed. Blurred vision has also been reported.

3.4.3)

A) WITH POISONING/EXPOSURE

1) MYDRIASIS has been frequently observed following exposure to these agents (Wood et al, 2010; Belhadj-Tahar & Sadeg, 2005; Emerson & Cisek, 1993).
2) CASE SERIES/SYNTHETIC CATHINONES: In a retrospective case series of patients (n=236) reporting to 2 poisons centers with exposure to various synthetic cathinones (ingredients detected in bath salt samples were limited to mephedrone, methylone, MDPV (methylenedioxypyrovalerone), mydriasis was observed in 31 (13%) patients. Blurred vision was also reported in 7 (3%) patients (Spiller et al, 2011).

Cardiovascular

3.5.1)

A) Mild hypertension and tachycardia with palpitations can occur. Dysrhythmias and myocardial ischemia have been reported infrequently.

3.5.2)

A) TACHYCARDIA

1) WITH POISONING/EXPOSURE

a) Mild to moderate tachycardia and palpitations have been reported following acute exposure to synthetic cathinone derivatives (Borek & Holstege, 2012; Durham, 2011; Dargan et al, 2011; Wood et al, 2011; Wood et al, 2010; Bentur et al, 2008; Calkins et al, 1995; Belhadj-Tahar & Sadeg, 2005; Emerson & Cisek, 1993), which is consistent with sympathomimetic toxicity (Wood et al, 2010).
b) INCIDENCE/SYNTHETIC CATHINONES: In a retrospective study of 362 calls of synthetic cathinone exposure to the Texas Poison Center Network (TPCN) during January 2010 through December 2011, tachycardia (n=166; 45.9%) was the most common clinical effects observed (Forrester, 2012).
c) CASE SERIES/SYNTHETIC CATHINONES: In a retrospective case series of patients (n=236) reporting to 2 poisons centers with exposure to various synthetic cathinones (ingredients detected in bath salt samples were limited to mephedrone, methylone, and MDPV [methylenedioxypyrovalerone]), tachycardia occurred in 132 (56%) patients. Of those patients reporting tachycardia, the mean heart rate was 124 beats/min (range: 100 to 178 beats/min) (Spiller et al, 2011).
d) CASE SERIES/MEPHEDRONE: In a series of 15 patients with self-reported mephedrone use, tachycardia (heart rate of equal to or greater than 100 beats/min) was observed in 6 (40%) patients. All patients in this series reported concomitant ethanol or other recreational drug (eg, GHB/GBL, cocaine, ketamine, hallucinogenic amphetamines) use. Most patients did not require any therapy and were discharged directly from the ED or after a short period of observation (Wood et al, 2011).
e) CASE SERIES/METHYLENEDIOXYPYROVALERONE: In an observational case series of consecutive patients admitted to Swedish hospitals from 2010 to 2014 with known or suspected exposure to new psychoactive substances (NPS), a total of 201 cases of analytically confirmed methylenedioxypyrovalerone (MDPV) exposures were found. Of the 201 cases, 193 had confirmed serum samples. The primary clinical events in these patients included agitation (n=130, 67%), tachycardia (greater than or equal to 100/min; n=106, 56%) and hypertension (systolic blood pressure of greater than or equal to 140 mmHg; n=65, 34%). Other potentially significant symptoms included: hallucinations (n=31, 16%), delirium (n=29, 15%), hyperthermia (greater than 39 degrees C; n=18, 10%), and rhabdomyolysis (n=16, 8%). MDPV serum levels of greater than 100 ng/mL resulted in more severe symptoms (Beck et al, 2015).
f) CASE REPORT/METHYLENEDIOXYPYROVALERONE: An adult developed a sudden onset of chest pain and palpitations after snorting 2 g of MDPV ("Ivory Wave"). The patient also developed tachycardia (pulse: 115 to 160 beats/min) and hypertension (BP 160/90). An ECG showed 2 mm ST depression. Symptoms resolved after receiving diazepam (Durham, 2011).
g) CASE REPORT: A 29-year-old woman was comatose upon admission after ingesting bromazepam (Lexomil(R)) dissolved in alcohol and a party-drug as reported by family members. Glasgow coma score was 9 on admission with mydriasis, rapid respirations, mild tachycardia (heart rate 92) and hypotension. Laboratory studies including a blood gas analysis were normal. Blood alcohol was 0.167 g/dL, urine screening was positive for methcathinone (17.24 mg/L), ephedrine (11.60 mg/L) and methylephedrine 11.10 mg/L) with a serum analysis by HPLC detecting bromazepam (8.89 mg/L), methcathinone (0.5 mg/L) and methylephedrine (0.19 mg/L). Following supportive care the patient clinically improved within 24 hours and was transferred for further psychiatric evaluation (Belhadj-Tahar & Sadeg, 2005). The typical presentation of methcathinone (ie, hypertension and convulsions) was likely altered by the combined use of alcohol and bromazepam.

B) HYPERTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) SUMMARY

1) CASE SERIES/ILLICIT CATHINONE: In a 10 month, prospective, observational study from Israel of 34 Hagigat users (illicit capsules containing 200 mg cathinone), hypertension (140/90 to 190/110 mmHg) was reported in 9 (26.5%) patients. The median age of users in this study was 25 years. The capsules were analyzed and contained a high dose of cathinone (ie, each capsule was the equivalent of 555.5 g Khat leaves as compared to an average chewing session that is equivalent to being exposed to 100 to 200 g of Khat leaves) (Bentur et al, 2008).
2) CASE SERIES/SYNTHETIC CATHINONES: In a retrospective case series of patients (n=236) reporting to 2 poisons centers with exposure to various synthetic cathinones (ingredients detected in bath salt samples were limited to mephedrone, methylone, and MDPV [methylenedioxypyrovalerone]), hypertension was reported in 41 (17%) patients (Spiller et al, 2011).
3) INCIDENCE/SYNTHETIC CATHINONES: In a retrospective study of 362 calls of synthetic cathinone exposure to the Texas Poison Center Network (TPCN) during January 2010 through December 2011, hypertension (n=76; 21%) was one of the most common clinical effects observed (Forrester, 2012).

b) 4-METHYLMETHCATHINONE/MEPHEDRONE

1) CASE SERIES/MEPHEDRONE: In a series of 15 patients with self-reported mephedrone use, hypertension (systolic blood pressure of 160 mmHg or greater) was observed in 3 (20%) patients. All patients in this series reported concomitant ethanol or other recreational drug (eg, GHB/GBL, cocaine, ketamine, hallucinogenic amphetamines) use. Most patients did not require any therapy and were discharged directly from the ED or after a short period of observation (Wood et al, 2011).
2) CASE REPORT: A 22-year old man purchased 4 g of mephedrone over the Internet and ingested 200 mg without reaching a "high" and then decided to dilute the remaining 3.8 g with sterile water and inject himself intramuscularly. Shortly afterwards he developed palpitations, "blurred tunnel vision", chest pressure, and sweating and sought medical help. Upon arrival, he was anxious and agitated, with hypertension (BP 177/111 mmHg), mild tachycardia (heart rate 105) and dilated pupils. His temperature was normal with no diaphoresis. Urine and serum analyses were positive for 4-methylmethcathinone; a routine toxicology screen was negative for other agents. Lorazepam (1 mg) was given for agitation and symptoms resolved gradually over a few hours and he was discharged from the Emergency Department to home 6 hours after arrival (Wood et al, 2010).

c) METHYLENEDIOXYPYROVALERONE (MDPV)

1) CASE SERIES: In an observational case series of consecutive patients admitted to Swedish hospitals from 2010 to 2014 with known or suspected exposure to new psychoactive substances (NPS), a total of 201 cases of analytically confirmed methylenedioxypyrovalerone (MDPV) exposures were found. Of the 201 cases, 193 had confirmed serum samples. The primary clinical events in these patients included agitation (n=130, 67%), tachycardia (greater than or equal to 100/min; n=106, 56%) and hypertension (systolic blood pressure of greater than or equal to 140 mmHg; n=65, 34%). Other potentially significant symptoms included: hallucinations (n=31, 16%), delirium (n=29, 15%), hyperthermia (greater than 39 degrees C; n=18, 10%), and rhabdomyolysis (n=16, 8%). MDPV serum levels of greater than 100 ng/mL resulted in more severe symptoms (Beck et al, 2015).
2) CASE REPORT: An adult developed a sudden onset of chest pain and palpitations after snorting 2 g of MDPV ("Ivory Wave") earlier in the day. The patient also developed tachycardia (pulse: 115 to 160 beats/min) and hypertension (BP 160/90). An ECG showed 2 mm ST depression. Symptoms resolved after receiving diazepam (Durham, 2011).

C) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) In a limited number of cases, moderate hypotension has been reported following methcathinone toxicity (Emerson & Cisek, 1993).

D) BRADYCARDIA

1) WITH POISONING/EXPOSURE

a) In a limited number of cases, bradycardia has been reported following methcathinone toxicity (Emerson & Cisek, 1993).

E) CONDUCTION DISORDER OF THE HEART

1) WITH POISONING/EXPOSURE

a) 4-METHYLMETHCATHINONE (MEPHEDRONE): Based on surveys and hospital admissions, a rapid, irregular heart rate and chest tightness were common findings of mephedrone users. It occurred in approximately 50% of users in one study (Independent Scientific Committee on Drugs, 2010).
b) METHCATHINONE: In Russia, cardiac dysrhythmias have been associated with deaths following methcathinone exposure (Emerson & Cisek, 1993).

F) PALPITATIONS

1) WITH POISONING/EXPOSURE

a) 4-METHYLMETHCATHINONE (MEPHEDRONE)

1) SUMMARY: Based on hospital admissions and calls to poison centers, palpitations have been reported frequently among mephedrone users (Dargan et al, 2011).
2) In a series of 15 patients with self-reported mephedrone use, palpitations developed in 2 (13.3%) patients (Wood et al, 2011).

b) METHYLENEDIOXYPYROVALERONE (MDPV)

1) CASE REPORT: An adult developed a sudden onset of chest pain and palpitations after snorting 2 g of MDPV ("Ivory Wave") earlier in the day. The patient also developed tachycardia (pulse: 115 to 160 beats/min) and hypertension (BP 160/90). An ECG showed 2 mm ST depression. Symptoms resolved after receiving diazepam (Durham, 2011).

G) CHEST PAIN

1) WITH POISONING/EXPOSURE

a) SUMMARY

1) CASE SERIES/SYNTHETIC CATHINONES: In a retrospective case series of patients (n=236) reporting to 2 poisons centers with exposure to various synthetic cathinones (ingredients detected in bath salt samples were limited to mephedrone, methylone, and MDPV [methylenedioxypyrovalerone]), chest pain was reported in 40 (17%) patients (Spiller et al, 2011).

b) 4-METHYLMETHCATHINONE (MEPHEDRONE)

1) SUMMARY: Based on hospital admissions and calls to poison centers, chest pain has been reported frequently among mephedrone users (Dargan et al, 2011).

c) METHYLENEDIOXYPYROVALERONE (MDPV)

1) CASE REPORT: An adult developed a sudden onset of chest pain and palpitations after snorting 2 g of MDPV ("Ivory Wave") earlier in the day. The patient also developed tachycardia (pulse: 115 to 160 beats/min) and hypertension (BP 160/90). An ECG showed 2 mm ST depression. Symptoms resolved after receiving diazepam (Durham, 2011).

H) MYOCARDIAL ISCHEMIA

1) WITH POISONING/EXPOSURE

a) CASE REPORTS: In a 10 month, prospective, observational study from Israel of 34 Hagigat users (illicit capsules containing 200 mg cathinone), myocardial ischemia was reported in 3 young adults (ranging in age from 16 to 35 years). Two patients developed myocardial ischemia and pulmonary edema. One patient, a 16-year-old male, required mechanical ventilation for several days. Each patient fully recovered (Bentur et al, 2008).

Respiratory

3.6.2)

A) TACHYPNEA

1) In a limited number of cases, mild tachypnea has been reported following methcathinone toxicity (Emerson & Cisek, 1993).

B) SUBCUTANEOUS EMPHYSEMA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 30-year-old healthy man developed nontraumatic spontaneous cervical subcutaneous emphysema a few hours after snorting mephedrone and having mild sneezing. He reported neck pain and upper chest swelling but was able to maintain his airway. His respiratory rate was normal along with stable cardiovascular and neurologic function. Physical exam noted fine subcutaneous crepitations of the neck and chest. A chest x-ray detected air throughout the subcutaneous tissue of the neck and some air in the mediastinum. No pneumothoraces were observed. Following monitoring for 48 hours the patient remained stable and was discharged to home. An underlying cause was not determined (Maan & D'Souza, 2012).

Neurologic

3.7.2)

A) RESTLESSNESS AND AGITATION

1) WITH POISONING/EXPOSURE

a) SUMMARY

1) Agitation, sometimes severe, has frequently occurred following acute exposure to these agents (Spiller et al, 2011; Calkins et al, 1995; Wood et al, 2010; Winstock et al, 2010).
2) INCIDENCE/SYNTHETIC CATHINONES: In a retrospective study of 362 calls of synthetic cathinone exposure to the Texas Poison Center Network (TPCN) during January 2010 through December 2011, agitation (n=142; 39.2%) and confusion (n=47; 13%) were the most common clinical events observed (Forrester, 2012).
3) CASE SERIES/SYNTHETIC CATHINONES: In a retrospective case series of patients (n=236) reporting to 2 poisons centers with exposure to various synthetic cathinones (ingredients detected in bath salt samples were limited to mephedrone, methylone, and MDPV [methylenedioxypyrovalerone]), agitation was reported in 194 (82%) patients. It was the most common adverse event reported. Combative violent behavior was also observed in 134 (57%) patients (Spiller et al, 2011).

b) 4-METHYLMETHCATHINONE (MEPHEDRONE)

1) SUMMARY: Based on surveys, hospital admissions, and calls to poison centers, agitation was the most commonly reported symptom among mephedrone users (Dargan et al, 2011; Independent Scientific Committee on Drugs, 2010).
2) CASE SERIES: In a series of 15 patients with self-reported mephedrone use, agitation was observed in 8 (53.3%) patients. All patients in this series reported concomitant ethanol or other recreational drug (eg, GHB/GBL, cocaine, ketamine, hallucinogenic amphetamines) use. Three (20%) patients needed to be treated with a benzodiazepine upon admission to the ED. All patients were discharged to home without permanent sequelae (Wood et al, 2011).
3) CASE REPORT: A 22-year old man purchased 4 g of mephedrone over the Internet and ingested 200 mg without reaching a "high" and then decided to dilute the remaining 3.8 g with sterile water and inject himself intramuscularly. Shortly afterwards he developed palpitations, "blurred tunnel vision", chest pressure, and sweating and sought medical help. Upon arrival, he was anxious and agitated, with hypertension (BP 177/111 mmHg), mild tachycardia (heart rate 105) and dilated pupils. His temperature was normal with no diaphoresis. Urine and serum analyses were positive for 4-methylmethcathinone; a routine toxicology screen was negative for other agents. Lorazepam (1 mg) was given for agitation and symptoms resolved gradually over a few hours and he was discharged from the Emergency Department to home 6 hours after arrival (Wood et al, 2010).

c) METHYLENEDIOXYPYROVALERONE (MDPV)

1) CASE SERIES: In an observational case series of consecutive patients admitted to Swedish hospitals from 2010 to 2014 with known or suspected exposure to new psychoactive substances (NPS), a total of 201 cases of analytically confirmed methylenedioxypyrovalerone (MDPV) exposures were found. Of the 201 cases, 193 had confirmed serum samples. The primary clinical events observed in these patients included agitation (n=130, 67%), tachycardia (greater than or equal to 100/min; n=106, 56%) and hypertension (systolic blood pressure of greater than or equal to 140 mmHg; n=65, 34%). Other potentially significant symptoms included: hallucinations (n=31, 16%), delirium (n=29, 15%), hyperthermia (greater than 39 degrees C; n=18, 10%), and rhabdomyolysis (n=16, 8%). Seizures, cardiac arrest, ventricular tachycardia and elevated troponin levels developed infrequently. MDPV serum levels of greater than 100 ng/mL resulted in more severe symptoms (Beck et al, 2015).
2) CASE REPORT: A 25-year-old man initially developed severe agitation and an altered mental status after injecting MDPV (confirmed by laboratory analysis) which progressed to multiorgan failure. He was admitted with hypertension, tachycardia (175 beats/min) and a rectal temperature of 106.3 degrees F. Immediate treatment included intubation, cooling measures and sedation with an improvement in vital signs. However, the patient developed renal failure, fulminant hepatic failure, DIC and rhabdomyolysis with a peak creatine kinase of 253,377 Units/L. Anuric renal failure was treated with continuous renal replacement therapy followed by hemodialysis. He gradually improved and was extubated on hospital day 9 with normal mentation by day 13. The patient was discharged on day 18, but required hemodialysis for 1 month. A urine screen for MDPV was positive on the day of admission; a urine hallucinogen screen was negative (Borek & Holstege, 2012)
3) CASE REPORT: An adult developed a sudden onset of chest pain and palpitations after snorting 2 g of MDPV ("Ivory Wave") earlier in the day. The patient was extremely agitated and experiencing hallucinations. He was also noted to have tachycardia (pulse: 115 to 160 beats/min) and hypertension (BP 160/90). An ECG showed 2 mm ST depression. Symptoms resolved after receiving diazepam (Durham, 2011).

B) HEADACHE

1) WITH POISONING/EXPOSURE

a) 4-METHYLMETHCATHINONE (MEPHEDRONE): In surveys, hospital admissions and calls to poison centers, headache was a common finding among mephedrone users (Dargan et al, 2011; Independent Scientific Committee on Drugs, 2010).

1) INCIDENCE: In a series of 15 patients with self-reported mephedrone use, headache developed in 1 (6.7%) patient (Wood et al, 2011).

b) METHCATHINONE: In a survey of 19 methcathinone users, headache has been described. In 4 users who had also taken amphetamines, methcathinone was reported to cause intense headaches compared to slight headaches with amphetamine use (Calkins et al, 1995).
c) CATHINONE: In a 10 month, prospective, observational study from Israel of 34 Hagigat users (illicit capsules containing 200 mg cathinone), headache (n=17 (50%)), restlessness (n=4 (11.8%)), paresthesias (n=4 (11.8%)), and dizziness (n=4 (11.8%)) were commonly reported neurotoxic effects. In 11 patients, prolonged headache was reported for up to 7 days after exposure. Other symptoms that were reported less frequently included: anxiety, nervousness, mood changes, hallucinations, and difficulty concentrating (Bentur et al, 2008).

C) SEIZURE

1) WITH POISONING/EXPOSURE

a) SYNTHETIC CATHINONE EXPOSURES

1) CASE SERIES/PEDIATRIC: In a review of the American Association of Poison Control Centers database, 1328 cases of pediatric (less than 20 years of age) synthetic cathinone exposures were identified from January 2010 through January 2013. Of the 3128 cases, 73 (5.5%) of the cases developed seizure activity with 37 (50.7%) experiencing a single seizure, 29 (39.7%) developed multiple seizures and 7 (9.6%) had status epilepticus. The development of fever (n=12 (16.4%)) and acidosis (n=9 (12.3%)) were significantly associated with any seizure activity. There was no correlation between children that developed multiple seizures or status epilepticus and electrolyte abnormalities, hallucinations and/or delusions, tachycardia or hypertension. Coingestants (typically THC, alcohol and opioids) were found in 33 (45%) of the cases that developed seizures. The authors suggest that hyperthermia may be a marker of more severe sympathomimetic toxicity that has been associated with synthetic cathinone exposure (Tekulve et al, 2014).

b) 4-METHYLMETHCATHINONE (MEPHEDRONE)

1) CASE SERIES: In a series of 15 patients with self-reported mephedrone use, 3 cases of prehospital seizure were reported. All patients in this series reported concomitant ethanol or other recreational drug (eg, GHB/GBL, cocaine, ketamine, hallucinogenic amphetamines) use. All patients were discharged to home without permanent sequelae (Wood et al, 2011).
2) Based on limited data, seizures have been reported by 4-methylmethcathinone (mephedrone) users (Independent Scientific Committee on Drugs, 2010).

c) ETHCATHINONE AND METHYLONE

1) CASE REPORT: A 22-year-old woman developed tonic-clonic seizures and repeat episodes of vomiting after ingesting "legal ecstasy" (a powdered mixture containing ethcathinone and methylone obtained from a head shop) and 3 alcoholic beverages. Other symptoms included euphoria, agitation, sweating and intense thirst. The patient consumed 3.5 L of water just prior to her first seizure. She required intubation for recurrent seizures and developed severe hyponatremia (Na 120 mmol/L) due to the MDMA-like characteristics of methylone (inducing inappropriate secretion of antidiuretic hormone) after arrival to the emergency department. She was extubated the following day and her serum sodium level normalized within 14 hours. The patient recovered completely (Boulanger-Gobeil et al, 2012).

d) METHYLENEDIOXYPYROVALERONE (MDPV)

1) CASE SERIES: In an observational case series of consecutive patients admitted to Swedish hospitals from 2010 to 2014 with known or suspected exposure to new psychoactive substances (NPS), a total of 201 cases of analytically confirmed methylenedioxypyrovalerone (MDPV) exposures were found. Of the 201 cases, 193 had confirmed serum samples. The primary clinical events in these patients include agitation (n=130, 67%), tachycardia (greater than or equal to 100/min; n=106, 56%) and hypertension (systolic blood pressure of greater than or equal to 140 mmHg; n=65, 34%). Seizures (n=4, 2%) were reported infrequently in this study and occurred in 2 patients following MDPV only intoxication and 2 patients with a mixed intoxication (Beck et al, 2015).

D) DELIRIUM

1) WITH POISONING/EXPOSURE

a) EXCITED DELIRIUM SYNDROME

1) SUMMARY: There have been reports of both intoxication and excited delirium following the use of MDPV (Kesha et al, 2013; Penders et al, 2012; Penders & Gestring, 2011).
2) 3,4-METHYLENEDIOXYPYROVALERONE (MDPV)

a) CASE REPORT: A 39-year-old man, with a history of depression, back pain and substance abuse, was found delusional and wandering aimlessly after taking bath salts. Soon after admission, he developed agitation, ventricular tachycardia and severe hyperthermia (peaked at 107.1 F). He rapidly developed asystole that was unresponsive to resuscitation efforts. The patient died 12 hours after presentation to the emergency department; postmortem biological testing was positive for MDPV (Kesha et al, 2013).
b) CASE REPORT: A 40 year-old-man with a history of bipolar disorder and cocaine abuse, died after injecting and snorting MDPV. His presentation was consistent with Excited Delirium Syndrome with delirium, severe agitation, hyperthermia (105.4 F), tachypnea, tachycardia (164 beats/minute) followed by cardiac arrest shortly after attempts at physical and pharmacologic restraint. His clinical course included an initial cardiac arrest, hyperkalemia, persistent hypotension, metabolic acidosis, oliguric renal failure, coagulopathy, GI bleeding, and rhabdomyolysis. Approximately, 42 hours after admission he was declared brain dead based on neurologic findings (pupils fixed and dilated with no response to noxious stimuli) and care was withdrawn. Laboratory analysis of serum and urine confirmed MDPV and trimethoprim (thought to be an adulterant); screening for drugs of abuse were negative along with a negative methadone level (Murray et al, 2012).
c) CASE REPORTS: Three young adults ingested MDPV and developed various degrees of Excited Delirium following high doses of bath salts (3 packets of 1500 mg in one patient and repeated dosing over several days in the other 2 patients) including paranoid delirium, delusions, confusion, hallucinations, fearfulness, agitation and violent behavior. Symptoms included profuse diaphoresis, hyperthermia (41 degrees C in one patient), elevated creatine kinase (range: 5000 to 32880 Units/L) and tachycardia (range: 150 to 170 beats/min). Two patients developed renal failure and one required intubation for CNS and respiratory depression. All required intensive medical care, but symptoms resolved completely within a few days (Penders et al, 2012).

E) SEROTONIN SYNDROME

1) WITH POISONING/EXPOSURE

a) BATH SALTS

1) CASE REPORT: A 42-year-old woman reported purchasing bath salts on line, and burning them on aluminum foil and inhaling the fumes for several weeks. Laboratory confirmation was not performed. Initially, the patient used 20 to 30 mg/day and was using up to 200 mg/day prior to presentation. She was admitted with agitation and bizarre behavior; vivid hallucinations were also present. Early treatment included lorazepam. Other manifestations present upon admission were restlessness, tremors, generalized hypertonicity (worse in the lower extremities), shivering with profuse sweating, flushed skin, tachycardia, hypertension, and fever (38.8 degrees C). Creatine kinase and creatinine (3.3 mg/dL) were the only laboratory studies that were elevated. Aggressive IV fluid administration was initiated along with lorazepam and haloperidol therapy. Her vital signs stabilized and her laboratory studies improved by day 2. The patient was discharged to home on day 4 after psychotic symptoms resolved; she recovered completely (Joksovic et al, 2012).

b) BUTYLONE AND METHYLONE

1) CASE REPORT: A 24-year-old woman was found unconscious with tachycardia (heart rate 132 beats/min) and hypotension (BP 80/60 mmHg) after ingesting 2 tablets thought to be Ecstasy (later confirmed to contain methylone and butylone only). She was admitted comatose, febrile, tachycardic, hypertensive, tachypneic, diaphoretic, tremulous, and hyperreflexic with sustained clonus. Treatment included external cooling, mechanical ventilation and fluid resuscitation. Lorazepam and midazolam were used to treat myoclonus symptoms and non-depolarizing neuromuscular blockers were added to stop all muscular activity and control hyperthermia. Her clinical course was further complicated by DIC, pulseless electrical activity that improved with resuscitation that was followed by ARDS and renal failure. The patient died 48 hours after admission of lactic acidosis and hypoxemia. An autopsy showed evidence of generalized coagulopathy, fatty liver and anoxic encephalopathy (Warrick et al, 2012).

c) MDPV

1) CASE REPORT: A 41-year-old woman with a previous history of alcohol abuse developed increasing agitation and confusion over a 2 day period after using a bath salt ("Blue Magic") by insufflation. On the day of admission, the patient was poorly responsive, unable to follow commands and became extremely agitated when not sedated. Initial laboratory studies and a head CT were normal. The following day the patient was hyperreflexic with inducible clonus and increased tone in her lower extremities. Treatment included propofol, benzodiazepines and a fentanyl infusion was added for sedation and analgesia. Over the next 2 days, the patient continued to be agitated and hyperreflexic; symptoms became less responsive to sedation. Cyproheptadine (12 mg via NG tube) was started on day 4 for serotonin syndrome (met Hunter criteria) and continued at 8 mg 4 hours later and then 8 mg every 6 hours; treatment was required for 8 days. Her clinical course was complicated by aspiration pneumonia and a pneumothorax. She was extubated on day 7 after some neurologic improvement, and had a complete resolution of all symptoms by day 11. The patient was discharged the following day. A toxicology screen was negative for amphetamines, antidepressants, or other serotonergic agents. The patient's prolonged course of serotonin syndrome associated with MDPV may be related to the addition of fentanyl (Mugele et al, 2012).

F) PARKINSONISM

1) WITH POISONING/EXPOSURE

a) Severe early onset parkinsonism has been reported in several patients with a history of methcathinone abuse; some of these patients have had elevated serum manganese concentrations. The manganese toxicity is believed to result from impurities present in the illicit methcathinone, which is manufactured by combining pseudoephedrine with potassium permanganate. Based on several small studies, the effects of manganese toxicity appear to be permanent (Stepens et al, 2014; Sikk et al, 2013).
b) CLINICAL/DIAGNOSTIC FINDINGS: In a study conducted from 2006 to 2012 of 38 methcathinone users, findings suggest that manganese exposure may produce a chronic neurodegenerative disease despite cessation of methcathinone. The onset of neurologic symptoms was highly variable (0.5 to 12 years). Common presenting features included gait disturbances, speech disturbances, and loss of balance. Plasma manganese concentrations were usually higher in active users compared to former users. Due to the rapid decline of manganese concentrations, it may not be a reliable biomarker of exposure. Brain MRI imaging (ie, high signal intensities in the globus pallidus, substantia nigra and periaquaductal gray matter) provided recent information regarding manganese exposure. Levodopa was also found to be ineffective in treating the parkinsonian syndrome observed in methcathinone users (Sikk et al, 2013). In another study of methcathinone abusers, MRI imaging showed decreased T1 weighted hyperintensity on basal ganglia in some former users with no clinical neurological improvement. Manganese concentrations were also normal following discontinuation of use (Stepens et al, 2014).
c) METHCATHINONE (EPHEDRONE): Four cases of manganism, presented as impaired postural control, hypophonic dysarthria, hypokinesia and dystonia were reported in persons using repeated intravenous injections of methcathinone solution, prepared by combining pseudoephedrine and potassium permanganate. Manganese content of the final mixture was 0.6 g/L with ephedrone yield of approximately 44% (Sikk et al, 2007). One man developed manganese-induced levodopa-resistant parkinsonism with profound hypophonia after intravenously injecting himself once or twice daily for several months with a methcathinone solution, prepared by combining 12 tablets containing 60 mg of pseudoephedrine hydrochloride with 0.3 g of potassium permanganate (deBie et al, 2007).
d) CASE REPORT: A 28-year-old Ukrainian man developed gait disturbances, loss of balance, altered speech and mental slowness along with limb bradykinesia and rigidity bilaterally after a 3-year period of daily intravenous ephedrone (mean dose: 4 injections/day). Symptoms were consistent with manganese intoxication. Despite standard Parkinson drug therapy (ie, courses of levodopa, dopamine agonists and anticholinergics), neurologic function continued to decline leading to generalized disability (Colosimo & Guidi, 2009).
e) CASE REPORTS: Three teenagers (15 to 19 years old) developed extrapyramidal abnormalities and movement disorders after chronic intravenous exposure to a mixture referred to as "Russian Cocktail". Elevated manganese concentrations (2100 microg/L and 3176 microg/L) were reported in 2 of the patients. Following supportive care the patients reported subjective improvement, but little change in objective measures was observed. The mixture was purportedly similar to methcathinone and contained ephedrine, aspirin and potassium permanganate (Varlibas et al, 2009).

G) CEREBRAL HEMORRHAGE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 28-year-old woman developed an intracerebral hemorrhage following cathinone abuse (ie, "Hagigat" - illicit capsules containing 200 mg cathinone) and required surgical intervention. She developed permanent spasticity of the left hand and paresis of the left leg (Bentur et al, 2008).

H) INSOMNIA

1) WITH POISONING/EXPOSURE

a) Insomnia and disturbed sleep have been described following binge use (ie, dosing every 30 minutes to 2 hours over a 24 to 36 hour period) of methcathinone (Calkins et al, 1995; Emerson & Cisek, 1993). Insomnia has also been reported among 4-methylmethcathinone (mephedrone) users (Independent Scientific Committee on Drugs, 2010).

I) CATATONIA

1) WITH POISONING/EXPOSURE

a) CASE SERIES/SYNTHETIC CATHINONES: In a retrospective case series of patients (n=236) reporting to 2 poisons centers with exposure to various synthetic cathinones (ingredients detected in bath salt samples were limited to mephedrone, methylone, and MDPV [methylenedioxypyrovalerone]), catatonia was observed in 1 (1%) patient (Spiller et al, 2011).

3.7.3)

A) ANIMAL STUDIES

1) BEHAVIORAL EFFECTS

a) Hypermotility and stereotyped behavior of animals induced by cathinone have been reported (Zelger et al, 1980). These are due to enhanced transmitter release from catecholaminergic nerve terminals in the CNS (Kalix, 1984a).

Gastrointestinal

3.8.2)

A) NAUSEA AND VOMITING

1) WITH POISONING/EXPOSURE

a) 4-METHYLMETHCATINONE (MEPHEDRONE)

1) SUMMARY: Based on hospital admissions and calls to poison centers, nausea and vomiting have been reported frequently among mephedrone users (Dargan et al, 2011).
2) CASE SERIES: In a series of 15 patients with self-reported mephedrone use, 2 (13.3%) patients developed vomiting. All patients in this series reported concomitant ethanol or other recreational drug (eg, GHB/GBL, cocaine, ketamine, hallucinogenic amphetamines) use. Antiemetics and IV fluids were given as needed (Wood et al, 2011).
3) Mephedrone users have reported nausea with use (Independent Scientific Committee on Drugs, 2010).

b) METHCATHINONE

1) In a survey of 19 methcathinone users, nausea and stomach cramps have been described. In 4 users who had a history of amphetamine use, methcathinone was reported to produce more intense nausea compared to amphetamine (Calkins et al, 1995).

c) HAGIGAT

1) HAGIGAT USERS: In a 10 month, prospective, observational study from Israel of 34 Hagigat users (illicit capsules containing 200 mg cathinone), vomiting (n=11 (32.4%)), nausea (n=8 (23.5%)), and abdominal pain (n=7 (20.6%)) were commonly reported toxic effects (Bentur et al, 2008).

B) LOSS OF APPETITE

1) Cathinone has a similar anorectic effect as amphetamine (Kalix, 1992).
2) Anorexia has developed in Hagigat users (illicit capsules containing 200 mg cathinone) (Bentur et al, 2008).

C) WEIGHT LOSS FINDING

1) WITH POISONING/EXPOSURE

a) Cyclic binging of methcathinone can result in extreme weight loss and dehydration (Emerson & Cisek, 1993).

Genitourinary

3.10.2)

A) ACUTE RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Upon admission a 39-year-old man was combative and confused with diaphoresis, tachycardia and hypertension (BP 200/92 mmHg) and was sedated and intubated to protect his airway. Initial laboratory studies showed a serum creatinine of 1.22 mg/dL and serum creatinine kinase (CK)1303 Units/L; a toxicology screen was positive for oxycodone. His family reported a history of poly substance abuse and bath salt use (several pills) a few hours before admission. The following day urine output declined (less than 100 mL/24 hours) and serum CK rose to 6600 Units/L. A renal ultrasound was normal; however acute tubular necrosis was suspected due to urinary fractional excretion of sodium. The patient continued to decline and developed hypotension and fluid overload. The following day the patient was started on continuous renal replacement therapy (CRRT) for oligoanuric renal failure for 48 hours. Over the next 48 hours, his renal output improved and blood pressure stabilized. He continued to improve and was extubated on day 13. He admitted to taking "bath salt pills" just prior to admission (Regunath et al, 2012)
b) CASE REPORT: A 26-year-old man was hospitalized twice following 2 separate episodes of "bath salts" toxicity. He developed agitation, confusion and paranoia and laboratory evidence of an elevated serum creatinine concentration after his first exposure. He was treated with IV normal saline and discharged the following day with normal renal function and follow-up with outpatient psychiatry. He was readmitted 5 days later with similar symptoms and reportedly had been using bath salts daily since his previous hospital discharge. By day 3, he had a peak serum creatinine concentration of 4.6 mg/dL. Intravenous saline was administered for 72 hours and by day 6 the serum creatinine concentration was 1.4 mg/dL when he was transferred to an inpatient psychiatric unit (Adebamiro & Perazella, 2012).
c) METHYLENEDIOXYPYROVALERONE (MDPV)

1) CASE REPORT: A 25-year-old man initially developed severe agitation and an altered mental status after injecting MDPV (confirmed by laboratory analysis) which progressed to multiorgan failure. He was admitted with hypertension, tachycardia (175 beats/min) and a rectal temperature of 106.3 degrees F. Immediate treatment included intubation, cooling measures and sedation with an improvement in vital signs. However, the patient developed renal failure, fulminant hepatic failure, DIC and rhabdomyolysis with a peak creatine kinase of 253,377 Units/L. Anuric renal failure was treated with continuous renal replacement therapy followed by hemodialysis. He gradually improved and was extubated on hospital day 9 with normal mentation by day 13. The patient was discharged on day 18, but required hemodialysis for 1 month. A urine screen for MDPV was positive on the day of admission; a urine hallucinogen screen was negative (Borek & Holstege, 2012).
2) CASE REPORT: A 37-year-old man ingested an unknown amount of bath salts 4 hours prior to admission. Upon presentation, he was agitated, tachycardic and hyperthermic. An initial creatine kinase level was 90,168 International Units/L. He complained of myalgias. Twelve hours later the patient had a creatine kinase of 350,000 International Units/L and creatine of 5.1 mg/dL. Despite 8.5 L of crystalloid fluids, the patient had a urine output of 345 mL. Temporary vascular dialysis was started. The patient also developed compartment syndrome with tenderness and firmness in the paraspinal regions requiring resection of deep paraspinous compartments due to necrotic muscle. A urine drug screen was positive for MDPV, caffeine and hydrocodone. At 5 months, the back was healed, but he remained in renal failure requiring ongoing hemodialysis (Levine et al, 2013).

Hematologic

3.13.2)

A) DISSEMINATED INTRAVASCULAR COAGULATION

1) WITH POISONING/EXPOSURE

a) METHLENEDIOXYPYROVALERONE (MDPV)

1) CASE REPORTS: Two patients died following exposure to MDPV (laboratory confirmation) after presenting with hyperthermia, agitated delirium and tachycardia. Both patients developed profound disseminated intravascular coagulation following (within hours in one patient) admission (Young et al, 2013):

a) A young adult was witnessed sniffing bath salts and seizing and became unresponsive. He was intubated and developed narrow complex tachycardia. His initial laboratory studies included: PT 43 s, INR 4.6, PTT 86.6 s an elevated WBC and a creatine kinase of 1163 Units/L. His course was complicated by hyperthermia (40.5 degrees C), epistaxis, and DIC (fibrinogen less than 50 mg/dL, PT greater than 200 s, INR greater than 15, PTT greater than 200 s and D-dimer 32). The patient was treated with boluses of fluid, fresh frozen plasma (FFP), cryoprecipitate and phytonadione. Shortly after transfer to ICU, he became pulseless and died 8 hours after admission.
b) The second patient was a 48 year-old woman with ethanol abuse who ingested bath salts and was found unresponsive by her family. She was alert upon arrival to the healthcare setting and soon became agitated with hypertension (BP 220/110 mmHg), tachycardia (148 beats/min) and febrile (39.4 degrees C). She was also noted to have bloody diarrhea. The patient was admitted to ICU and started on dexmetomidine and nicardipine. By day 2, the patient had evidence of DIC and was given FFP and packed red blood cells. The following day the patient had bleeding from the mouth and vagina and was anuric. Creatine kinase rose to 46000 Units/L and became further hypotensive despite ongoing inotropic support. The patient died on hospital day 4; a blood sample sent to a tertiary laboratory confirmed MDPV (29 ng/mL).

Dermatologic

3.14.2)

A) EXCESSIVE SWEATING

1) WITH POISONING/EXPOSURE

a) Diaphoresis has been reported in some cases of synthetic cathinone use (Emerson & Cisek, 1993).
b) 4-METHYLMETHCATHINONE (MEPHEDRONE): In surveys and hospital admissions, excessive sweating was a common finding among mephedrone users (Independent Scientific Committee on Drugs, 2010).

1) INCIDENCE: In a series of 15 patients with self-reported mephedrone use, excessive sweating developed in 2 (13.3%) patients (Wood et al, 2011).

B) DERMATOLOGICAL FINDING

1) WITH POISONING/EXPOSURE

a) Cyclic binging of methcathinone can result in acne vulgaris, acrocyanosis, and a waxen complexion (Emerson & Cisek, 1993).
b) 4-METHYLMETHCATHINONE (MEPHEDRONE): Skin discoloration, cold or blue extremities have been described by mephedrone users (Independent Scientific Committee on Drugs, 2010). In another series of 15 patients with self-reported mephedrone use, there were no reports of skin discoloration or cold extremities (Wood et al, 2011)

C) CELLULITIS

1) WITH POISONING/EXPOSURE

a) CASE SERIES: Four adults developed soft tissue complications which included cellulitis, thrombophlebitis and localized and extensive abscess after intravenous administration of a synthetic cathinone (eg, mephedrone, methylone, and flephedrone). Symptoms of increasing cellulitis were observed 1 to 7 days after injection. Three patients required surgical debridement and all received intravenous antibiotic therapy. One patient developed an extensive abscess and skin and muscle necrosis of the left upper arm that required surgical debridement and a split-thickness skin graft to close the wound. These events are likely multifactorial (ie, poor hygiene, lack of sterile technique, contamination of the substance), it is unclear how much the "bath salts" contributed to the tissue injury (Dorairaj et al, 2012).

D) NECROTIZING FASCIITIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 34-year-old woman with a history of substance abuse was admitted with a 2 day history of increasing right forearm pain and erythema after injecting bath salts intramuscularly (she was unable to inject herself intravascularly). Broad spectrum antibiotics were started and erythema was starting to improve. However, the following day further erythema was noted, as well as sloughing around the injection site and malodorous drainage. Immediate surgical debridement was undertaken, but rapid necrotizing fascitis developed requiring forequarter amputation with radical mastectomy and chest wall debridement to identify healthy tissue margins. She was diagnosed with streptococcal necrotizing fascitis and myonecrosis. Extensive split-thickness skin grafting was needed. At follow-up she was progressing well and receiving rehabilitative care (Russo et al, 2012).

Musculoskeletal

3.15.2)

A) MYOCLONUS

1) WITH POISONING/EXPOSURE

a) CASE SERIES/SYNTHETIC CATHINONES: In a retrospective case series of patients (n=236) reporting to 2 poisons centers with exposure to various synthetic cathinones (ingredients detected in bath salt samples were limited to mephedrone, methylone, and MDPV [methylenedioxypyrovalerone]), myoclonus was reported in 45 (19%) patients (Spiller et al, 2011).

B) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) CASE SERIES/SYNTHETIC CATHINONES: In a retrospective case series of patients (n=236) reporting to 2 poisons centers with exposure to various synthetic cathinones (ingredients detected in bath salt samples were limited to mephedrone, methylone, and MDPV [methylenedioxypyrovalerone]), an increase in CPK was observed in 22 (9%) patients. The mean CPK reported was 1825 U/L (range: 301 to 4400 U/L) (Spiller et al, 2011).
b) BATH SALTS

1) Severe rhabdomyolysis developed in 3 cases of bath salt exposure along with delayed compartment syndrome (Levine et al, 2013).
2) CASE REPORTS

a) An 18-year-old man with a history of substance abuse was admitted with severe agitation, tachycardia (heart rate 160 beats/min) and hyperthermia (42.1 degrees C) requiring immediate intubation due to apnea. His initial laboratory studies were significant for a creatine kinase of 64,578 International Units/L, hyperkalemia (6.3 mmol/L), hypoglycemia (glucose 45 mg/dL) and metabolic acidosis (pH 7.18). Approximately 12 hours after admission, the patient extubated himself and complained of right forearm pain with some firmness of the forearm and a creatine kinase levels of 201,564 International/Units. Compartment pressures were elevated in the right arm requiring a fasciotomy and a carpal tunnel release because of elevated pressures. A split-thickness skin graft was also needed for ongoing firmness of the contralateral forearm. A left forearm fasciotomy and carpal tunnel release was also needed. The patient admitted to injecting bath salts in his left arm shortly before admission; the right arm had not been injected for several months. The patient gradually improved over several months (Levine et al, 2013).
b) A 37-year-old man ingested an unknown amount of bath salts 4 hours prior to admission. Upon presentation, he was agitated, tachycardic and hyperthermic. An initial creatine kinase level was 90,168 International Units/L. He complained of myalgias; muscle compartments were soft. Twelve hours later the patient had a creatine kinase of 350,000 International Units/L and noted tenderness and firmness in the paraspinal regions along with oliguric renal failure. Hemodialysis was initiated. Fasciotomy of deep paraspinous compartments of the lumbar spine was performed with resection of necrotic muscle; the patient was taken back to surgery for further removal of necrotic muscle the following day. At 5 months, the back was healed, but he remained in renal failure requiring ongoing hemodialysis (Levine et al, 2013).
c) A 43-year-old man with a history of substance abuse was admitted due to acting "strangely" after snorting 2 vials of bath salts. He complained of generalized pain with significant low back pain along with agitation and tachycardia. An initial creatine kinase level was 27,025 International Units/L. By the following day, the patient was neurologically improved with supportive care but continued to complain of pain in the paraspinal muscles of the thoracolumbar region. Creatine kinase rose to 126,087 International Units/L and peaked at 162,495 International Unit/L. A MRI of the back showed bilateral paraspinal muscular edema of the lower thoracic region and the entire lumbar spine; conservative therapy was started. Symptomatic improvement was noted as the creatine kinase level declined (Levine et al, 2013).

c) ETHCATHINONE AND METHYLONE

1) CASE REPORT: A 22-year-old woman developed tonic-clonic seizures and repeat episodes of vomiting after ingesting "legal ecstasy" (a powdered mixture containing ethcathinone and methylone obtained from a head shop) and 3 alcoholic beverages. Other symptoms included euphoria, agitation, sweating and intense thirst. The patient consumed 3.5 L of water just prior to her first seizure. She required intubation for recurrent seizures and developed severe hyponatremia (Na 120 mmol/L). She was extubated the following day with no further seizures. Upon admission, the creatine kinase concentration was elevated (195 Units/L) and peaked at 36,648 Units/L on the evening of day 3. The patient was hospitalized for several days until the level improved with no evidence of renal failure. The patient recovered completely (Boulanger-Gobeil et al, 2012).

d) METHYLENEDIOXYPYROVALERONE (MDPV)

1) CASE REPORT: A 25-year-old man initially developed severe agitation and an altered mental status after injecting MDPV (confirmed by laboratory analysis) which progressed to multiorgan failure. He was admitted with hypertension, tachycardia (175 beats/min) and a rectal temperature of 106.3 degrees F. Immediate treatment included intubation, cooling measures and sedation with an improvement in vital signs. However, the patient developed renal failure, fulminant hepatic failure, DIC and rhabdomyolysis with a peak creatine kinase of 253,377 Units/L. Anuric renal failure was treated with continuous renal replacement therapy followed by hemodialysis. He gradually improved and was extubated on hospital day 9 with normal mentation by day 13. The patient was discharged on day 18, but required hemodialysis for 1 month. A urine screen for MDPV was positive on the day of admission; a urine hallucinogen screen was negative (Borek & Holstege, 2012).
2) CASE SERIES: In an observational case series of consecutive patients admitted to Swedish hospitals from 2010 to 2014 with known or suspected exposure to new psychoactive substances (NPS), a total of 201 cases of analytically confirmed methylenedioxypyrovalerone (MDPV) exposures were found. Of the 201 cases, 193 had confirmed serum samples. The primary clinical events in these patients included agitation (n=130, 67%), tachycardia (greater than or equal to 100/min; n=106, 56%) and hypertension (systolic blood pressure of greater than or equal to 140 mmHg; n=65, 34%). Other potentially significant symptoms included: hallucinations (n=31, 16%), delirium (n=29, 15%), hyperthermia (greater than 39 degrees C; n=18, 10%), and rhabdomyolysis (n=16, 8%). MDPV serum levels of greater than 100 ng/mL resulted in more severe symptoms (Beck et al, 2015).

C) COMPARTMENT SYNDROME

1) WITH POISONING/EXPOSURE

a) SUMMARY

1) Acute compartment syndrome has been observed following the abuse of synthetic cathinones. These events occurred following a history of injecting or ingesting "bath salts" (Levine et al, 2013).

a) CASE REPORTS

1) An 18-year-old man with a history of substance abuse was admitted with severe agitation, tachycardia (heart rate 160 beats/min) and hyperthermia (42.1 degrees C) requiring immediate intubation due to apnea. His initial laboratory studies were significant for a creatine kinase of 64,578 International Units/L, hyperkalemia (6.3 mmol/L), hypoglycemia (glucose 45 mg/dL) and metabolic acidosis (pH 7.18). Approximately 12 hours after admission, the patient extubated himself and complained of right forearm pain with some firmness of the forearm and a creatine kinase levels of 201,564 International/Units. Compartment pressures were elevated in the right arm requiring a fasciotomy and a carpal tunnel release because of elevated pressures. A split-thickness skin graft was also needed for ongoing firmness of the contralateral forearm. A left forearm fasciotomy and carpal tunnel release was also needed. The patient admitted to injecting bath salts in his left arm shortly before admission; the right arm had not been injected for several months. The patient gradually improved over several months (Levine et al, 2013).
2) A 37-year-old man ingested an unknown amount of bath salts 4 hours prior to admission. Upon presentation, he was agitated, tachycardic and hyperthermic. An initial creatine kinase level was 90,168 International Units/L. He complained of myalgias; muscle compartments were soft. Twelve hours later the patient had a creatine kinase of 350,000 International Units/L and noted tenderness and firmness in the paraspinal regions along with oliguric renal failure. Hemodialysis was initiated. Fasciotomy of deep paraspinous compartments of the lumbar spine was performed with resection of necrotic muscle; the patient was taken back to surgery for further removal of necrotic muscle the following day. At 5 months, the back was healed, but he remained in renal failure requiring ongoing hemodialysis (Levine et al, 2013).
3) A 43-year-old man with a history of substance abuse was admitted due to acting "strangely" after snorting 2 vials of bath salts. He complained of generalized pain with significant low back pain along with agitation and tachycardia. An initial creatine kinase level was 27,025 International Units/L. By the following day, the patient was neurologically improved with supportive care but continued to complain of pain in the paraspinal muscles of the thoracolumbar region. Creatine kinase rose to 126,087 International Units/L and peaked at 162,495 International Unit/L. A MRI of the back showed bilateral paraspinal muscular edema of the lower thoracic region and the entire lumbar spine; conservative therapy was started. Symptomatic improvement was noted as the creatine kinase level declined (Levine et al, 2013).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs and neurologic function frequently.
B) Monitor serum electrolytes, renal function and hepatic enzymes in symptomatic patients. Monitor CPK in patients with prolonged agitation or seizures. Obtain an ECG and institute continuous cardiac monitoring in all patients.
C) Monitor core temperature. Hyperthermia above 40 degrees C is life threatening and mandates immediate cooling and sedation.
D) Synthetic cathinone derivatives (ie, cathinone, methcathinone) are not detected on routine urine drug screens.
E) Additional studies may include a CBC, coagulation profile, chest x-ray, CT of the head, a lumbar puncture as clinically indicated if the diagnosis is unclear.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Monitor serum electrolytes, renal function and hepatic enzymes in symptomatic patients. Monitor CPK in patients with prolonged agitation or seizures.
2) Additional studies may include a CBC and coagulation profile if the diagnosis is unclear.

4.1.4)

A) OTHER

1) CARDIAC MONITORING

a) Obtain a baseline ECG in all patients and repeat as necessary. Continuous cardiac monitoring is indicated.

2) HEAD CT

a) A CT of the head may be indicated in patients with an altered level of consciousness if the diagnosis is unclear.

Radiographic Studies

A)

Methods

A)

1) SUMMARY: Synthetic cathinone derivatives (ie, cathinone, methcathinone) have been identified in some laboratory methods, but are not likely to be clinically useful following acute exposure.
2) CASE REPORT: A 29-year-old woman was comatose upon admission after ingesting bromazepam (Lexomil(R)) dissolved in alcohol and a party drug as reported by family members. Glasgow coma score was 9 on admission with mydriasis, rapid respirations, mild tachycardia (heart rate 92) and hypotension. Laboratory studies including a blood gas analysis were normal. Blood alcohol was 0.167 g/dL, urine screening was positive for methcathinone (17.24 mg/L), ephedrine (11.60 mg/L) and methylephedrine 11.10 mg/L) with a serum analysis by HPLC detecting bromazepam (8.89 mg/L), methcathinone (0.5 mg/L) and methylephedrine (0.19 mg/L). Following supportive care the patient clinically improved within 24 hours and was transferred for further psychiatric evaluation (Belhadj-Tahar & Sadeg, 2005). Based on the clinical (ie, rapid respirations without acidosis) and laboratory findings, coma was attributed to methcathinone toxicity associated with bromazepam, with the typical presentation of methcathinone (ie, hypertension and convulsions) likely altered by the combined use of alcohol and bromazepam.

B)

1) SYNTHETIC CATHINONE DERIVATIVES: A liquid chromatography-mass spectrometry/mass spectrometry method (LC-MS/MS) was developed for the selective detection of 31 designer drugs including cathinone and methcathinone in serum. The limits of detection were determined by analyzing S/N ratios and were found to be between 1 and 5 ng/mL. The extraction efficacy (mean +/- SD, %) was 83 (+/- 17.3) for cathinone and 81 (+/-18.3) for methcathinone (Wohlfarth et al, 2010).
2) 4-METHYLMETHCATHINONE: Liquid chromatography with tandem mass spectrometric (LC/MS) detection was used to quantitatively detect 4-methylmethcathinone in serum following intentional exposure in a young adult (Wood et al, 2010). The authors used synthesized methcathinone as the reference standard, since no certified reference standard existed.
3) METHCATHINONE: A method to detect methcathinone in human plasma by LC-MS/MS was found to be sensitive and precise. The lower limit of quantification was 10 ng/mL (Beyer et al, 2007).

C)

1) 4-METHYLMETHCATHINONE: Gas chromatography/mass spectrometry (GC/MS) was used to qualitatively detect 4-methylmethcathinone (mephedrone) in urine and serum samples following intentional exposure in a young adult (Wood et al, 2010).

a) GC/MS: Blood and/or urine concentrations were quantified using Agilent 7890A/5975c which was able to detect 4-methylmethcathinone (mephedrone), methylenedioxypyrovalerone (MDPV), and 4-methylenedioxy-N-methylcathinone (methylone) (Spiller et al, 2011).

2) CATHINONE and METHCATHINONE: A method using GC/MS was developed to detect cathinone and methcathinone in the urine which is similar to methods used for amphetamine and methamphetamine. To detect cathinone and methcathinone the use of oxidizing agents was not recommended because the compounds were lost to oxidation; therefore, 4-carboethoxyhexafluoroubutyryl (4-CB) derivatives demonstrated better ion selection and chromatographic resolution than heptafluorobutyric derivatives (Paul & Cole, 2001).
3) ETHYLONE/POSTMORTEM: Gas chromatography/mass spectrometry was used to confirm the presence of ethylone in the blood followed by quantification using GC-MS SIM analysis in a young adult that was found dead after illicit drug use the evening before. The cause of death was determined to be due to a mixed ingestion of ethylone, heroin and alprazolam intoxication. It was unclear if the patient had a history of illicit drug use, but hypodermic needles and a metal spoon with a dark tarry substance were found at the scene (McIntyre et al, 2015).
4) FLUOROMETHCATHINONE: GC/MS has been used to detect the 3 isomers of fluoromethcathinone (ie, 4'-fluoromethcathinone, 3'-fluoromethicathinone, and 2'-fluoromethcathinone) and their respective N-acetyl derivatives. It was also possible to provide a rapid method to determine the positional isomers of fluoromethcathinone using nuclear magnetic resonance spectroscopy (ie, Attenuated Total Reflectance Fourier transform infrared spectroscopy (ATR-FTIR) (Archer, 2009).
5) PENTEDRONE AND alpha-PYRROLIDINOVALEROPHENONE/POSTMORTEM: A man, with a history of designer-drug use, died following ingestion of pentedrone (an alpha-pentyl-beta-keto analog of 3,4-methylenedioxy-N-methylamphetamine (MDMA)) and alpha-pyrrolidinovalerophenone. Postmortem samples were measured using gas chromatography-mass spectrometry after liquid-liquid extraction (Sykutera et al, 2015).

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with significant persistent central nervous system toxicity (ie, hallucinations, somnolence, delirium, coma), hyponatremia, or persistent tachycardia should be admitted. Patients with coma, seizures, dysrhythmias, serotonin syndrome or delirium should be admitted to an intensive care setting.

1) CASE SERIES/SYNTHETIC CATHINONES: In a retrospective case series of patients (n=236) reporting to 2 poisons centers with exposure to various synthetic cathinones (ingredients detected in bath salt samples were limited to mephedrone, methylone, MDPV (methylenedioxypyrovalerone), 116 (49%) patients were treated and released from the ED, 50 (21%) were admitted to an intensive care unit, 29 (12%) were admitted to a mental health setting (behavioral or psychiatry), and 13 (6%) were managed at a non-healthcare facility (Spiller et al, 2011).
2) CASE SERIES/MEPHEDRONE: In a series of 15 patients with self-reported mephedrone use, the most common clinical findings were cardiovascular or neurologic. Most patients (n=11) were discharged directly from the ED following observation or treatment. Of the 4 patients admitted, one required admission to intensive care. All patients were discharged without permanent sequelae; the average length of stay (with the exception of one patient) was 8.4 (range: 1.2 to 28 hr) hours (Wood et al, 2011).

6.3.1.2) HOME CRITERIA/ORAL

A) Asymptomatic adults may be monitored at home. However, it is unlikely that a patient will be asymptomatic if a binge user.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (ie, seizures, dysrhythmias, severe delirium, coma), or in whom the diagnosis is not clear.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with deliberate self-harm ingestions or children with any ingestion and symptomatic patients should be sent to a healthcare facility for observation for 6 to 8 hours.

1) CASE SERIES/SYNTHETIC CATHINONES: In a retrospective case series of patients (n=236) reporting to 2 poisons centers with exposure to various synthetic cathinones (ingredients detected in bath salt samples were limited to mephedrone, methylone, MDPV (methylenedioxypyrovalerone), 116 (49%) patients were treated and released from the ED, 50 (21%) were admitted to an intensive care unit, 29 (12%) were admitted to a mental health setting (behavioral or psychiatry), and 13 (6%) were managed at a non-healthcare facility (Spiller et al, 2011).
2) CASE SERIES/MEPHEDRONE: In a series of 15 patients with self-reported mephedrone use, the most common clinical findings were cardiovascular or neurologic. Most patients (n=11) were discharged directly from the ED following observation or treatment. Of the 4 patients admitted, one required admission to intensive care. All patients were discharged without permanent sequelae; the average length of stay (with the exception of one patient) was 8.4 (range: 1.2 to 28 hr) hours (Wood et al, 2011).

Monitoring

A)

B)

C)

D)

E)

Oral Exposure

6.5.1)

A) EMESIS/NOT RECOMMENDED

1) Prehospital decontamination is not recommended because of the risk of aspiration (delirium, seizures) potentially outweighs any potential benefit.

6.5.2)

A) SUMMARY

1) Decontamination may not be indicated based on the route of exposure. Emesis is not recommended due to the potential for CNS stimulation (eg, agitation/delirium, seizures). Activated charcoal may be considered if a recent oral exposure and the patient is able to protect their airway or the airway is protected.

B) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.3)

A) SUPPORT

1) Treatment is symptomatic and supportive; patients may only require observation. Benzodiazepines should be given for sedation as needed; liberal amounts may be needed for severely agitated/delirious patients. Provide a calm and supportive environment. Goal of therapy is to control agitation and minimize any potential end-organ toxicity.

a) CASE SERIES/SYNTHETIC CATHINONES: In a retrospective case series of patients (n=236) reporting to 2 poisons centers with exposure to various synthetic cathinones (ingredients detected in bath salt samples were limited to mephedrone, methylone, MDPV (methylenedioxypyrovalerone), treatment was primarily provided for sedation and persistent myoclonus. Benzodiazepines (eg, diazepam, lorazepam, midazolam) were used to treat most patients (n=125 (53%)). Antipsychotics (ie, haloperidol, ziprasidone) were also used to treat 47 (20%) patients, and a small number of patients received propofol and diphenhydramine. Many patients (n=116 (49%)) were treated and discharged from the ED (Spiller et al, 2011).

2) Intravenous fluids and antiemetics may be needed.
3) Orotracheal intubation is indicated for airway protection in cases of severe agitation, coma or seizure activity.

B) DELIRIUM

1) BENZODIAZEPINES (eg, diazepam or lorazepam) are the main stay of therapy (Mas-Morey et al, 2013). It may be given orally or intravenously.

a) DIAZEPAM Dose: ADULT: 10 mg orally or 5 mg intravenously with repeated doses if not responsive. CHILD: 0.1 mg/kg intravenous or 0.3 mg/kg orally.
b) LORAZEPAM Dose: ADULT: 2 to 4 mg IV repeat every 5 to 10 minutes as needed; CHILD: 0.05 to 0.1 mg/kg repeat every 5 to 10 minutes as needed.
c) Monitor for hypotension, respiratory depression and the need for endotracheal intubation.

C) HYPERTENSIVE EPISODE

1) SUMMARY

a) Hypertension is generally mild and responds to sedation with benzodiazepines.

D) SEIZURE

1) These amphetamine-like agents may produce CNS stimulation (Kalix, 1992). Phenytoin should be avoided in these patients as it may precipitate dysrhythmias (Mas-Morey et al, 2013).
2) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

3) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

4) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

5) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

6) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

7) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

8) RECURRING SEIZURES

a) If seizures are not controlled by the above measures, patients will require endotracheal intubation, mechanical ventilation, continuous EEG monitoring, a continuous infusion of an anticonvulsant, and may require neuromuscular paralysis and vasopressor support. Consider continuous infusions of the following agents:

1) MIDAZOLAM: ADULT DOSE: An initial dose of 0.2 mg/kg slow bolus, at an infusion rate of 2 mg/minute; maintenance doses of 0.05 to 2 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: 0.1 to 0.3 mg/kg followed by a continuous infusion starting at 1 mcg/kg/minute, titrated upwards every 5 minutes as needed (Loddenkemper & Goodkin, 2011).
2) PROPOFOL: ADULT DOSE: Start at 20 mcg/kg/min with 1 to 2 mg/kg loading dose; maintenance doses of 30 to 200 mcg/kg/minute continuous infusion dosing, titrated to EEG; caution with high doses greater than 80 mcg/kg/minute in adults for extended periods of time (ie, longer than 48 hours) (Brophy et al, 2012); PEDIATRIC DOSE: IV loading dose of up to 2 mg/kg; maintenance doses of 2 to 5 mg/kg/hour may be used in older adolescents; avoid doses of 5 mg/kg/hour over prolonged periods because of propofol infusion syndrome (Loddenkemper & Goodkin, 2011); caution with high doses greater than 65 mcg/kg/min in children for extended periods of time; contraindicated in small children (Brophy et al, 2012).
3) PENTOBARBITAL: ADULT DOSE: A loading dose of 5 to 15 mg/kg at an infusion rate of 50 mg/minute or lower; may administer additional 5 to 10 mg/kg. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: A loading dose of 3 to 15 mg/kg followed by a maintenance dose of 1 to 5 mg/kg/hour (Loddenkemper & Goodkin, 2011).
4) THIOPENTAL: ADULT DOSE: 2 to 7 mg/kg, at an infusion rate of 50 mg/minute or lower. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusing dosing, titrated to EEG (Brophy et al, 2012)

b) Endotracheal intubation, mechanical ventilation, and vasopressors will be required (Brophy et al, 2012) and consultation with a neurologist is strongly advised.
c) Neuromuscular paralysis (eg, rocuronium bromide, a short-acting nondepolarizing agent) may be required to avoid hyperthermia, severe acidosis, and rhabdomyolysis. If rhabdomyolysis is possible, avoid succinylcholine chloride, because of the risk of hyperkalemic-induced cardiac dysrhythmias. Continuous EEG monitoring is mandatory if neuromuscular paralysis is used (Manno, 2003).

E) BODY TEMPERATURE ABOVE REFERENCE RANGE

1) Hyperthermia is a marker of severe toxicity and must be treated rapidly and aggressively to avoid complications. Administer benzodiazepines to control agitation, large doses or the addition of a second agent such as propofol may be required. Neuromuscular paralysis and endotracheal intubation may be necessary in severe cases. Monitor core temperature continuously. Cooling measures include keeping the skin moist and encouraging evaporation with fans. Ice packs at the groin and axilla, cooled IV fluids, a cooling blanket, and ventilation with cool air can also be used. For severe hyperthermia, place the patient in an ice water bath for rapid cooling.
2) BENZODIAZEPINES: Administer intravenous benzodiazepines; large doses or the addition of a second agent such as propofol may be required .

a) Diazepam: Adults: 5 to 10 mg IV repeat every 5 to 10 minutes as needed, Children: 0.1 to 0.3 mg/kg IV repeat every 5 to 10 minutes as required.
b) Lorazepam: Adults 2 to 4 mg IV repeat every 5 to 10 minutes as needed; Children: 0.05 to 0.1 mg/kg IV repeat every 5 to 10 minutes as needed.

3) Large doses may be required. Monitor respiratory adequacy and airway. Neuromuscular paralysis and endotracheal intubation may be necessary in severe cases.
4) Cooling measures include keeping the skin moist and encouraging evaporation with fans or packing the patient in ice from head to toe, anteriorly and posteriorly. For severe hyperthermia, place the patient in an ice water bath for rapid cooling. Intubation is usually required in patients with severe hyperthermia.
5) Monitor temperature continuously with a rectal or bladder probe until below 38 degrees C.

F) PSYCHIATRIC SYMPTOM

1) ELECTROCONVULSIVE THERAPY

a) CHRONIC SYMPTOMS/METHYLENEDIOXYPYROVALERONE: A 26-year-old woman, had used bath salts via nasal insufflation for 13 months before admission, was admitted to an inpatient care setting after reporting persistent visual hallucinations of terrifying animals, suspiciousness, and social withdrawal. Hallucinations started after 5 months of bath salts use and continued for up to 8 months after discontinuing the exposure. The patient had no previous history of mental health disorders. Prior treatment with haldoperidol and risperidone were ineffective. Other medications included lurasidone (120 mg) with minimal improvement and citalopram and trazodone were added. Due to a lack of improvement with pharmacologic agents, modified bilateral (left anterior and right temporal stimulus placement) electroconvulsive therapy (ECT) was administered. Pretreatment anesthesia consisted of methohexital 100 mg IV and succinylcholine 100 mg IV. Following 2 treatments, the patient felt significantly better with improved mood and affect. The patient was discharged following a total of 4 ECT treatments. The patient was lost to follow-up but her outpatient psychiatrist reported that the patient continued to have occasional hallucinations, but decreased psychotic symptoms and decreased social anxiety (Penders et al, 2013).

Enhanced Elimination

A)

1) Hemodialysis and hemoperfusion are of no value.

Abstracts

Range Of Toxicity

Maximum Tolerated Exposure

A)

1) These agents are likely combined with other stimulants, alcohol or marijuana, which can increase the risk of severe clinical effects (Winstock et al, 2010; Calkins et al, 1995) or produce unpredictable events.

B)

1) SYNTHETIC CATHINONES: In a retrospective case series of patients (n=236) reporting to 2 poisons centers with exposure to various synthetic cathinones (ingredients detected in bath salt samples were limited to mephedrone, methylone, MDPV (methylenedioxypyrovalerone), one fatality occurred, 8 major clinical events, and 130 moderate cases. Symptoms included: agitation (n=194; 82%), combative violent behavior (n=134; 57%), tachycardia (n=132; 56%), hallucinations (n=94; 40%), paranoia (n=86; 36%), confusion (n=83; 34%), myoclonus (n=45; 19%), hypertension (n=41; 17%), chest pain (n=40; 17%), mydriasis (n=31; 13%), and CPK elevations (n=22; 9%). There were infrequent reports of hypokalemia, blurred vision and catatonia. Clinical events were similar to previous reports of synthetic cathinone use, but there were more frequent reports of aggressive violent behavior (ie, a fatal self-inflicted gun shot, jumping out of windows, randomly discharging a gun secondary to hallucinations/paranoia, abandoning a child thought to be a demon), hallucinations and paranoia. Individuals with prior illicit stimulant (cocaine, methamphetamine) use appeared to have more episodes of severe neurologic or psychiatric symptoms (Spiller et al, 2011).
2) CASE SERIES/MEPHEDRONE: In a series of 15 patients with self-reported mephedrone use, the most common clinical findings were cardiovascular or neurologic. Symptoms included: agitation (53.3%), tachycardia (40%), hypertension (20%), seizures (20%), palpitations (13.3%), vomiting (13.3%), and excessive sweating (13.3%). Headache, bruxism, and hyperreflexia were infrequently reported. Most patients (n=11) were discharged directly from the ED following observation or treatment. Of the 4 patients admitted, one required admission to intensive care. All patients were discharged with permanent sequelae; the average length of stay (with the exception of one patient) was 8.4 (range: 1.2 to 28 hr) hours (Wood et al, 2011).
3) CASE SERIES/METHYLENEDIOXYPYROVALERONE: In an observational case series of consecutive patients admitted to Swedish hospitals from 2010 to 2014 with known or suspected exposure to new psychoactive substances (NPS), a total of 201 cases of analytically confirmed methylenedioxypyrovalerone (MDPV) exposures were found. Of the 201 cases, 193 had confirmed serum samples. The primary clinical events observed in these patients included agitation (n=130, 67%), tachycardia (greater than or equal to 100/min; n=106, 56%) and hypertension (systolic blood pressure of greater than or equal to 140 mmHg; n=65, 34%). Other potentially significant symptoms included: hallucinations (n=31, 16%), delirium (n=29, 15%), hyperthermia (greater than 39 degrees C; n=18, 10%), and rhabdomyolysis (n=16, 8%). Seizures, cardiac arrest, ventricular tachycardia and elevated troponin levels developed infrequently. MDPV serum levels of greater than 100 ng/mL resulted in more severe symptoms (Beck et al, 2015).

C)

1) 4-METHYLMETHCATHINONE (MEPHEDRONE): A 22-year-old purchased 4 g of mephedrone from the Internet and ingested 200 mg orally and then injected himself intramuscularly with the remaining 3.8 g after there was no desired effect. Shortly after parenteral exposure, the patient felt ill with complaint of chest pressure, palpitations, diaphoresis, and tunnel vision and sought medical attention. His symptoms were consistent with sympathomimetic toxicity (ie, hypertension, tachycardia, agitation and mydriasis; however, no evidence of seizures), which gradually resolved over 4 hours with oral lorazepam. Qualitative and quantitative analyses were positive for 4-methylmethcathinone (Wood et al, 2010).
2) CHRONIC SYMPTOMS/METHYLENEDIOXYPYROVALERONE: A 26-year-old woman, had used bath salts via nasal insufflation for 13 months before admission, was admitted to an inpatient care setting after reporting persistent visual hallucinations of terrifying animals, suspiciousness, and social withdrawal. Hallucinations started after 5 months of bath salts use and continued for up to 8 months after discontinuing the exposure. The patient had no previous history of mental health disorders. Prior treatment with haldoperidol and risperidone were ineffective. Other medications included lurasidone (120 mg) with minimal improvement and citalopram and trazodone were added. Due to a lack of improvement with pharmacologic agents, modified bilateral electroconvulsive therapy (ECT) was administered. Following 2 treatments, the patient felt significantly better with improved mood and affect. The patient was discharged following a total of 4 ECT treatments. The patient was lost to follow-up but her outpatient psychiatrist reported that the patient continued to have occasional hallucinations, but decreased psychotic symptoms and decreased social anxiety (Penders et al, 2013).

D)

1) CHRONIC USE: Chronic methcathinone users have described a "typical dose" as being 0.5 to 1 g per day. Administration is usually by intranasal or intravenous routes (Goldstone, 1993).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) SURVIVAL

a) METHCATHINONE: A 29-year-old woman ingested an unknown amount of bromazepam, alcohol and an "amphetamine-like" drug and was admitted to an Emergency Department in a coma. A methcathinone concentration of 17.24 mg/L was detected in the urine and a serum analysis detected the following concentrations: methcathinone (0.50 mg/L), bromazepam (8.89 mg/L) and methylephedrine (0.19 mg/L). A toxicological analysis revealed a blood alcohol level of 0.167 g/dL. Within 24 hours, the patient had fully recovered with supportive care (Belhadj-Tahar & Sadeg, 2005).
b) 4-METHYLMETHCATHINONE (MEPHEDRONE): A 22-year-old purchased 4 g of mephedrone and ingested 200 mg orally and then injected himself intramuscularly with the remaining 3.8 g after there was no desired effect. The patient developed symptoms consistent with sympathomimetic toxicity. Qualitative and quantitative analyses were positive for 4-methylmethcathinone; the serum concentration was estimated to be 0.15 mg/L (Wood et al, 2010).
c) 3,4-METHYLENEDIOXYPYROVALERONE (MDPV): A woman used MDPV by insufflation and developed severe serotonin syndrome requiring intensive supportive care but recovered. Urine MDPV level was 3100 ng/mL (detection limit 100 ng/mL) on the day of presentation, 2 days after drug exposure (Mugele et al, 2012).
d) CASE SERIES/SYNTHETIC CATHINONES: In a retrospective case series of patients (n=236) reporting to 2 poisons centers with exposure to various synthetic cathinones (ingredients detected in bath salt samples were limited to mephedrone, methylone, MDPV (methylenedioxypyrovalerone), a small number of patients (6%) had laboratory confirmation of exposure. MDPV was detected in the blood/serum of 13 of 17 patients (range: 14 to 241 ng/mL; mean: 58 ng/mL). Three of 5 patients had MDPV detected in urine (range: 34 to 1386 ng/mL; mean: 856 ng/mL) (Spiller et al, 2011).

2) FATALITY

a) 4-METHYLMETHCATHINONE (MEPHEDRONE): A 36-year-old man died after ingesting mephedrone which produced an excited state of delirium. Significant blood loss (the man was severely injured with multiple wounds after smashing multiple windows) likely contributed to the patient's death. The postmortem concentration of mephedrone in femoral blood was 5.1 mg/L, 186 mg/L in urine and 1.04 g/L in the stomach. Traces of cocaine, MDMA and oxazepam were also detected in femoral blood. Mephedrone was confirmed in tablets (approximately 140 mg per tablet) found in the patient's home (Lusthof et al, 2011).
b) METHYLENEDIOXYPYROVALERONE (MDPV): A 21-year-old man died of a self-inflicted gun shot wound. Prior to his death his family witnessed an active delusional episode. Postmortem analysis detected MDPV in the blood at 170 ng/mL and in urine at 1400 ng/mL; no other synthetic cathinones were present (Spiller et al, 2011).

Toxicity Information

7.7.1)

A) LD50- (ORAL)RAT:

1) 99 (+/- 5) mg/kg (Emerson & Cisek, 1993)

B) LD50- (SUBCUTANEOUS)MOUSE:

1) 233 (+/- 4) mg/kg (Emerson & Cisek, 1993)

C) LD50- (SUBCUTANEOUS)RAT:

1) 86 (+/- 8) mg/kg (Emerson & Cisek, 1993)

D) METHCATHINONE

1) LD50- (ORAL)MOUSE:

a) 342 (+/- 16) mg/kg (Emerson & Cisek, 1993)

Summary

A)

B)

Minimum Lethal Exposure

A)

1) Fatalities associated with these agents have been reported in the media, but toxicity data are limited. In the United Kingdom, most of the deaths reported included coingestion of CNS depressants (ie, alcohol, opioids, sedatives) (Winstock et al, 2010). Fatalities have also been reported secondary to violent/aggressive behavior induced by the drugs rather than direct toxicity.
2) In general, stimulant related deaths likely result from a sympathomimetic toxidrome (ie, a constellation of symptoms that can produce cardiac conduction effects, cerebral hemorrhage, and occasionally hyperpyrexia) (Winstock et al, 2010).
3) 4-METHYLMETHCATHINONE (MEPHEDRONE): Mephedrone has been implicated in several deaths, but the exact cause(s) of death is unknown (Winstock et al, 2010). In one study, it was found that fatal cases in which death was directly attributed to mephedrone toxicity, the blood concentration was approximately 2 mg/L (consistent with previously reported cases) (Loi et al, 2015).

a) In a data analysis conducted by the UK National Program on Substance Abuse Deaths, 90 cases of mephedrone-related fatalities were identified with 69 cases confirmed as mephedrone toxicity. Causes of death included: acute toxicity (n=26) due to mephedrone (either taken alone or in combination with other psychoactive agents), increase in body temperature while clubbing (n=5), and multi organ failure after several weeks of hospitalization (n=5). Of note, 18 cases were due to self-inflicted injury; 11 cases were due to hanging and 6 patients died under bizarre or risk taking behaviors (n=6) (ie, swimming across a lake and drowning; victim of homicide and car accident) (Schifano et al, 2012).

B)

1) METHYLENEDIOXYPYROVALERONE (MDPV): In a retrospective case series of patients (n=236) reporting to 2 poison centers with exposure to various synthetic cathinones (ingredients detected in bath salt samples were limited to mephedrone, methylone, MDPV (methylenedioxypyrovalerone), a single fatality was reported in a 21-year-old man of a self-inflicted gun shot wound. Prior to his death his family witnessed an active delusional episode. Postmortem analysis detected MDPV in the blood and urine; no other synthetic cathinones were present (Spiller et al, 2011).
2) 4-METHYLMETHCATHINONE (MEPHEDRONE): A 36-year-old man died after ingesting mephedrone which produced an excited state of delirium. Significant blood loss (the man was severely injured with multiple wounds after smashing windows) likely contributed to the patient's death. Postmortem analysis confirmed the presence of mephedrone in the blood, along with traces of cocaine, MDMA and oxazepam. Mephedrone was confirmed in tablets (approximately 140 mg per tablet) found in the patient's home (Lusthof et al, 2011).
3) METHYLONE: Three young adults died after ingesting methylone (confirmed by gas chromatography/mass spectrometry in each patient). Each patient developed seizure-like activity and increased body temperature (range: 103.9 to 107 degrees F) and 2 patients had metabolic acidosis. A 23-year-old man went into cardiac arrest approximately 3.5 hours after admission and had 4 more episodes of cardiac arrest along with the development of disseminated intravascular coagulation, thrombocytopenia and metabolic acidosis. The patient died 24 hours after admission. A second patient had cardiac arrest during transport; resuscitation was unsuccessful. The last patient developed seizures, acidosis and hyperthermia after being left in a car by his friends. He died about 45 minutes after arrival to the ED (Pearson et al, 2012).
4) BUTYONE AND METHYLONE: A 24-year-old woman was found unconscious with hyperthermia, tachycardia and hypotension after ingesting 2 tablets thought to be Ecstasy (later confirmed to contain methylone 422 mg and butylone 53 mg per capsule; estimated amount ingested was 844 mg of methylone and 106 mg of butylone). She developed a effects consistent with serotonin syndrome that was immediately treated with cooling measures, mechanical ventilation and pharmacologic management. However, the clinical course was complicated by DIC, pulseless electrical activity that improved with resuscitation that was followed by ARDS and renal failure. The patient died 48 hours after admission of lactic acidosis and hypoxemia. A toxicology screen was negative for other drugs of abuse. An autopsy showed evidence of generalized coagulopathy, fatty liver and anoxic encephalopathy (Warrick et al, 2012).
5) 3,4-METHYLENEDIOXYPYROVALERONE (MDPV): A 40 year-old-man with a history of bipolar disorder and cocaine abuse, died after injecting and snorting MDPV. His presentation was consistent with Excited Delirium Syndrome with delirium, severe agitation, hyperthermia (105.4 F), tachypnea, tachycardia (164 beats/minute) followed by cardiac arrest shortly after attempts at physical and pharmacologic restraint. His clinical course included an initial cardiac arrest, hyperkalemia, persistent hypotension, metabolic acidosis, oliguric renal failure, coagulopathy, GI bleeding, and rhabdomyolysis. Approximately, 42 hours after admission he was declared brain dead based on neurologic findings (pupils fixed and dilated with no response to noxious stimuli) and care was withdrawn. Laboratory analysis of serum and urine confirmed MDPV and trimethoprim (thought to be an adulterant); screening for drugs of abuse were negative along with a negative methadone level (Murray et al, 2012).
6) 3,4-METHYLENEDIOXYPYROVALERONE (MDPV)/CASE REPORTS: Two patients died following exposure to MDPV (laboratory confirmation) after presenting with hyperthermia, agitated delirium and tachycardia. Both patients developed profound disseminated intravascular coagulation following admission (likely a complication of hyperthermia) that did not respond to aggressive care (Young et al, 2013).
7) PENTEDRONE AND alpha-PYRROLIDINOVALEROPHENONE: A man, with a history of designer-drug use, was admitted in asystole and died after failed resuscitation efforts. Postmortem examination included laboratory confirmation of pentedrone and alpha-pyrrolidinovalerophene. Pentedrone is the alpha-pentyl-beta-keto analog of 3,4-methylenedioxy-N-methylamphetamine (MDMA). Postmortem blood concentration of alpha-PVP was consistent with an acute intoxication leading to death and pentedrone likely had a secondary role in the patient's death (Sykutera et al, 2015).

C)

1) METHCATHINONE: Doses of greater than 30 mg/kg produced significant lethality in rats (Gygi et al, 1996).

Pharmacology Toxicology

Pharmacologic Mechanism

A)

B)

1) In rats, multiple dose of methcathinone produced a reduction in serotonergic and dopaminergic parameters in the striatum and a reduction of serotonergic levels in the hippocampus and frontal cortex. These findings were similar to methamphetamine in which neurotransmitter and neurotransmitter metabolite concentrations were reduced after multiple doses. It appears that methcathinone has the potential to produce significant neuronal damage (Gygi et al, 1996).

C)

Physicochemical

Physical Characteristics

A)

B)

Molecular Weight

A)

Animal Toxicology

References

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SYNTHETIC CATHINONE DERIVATIVES

Classification | Detailed evidence-based information

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Specific Substances

Available Forms Sources

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Heent

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General Bibliography