Substances Included Synonyms

Therapeutic Toxic Class

A)

Specific Substances

1) 4-iodo-2,5-dimethoxy-N-(2-methoxybenzyl) phenethylamine (synonym)
2) 25-I (synonym)
3) 25I-NBOMe (synonym)
4) 25B-NBOMe (synonym)
5) 25C-NBOMe (synonym)
6) 2CBFly-NBOMe (synonym)
7) 2CBCBNBOMe (synonym)
8) 2CT-NBOMe (synonym)
9) 25D-NBOMe (synonym)
10) 25E-NBOMe (synonym)
11) INB-MeO (slang term for 25I-NBOMe)
12) N-bomb (slang term for 25I-NBOMe)
13) Smiles (slang term for 25I-NBOMe)
14) Solaris (slang term for 25I-NBOMe)
15) Cimbi-5 (slang term for 25I-NBOMe)
16) 25G-NBOMe (synonym)
17) 25H-NBOMe (synonym)
18) 25I-NBMD (synonym)
19) 25l-NBF (synonym)
20) 25T4-NBOMe (synonym)
21) 25TFM-NBOMe (synonym)
22) 25N-NBOMe (synonym)
23) 25P-NBOMe (synonym)

Available Forms Sources

A)

1) 25I-NBOME: As of 2011, 25I-NBOMe became more widely available for use (Poklis et al, 2013; Rose et al, 2013). During this period, blotting papers containing 25I-NBOMe began to be sold (Kyriakou et al, 2015; Poklis et al, 2013).

a) OTHER FORMULATIONS: Based on case reports, 25I-NBOMe is also available as a powder, liquid or capsule for ingestion or nasal insufflation (snorting). In one case, severe toxicity was reported after intravenous administration of liquid 25I-NBOMe (concentration unknown) (Hill et al, 2013). 25I-NBOMe has also be used by the sublingual and buccal route (Halberstadt & Geyer, 2014).

2) WIDELY USED PRODUCTS: Commonly used NBOMe substances include 25l-NBOMe (street names: 25l, INBMeO, N-bomb, Smiles, Solaris and Cimbi-5); N-(2-methoxybenzyl)-2,5-dimethoxy-4-bromophenethylamine (25B-NBOMe) and 25CNBOMe (street names: C-Boom, Cimbi-82, Pandora and Dime). Most products are sold on blotting papers (Kyriakou et al, 2015). It has been reported that these blotting papers are inadvertently thought to contain LSD (lysergic acid diethylamide) by some consumers (Isbister et al, 2015).

a) Other drugs belonging to the NBOMe class (Kyriakou et al, 2015):

1) 25D-NBOMe
2) 25E-NBOMe
3) 25G-NBOMe
4) 25H-NBOMe
5) 25l-NBF
6) 25T4-NBOMe
7) 2CT-NBOMe
8) 2CBFly-NBOMe
9) 2CBCBNBOMe
10) 25TFM-NBOMe
11) 25N-NBOMe
12) 25P-NBOMe

3) ADULTERATED SUBSTANCE: During 2013, there were reports that drugs in the NBOMe class were being sold as LSD. Due to the ease of procuring and counterfeiting NBOMe as LSD, some substance abusers may be unknowingly consuming substances from the NBOMe series. NBOMe intoxication is potentially much more severe than LSD and may include the following adverse events: seizures, metabolic acidosis, elevated creatine kinase, acute renal injury and death. Clinical management of patients that have ingested a possible hallucinogenic substance may need a higher level of care if NBOMe has been substituted for LSD (Ninnemann & Stuart, 2013).
4) OTHER AGENTS: At the time of this review, little has been reported about the other agents that are part of this class.

B)

1) N-benzyl substituted phenethylamine 2C derivatives act as potent 2A (5-HT2A) receptor agonists. These agents are psychoactive substances that are related to the phenethylamines of the 2C and 2D series of designer drugs. Similar to these compounds, the N-benzyl series act as serotonergic hallucinogens and are used as recreational drugs. The following compounds are part of this class: 4-iodo-2,5-N-(2-methoxybenzyl) phenethylamine OR N-(2-methoxybenzyl)-2,5-dimethoxy-4-iodophenethylamine (25I-NBOMe); N-(2-methoxybenzyl)-2,5-dimethoxy-4-chlorophenethylamine (25C-NBOMe); N-(2-methoxybenzyl)-2,5-dimethoxy-4-methylphenethylamine (25D-NBOMe) and N-(2,3-methylenedioxybenzyl)-2,5-dimethoxy-4-iodophenethylamine (25I-NBMD). N-benzylphenthylamines have been shown to be behaviorally active and highly potent (Hill et al, 2013; Halberstadt & Geyer, 2014). Two examples of relatively new designer N-benzyl substituted derivatives of 2C-I (2,5-dimethoxy-4-idophenethylamine) are 25I-NBOMe and 25I-NBMD (Halberstadt & Geyer, 2014).
2) As of November 2013, the Drug Enforcement Administration has issued a temporary order for 3 synthetic phenethylamines (includes 25I-NBOMe, 25C-NBOMe, and 25B-NBOMe) to be placed as Schedule l agents under the Controlled Substances Act. It was noted that these substances are a potential risk to the public and have no recognized therapeutic use (Drug Enforcement Administration, 2013).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: N-benzyl substituted phenethylamine 2C derivatives act as potent 2A (5-HT2A) receptor agonists. These agents are psychoactive substances that are related to the phenethylamines of the 2C and 2D series of designer drugs. Similar to these compounds, the N-benzyl series act as serotonergic hallucinogens and are increasingly being abused as recreational drugs.
B) TOXICOLOGY: Limited data. Although the mechanism of action of phenethylamines (including the N-benzyl derivatives) is not completely understood, it is thought that all hallucinogens share a common site of action on central 5-HT2 receptors. Following N-benzyl derivative intoxication, patients have presented with either a sympathomimetic syndrome, serotonin toxicity, hallucinogenic effects, or a combination of all of these clinical effects.
C) EPIDEMIOLOGY: These agents are relatively new substances of abuse and have produced significant toxicity and rarely death. It appears that 25I-NBOMe (a derivative of phenethylamine hallucinogen 2C-I) may be emerging in the market in both Europe and the United States.
D) WITH POISONING/EXPOSURE

1) OVERDOSE: Minimal information has been reported in the literature. At the time of this review, most cases of exposure have been limited to 25I-NBOMe. ROUTE: It is most commonly ingested or nasally insufflated, but intentional parenteral abuse has been reported and resulted in significant toxicity.
2) MILD TO MODERATE TOXICITY: Based on limited case reports, 25I-NBOMe has produced euphoria, auditory and/or visual hallucinations, mydriasis, agitation, tachycardia and hypertension consistent with a sympathomimetic toxidrome. Ongoing agitation and physical aggression have occurred in some cases.
3) SEVERE TOXICITY: Clinical effects may include severe and prolonged agitation (lasting several days in some cases), hallucinations, bizarre behavior, tachypnea, hyperthermia, delirium, seizures, and metabolic acidosis. Rhabdomyolysis and renal failure may develop in patients with prolonged agitation, hyperthermia, coma or seizures. One patient developed serotonin toxicity after ingesting 25I-NBOMe powder. There have been limited reports of fatalities with 25I-NBOMe.
4) ADULTERATED SUBSTANCE: During 2013, there were reports that drugs in the NBOMe class were being sold as LSD. Due to the ease of procuring and counterfeiting NBOMe as LSD, some substance abusers may be unknowingly consuming NBOMe. NBOMe intoxication is potentially much more severe than LSD.

0.2.3)

A) WITH POISONING/EXPOSURE

1) Tachycardia, hypertension and pyrexia are likely to occur with exposure.

Laboratory Monitoring

A)

B)

C)

D)

E)

F)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Patients are most likely to present with agitation and auditory and/or visual hallucinations. Hypertension and tachycardia are generally well tolerated and can be treated with benzodiazepines. Mildly intoxicated patients may do best in quiet, dark rooms with minimal stimulation. It may be helpful to remind the patient that they are experiencing a drug effect that will eventually wear off. Clinical manifestations usually resolve quickly with benzodiazepines and supportive care.

B) MANAGEMENT OF SEVERE TOXICITY

1) The goal of treatment is to manage agitation and prevent end-organ damage. Orotracheal intubation for airway protection should be performed early. Severe agitation or physical aggression may develop and require large doses of benzodiazepines for sedation. Seizures may require aggressive use of benzodiazepines, propofol and/or barbiturates. Monitor and treat for dysrhythmias. Monitor core temperature and treat hyperthermia with aggressive benzodiazepine sedation to control agitation, and external cooling.

C) DECONTAMINATION

1) PREHOSPITAL: Prehospital gastrointestinal decontamination is not recommended because of the potential for agitation and seizures and subsequent aspiration.
2) HOSPITAL: Gastrointestinal decontamination is generally NOT indicated because the patient presents several hours after ingestion when absorption is complete and because the risk of aspiration outweighs potential benefit.

D) AIRWAY MANAGEMENT

1) Perform early in a patient with severe intoxication (ie, seizures, dysrhythmias, hyperthermia).

E) ANTIDOTE

1) None.

F) SEIZURES

1) Treat seizures with IV benzodiazepines, add propofol or barbiturates if seizures persist or recur.

G) HYPERTHERMIA

1) Control agitation with benzodiazepines; initiate aggressive external cooling measures. Remove the patient's clothing, keep skin damp and use fans to enhance evaporative cooling. A cooling blanket and ice packs to the groin and axilla may be useful. For severe cases, ice water immersion may be necessary but it can make access to the patient for resuscitation more cumbersome. If needed, intubate, sedate and paralyze.

H) PSYCHOMOTOR AGITATION

1) Sedate patient with benzodiazepines as necessary; large doses may be required. Consider antipsychotics in patients with persistent aggression, despite high-dose benzodiazepines. Minimize external stimuli; place in quiet, dark room.

I) SEROTONIN SYNDROME

1) Treat aggressively with benzodiazepines, external cooling measures, if needed. Severe cases may require orotracheal intubation and neuromuscular paralysis. CYPROHEPTADINE is an oral antihistamine with serotonin antagonism at 5-hydroxytryptamine (HT)-1A and 5-HT-2A receptors. It is used to improve mild to moderate symptoms of serotonin syndrome (eg, core temperature greater than 38.5 degrees C or severe muscle rigidity requiring neuromuscular paralysis). DOSE: ADULT: Administer an initial dose of 12 mg, then 2 mg every 2 hours if the patient remains symptomatic. Maintenance: 8 mg every 6 hours. Maximum dose: 32 mg in 24 hours. CHILD: 0.25 mg/kg/day divided every 6 hours, maximum 12 mg/day. It may be crushed and administered via a nasogastric tube.

J) ENHANCED ELIMINATION

1) At the time of this review, it is unknown if hemodialysis or hemoperfusion would be beneficial.

K) PATIENT DISPOSITION

1) HOME CRITERIA: Severe toxicity has been reported after recreational doses, there is no data to support home observation.
2) OBSERVATION CRITERIA: Exposed patients should be sent to a healthcare facility for evaluation, treatment and observation.
3) ADMISSION CRITERIA: Patients with significant persistent central nervous system toxicity (ie, hallucinations, somnolence, coma), or persistent tachycardia should be admitted. Patients with coma, seizures, serotonin syndrome or severe toxicity 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 (ie, persistent seizures, rhabdomyolysis, serotonin syndrome), or in whom the diagnosis is not clear. Refer patients for substance abuse counseling as appropriate.

L) PITFALLS

1) Failure to control agitation and manage hyperthermia and seizures can result in death and irreversible end-organ damage. Patients with altered mentation should be evaluated for intracranial hemorrhage, infection, and metabolic disturbance.

M) TOXICOKINETICS

1) N-benzyl substituted phenethylamine 2C derivatives act as potent 2A (5-HT2A) receptor agonists. Little is known about the pharmacokinetics of these agents. 25I-NBOMe: INSUFFLATION: DURATION: range: 2 to 4 hours; SUBLINGUAL: range: 6 to 12 hours.

N) DIFFERENTIAL DIAGNOSIS

1) Thyrotoxicosis, hypoglycemia, central nervous system infection, other sympathomimetic poisoning (such as cocaine, amphetamines), 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)

1) OVERDOSE: Minimal information has been reported in the literature. At the time of this review, most cases of exposure have been limited to 25I-NBOMe. ROUTE: It is most commonly ingested or nasally insufflated, but intentional parenteral abuse has been reported and resulted in significant toxicity.
2) MILD TO MODERATE TOXICITY: Based on limited case reports, 25I-NBOMe has produced euphoria, auditory and/or visual hallucinations, mydriasis, agitation, tachycardia and hypertension consistent with a sympathomimetic toxidrome. Ongoing agitation and physical aggression have occurred in some cases.
3) SEVERE TOXICITY: Clinical effects may include severe and prolonged agitation (lasting several days in some cases), hallucinations, bizarre behavior, tachypnea, hyperthermia, delirium, seizures, and metabolic acidosis. Rhabdomyolysis and renal failure may develop in patients with prolonged agitation, hyperthermia, coma or seizures. One patient developed serotonin toxicity after ingesting 25I-NBOMe powder. There have been limited reports of fatalities with 25I-NBOMe.
4) ADULTERATED SUBSTANCE: During 2013, there were reports that drugs in the NBOMe class were being sold as LSD. Due to the ease of procuring and counterfeiting NBOMe as LSD, some substance abusers may be unknowingly consuming NBOMe. NBOMe intoxication is potentially much more severe than LSD.

Vital Signs

3.3.1)

A) WITH POISONING/EXPOSURE

1) Tachycardia, hypertension and pyrexia are likely to occur with exposure.

3.3.3)

A) WITH POISONING/EXPOSURE

1) CASE SERIES (25I-NBOMe): Hyperpyrexia developed in 3 of 7 patients after using 25I-NBOMe (Hill et al, 2013).
2) CASE REPORTS: Hyperthermia was reported in 2 patients that developed sympathomimetic symptoms following exposure to 25-NBOMe (Tang et al, 2014).

3.3.4)

A) WITH POISONING/EXPOSURE

1) CASE SERIES (25I-NBOMe): Hypertension developed in 4 of 7 patients after using 25I-NBOMe (Hill et al, 2013).
2) CASE REPORTS: Significant hypertension was reported in 2 patients that developed sympathomimetic symptoms following exposure to 25-NBOMe (Tang et al, 2014).

3.3.5)

A) WITH POISONING/EXPOSURE

1) Tachycardia is common. In a small case series (n=7) of 25I-NBOMe exposure, tachycardia developed in each patient (Rose et al, 2013).
2) CASE REPORTS: Tachycardia was reported in 2 patients that developed sympathomimetic symptoms following exposure to 25-NBOMe (Tang et al, 2014).

Heent

3.4.3)

A) WITH POISONING/EXPOSURE

1) MYDRIASIS is likely to occur following 25I-NBOMe use (Hill et al, 2013).
2) CASE SERIES (NBOMe): In a review, a series of 25 cases (ie, 25I-NBOMe in 19 cases; 25C-NBOMe in 3 cases; in further 3 cases, exact NBOMe was not identified) of NBOMe exposure were reported to a poison center during 2012 to 2013, mydriasis (20%) was a frequent adverse effect. In the majority of cases (n=21 (84%)), no other substances were used (Wood et al, 2015).

Cardiovascular

3.5.2)

A) TACHYCARDIA

1) WITH POISONING/EXPOSURE

a) SUMMARY

1) Tachycardia is common (Rose et al, 2013; Tang et al, 2014; Wood et al, 2015).

b) CASE SERIES

1) CASE SERIES (25I-NBOMe): Tachycardia (range, 104 to 160 beats/min) developed in all patients (n=7) after using 25I-NBOMe (Hill et al, 2013).
2) CASE SERIES (2C-I-NBOMe): In a series of 10 patients that had ingested and/or insufflated 2C-l-NBOMe, the most common symptoms were tachycardia, hypertension, agitation and hallucinations (Nikolaou et al, 2015).
3) CASE SERIES (NBOMe): In a review, a series of 25 cases (ie, 25I-NBOMe in 19 cases; 25C-NBOMe in 3 cases; in further 3 cases, exact NBOMe was not identified) of NBOMe exposure were reported to a poison center during 2012 to 2013, tachycardia (52%) was the most common adverse effect reported. In the majority of cases (n=21 (84%)), no other substances were used (Wood et al, 2015).

c) CASE REPORTS

1) CASE REPORT: A 29-year-old man presented with agitation, aggression, seizures, tachycardia, hypertension, tachypnea, and fever after the intravenous injection of 3 mL of 25I-NBOMe (unknown concentration). Laboratory results revealed respiratory and metabolic acidosis, elevation of creatine kinase, impaired renal function, and elevated alanine transaminase. A CT scan of the head showed mild cerebral edema. Despite supportive care, he developed anuric renal failure within the next 2 days and he underwent continuous veno-venous hemofiltration (CVVH). His condition deteriorated later with fever, high-oxygen and vasopressor requirements and worsening renal impairment. Acute lung injury and pulmonary abscesses were observed in chest radiographs. Following a complicated hospital course and aggressive supportive care, his condition gradually normalized and he was discharged home 43 days after presentation (Hill et al, 2013).
2) CASE REPORT: A 21-year-old man developed agitation, hallucinations, tachycardia, and fever after insufflating approximately 0.1 g of 25I-NBOMe powder. He recovered gradually following supportive care (Hill et al, 2013).
3) CASE REPORT: An 18-year-old man was admitted to the ED with severe agitation and hallucinations following the use of 25I-NBOMe. Initial vital signs included significant tachycardia (heart rate 150s beats per min) and hypertension (blood pressure 150 to 170 mm Hg systolic and 110 mm Hg diastolic). An ECG showed sinus tachycardia. Vital signs normalized approximately 12 hours after admission following an initial bolus and a continuous infusion of lorazepam (1.5 mg/h). However, he continued to have episodes of aggressiveness for the next 24 hours (Rose et al, 2013).
4) CASE REPORT: A 17-year-old boy, with a history of cannabis use, was admitted with agitation and confusion after taking one pill containing NBOMe. Initial vital signs included tachycardia (140 beats/min), hypertension (215/94 mmHg), and hyperthermia (38.4 degrees C). Seizures and severe sympathomimetic symptoms developed shortly after admission. High doses of diazepam (total 17.5 mg ) were administered to treat sympathomimetic toxicity. The patient was also intubated and sedated with midazolam. Approximately 12 hours later, the patient was fully alert. By day 5, the patient was fully recovered. A urine sample was positive for 25-NBOMe (Tang et al, 2014).

B) HYPERTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Hypertension may occur (Rose et al, 2013).
b) CASE SERIES (25I-NBOMe): Hypertension developed in 4 of 7 patients after using 25I-NBOMe (Hill et al, 2013).

1) CASE SERIES (NBOMe): In a review, a series of 25 cases (ie, 25I-NBOMe in 19 cases; 25C-NBOMe in 3 cases; in further 3 cases, exact NBOMe was not identified) of NBOMe exposure were reported to a poison center during 2012 to 2013, hypertension (32%) was a frequent adverse event. In the majority of cases (n=21 (84%)), no other substances were used (Wood et al, 2015).
2) CASE SERIES (2C-I-NBOMe): In a series of 10 patients that had ingested and/or insufflated 2C-l-NBOMe, the most common symptoms were tachycardia, hypertension, agitation and hallucinations (Nikolaou et al, 2015).
3) CASE REPORT: A 29-year-old man presented with agitation, aggression, seizures, tachycardia (pulse 160), hypertension (187/171), tachypnea, and fever after the intravenous injection of 3 mL of 25I-NBOMe (unknown concentration). Laboratory results revealed respiratory and metabolic acidosis, elevation of creatine kinase, impaired renal function, and elevated alanine transaminase. A CT scan of the head showed mild cerebral edema. Despite supportive care, he developed anuric renal failure within the next 2 days and he underwent continuous veno-venous hemofiltration (CVVH). His condition deteriorated later with fever, high-oxygen and vasopressor requirements and worsening renal impairment. Following a complicated hospital course and aggressive supportive care, his condition gradually normalized and he was discharged home 43 days after presentation (Hill et al, 2013).

c) CASE REPORT: A 17-year-old boy, with a history of cannabis use, was admitted with agitation and confusion after taking one pill containing NBOMe. Initial vital signs included tachycardia (140 beats/min), hypertension (215/94 mmHg), and hyperthermia (38.4 degrees C). Seizures and severe sympathomimetic symptoms developed shortly after admission. High doses of diazepam (total 17.5 mg ) were administered to treat sympathomimetic toxicity. The patient was also intubated and sedated with midazolam. Approximately 12 hours later, the patient was fully alert. By day 5, the patient was fully recovered. A urine sample was positive for 25-NBOMe (Tang et al, 2014).
d) CASE REPORT: Approximately 6.5 hours after ingesting an estimated 10 g of 25NBOMe, a 31-year-old man, with a history of substance abuse, was admitted with sympathomimetic symptoms (ie, agitation, tachycardia, hypertension (BP 160/123 mmHg), and hyperthermia). His initial symptoms were followed by rhabdomyolysis, impaired renal function (plasma urea 6.2 mmol/L and plasma creatinine 170 micromol/L) and elevated liver enzymes (ALT 463 Units/L, AST 492 Units/L). Early treatment included IV fluids, lorazepam (total dose: 12 mg) and supportive care (ice packs). Creatine kinase peaked at 11,066 Units/L. Sodium bicarbonate was added for urine alkalization. Acute renal impairment resolved with treatment. On day 3, the patient demanded to be discharged and left against medical advice. 25B-NBOMe and 25C-NBOMe were detected in urine (Tang et al, 2014).
e) CASE REPORT: An 18-year-old man was admitted to the ED with severe agitation and hallucinations following the use of 25I-NBOMe. Initial vital signs included significant tachycardia (heart rate 150s beats per min) and hypertension (blood pressure 150 to 170 mm Hg systolic and 110 mm Hg diastolic). Laboratory results revealed hypokalemia (potassium 2.8 mEq/L). Vital signs normalized approximately 12 hours after admission following an initial bolus and a continuous infusion of lorazepam (1.5 mg/h). However, he continued to have episodes of aggressiveness for the next 24 hours (Rose et al, 2013).

Respiratory

3.6.2)

A) RESPIRATORY INSUFFICIENCY

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 29-year-old man injected 3 mL of liquid 25I-NBOMe (concentration unknown) and was admitted with agitation, aggression, and seizures. Initial laboratory studies included an elevated creatinine, and respiratory and metabolic acidosis. Initial care included intubation and ventilation and IV sedation (propofol and midazolam). During the first 24 to 48 hours, anuric renal failure developed. Veno-venous hemofiltration (CVVH) was started on day 1. However, the patient's clinical course remained complicated with worsening renal function, acute respiratory insufficiency and difficulty maintaining adequate ventilation (ie, high ventilatory pressures secondary to acute lung injury and pulmonary abscesses). Treatment included IV antibiotics with gradual respiratory improvement. By day 17, ventilatory support was normal and a tracheostomy was inserted the following day. Large doses of multimodal sedation were required throughout the course of his care. By 4 weeks, urine output had restarted and he was able to tolerate brief periods of continuous positive airway pressure (CPAP). The patient was discharged to home by day 43 with no permanent sequelae (Hill et al, 2013).

Neurologic

3.7.2)

A) PSYCHOMOTOR AGITATION

1) WITH POISONING/EXPOSURE

a) SUMMARY

1) Agitation, sometimes severe, is a common adverse event following NBOMe exposure. Hallucinations commonly occur with agitation (Nikolaou et al, 2015; Isbister et al, 2015a; Rose et al, 2013).

b) CASE SERIES (25I-NBOMe): In a small study, agitation was reported in most (5 of 7) patients following 25I-NBOMe use (Hill et al, 2013).
c) CASE SERIES (NBOMe): In a review, a series of 25 cases (ie, 25I-NBOMe in 19 cases; 25C-NBOMe in 3 cases; in further 3 cases, exact NBOMe was not identified) of NBOMe exposure were reported to a poison center during 2012 to 2013, agitation/irritability (48%) was a frequent adverse event. In the majority of cases (n=21 (84%)), no other substances were used (Wood et al, 2015).
d) CASE SERIES (2C-I-NBOMe): In a series of 10 patients that had ingested and/or insufflated 2C-l-NBOMe, the most common symptoms were tachycardia, hypertension, agitation and hallucinations (Nikolaou et al, 2015).
e) CASE REPORT: An 18-year-old man was admitted to the ED with severe agitation and hallucinations after using 25I-NBOMe. Following initial treatment with lorazepam (2 doses of 2 mg), the patient became alert and cooperative. However, an ongoing infusion of lorazepam at 1.5 mg/h for 24 hours was necessary to treat agitation and restlessness when awake. A head CT was normal. At 24 hours, the patient continued to be agitated and the infusion was increased to 2 mg/h and restraints were also needed. By the following day, the infusion was discontinued but the patient continued to have intermittent episodes of aggressiveness. An oral antipsychotic (ziprasidone) was started after psychiatric evaluation. Screening was positive for cannabinoids only (urine screen) and a blood ethanol level of 25 mg/dL (Rose et al, 2013).

B) SEIZURE

1) WITH POISONING/EXPOSURE

a) SUMMARY: Seizure activity has been reported following the ingestion of various types of NBOMes and include: 25I-NBOMe, 25C-NBOMe, 2C-I-NBOMe and 25B-NBOMe (Isbister et al, 2015a; Nikolaou et al, 2015; Hill et al, 2013; Wood et al, 2015; Poklis et al, 2014).
b) CASE SERIES (25I-NBOMe): Seizures developed in 3 of 7 patients after using 25I-NBOMe (Hill et al, 2013).
c) CASE SERIES (NBOMe): In a review, a series of 25 cases (ie, 25I-NBOMe in 19 cases; 25C-NBOMe in 3 cases; in further 3 cases, exact NBOMe was not identified) of NBOMe exposure were reported to a poison center during 2012 to 2013, seizures (4%) were reported infrequently. In the majority of cases (n=21 (84%)), no other substances were used (Wood et al, 2015).
d) CASE REPORT: A 16-year-old teenager ingested "acid" on blotting paper (thought to be LSD) and developed multiple seizures prior to admission. Upon admission, he had a fourth seizure and was intubated and ventilated and received IV sedation. He was transferred to an intensive care setting and remained stable and was successfully extubated the next day. A rising creatinine and creatine kinase were observed on day 2 and his creatinine peaked at 246 mmol/L and CK at 34,778 International Units approximately 90 hours after exposure. No further signs or symptoms were reported and he was discharged to home on day 5. A blood sample using high performance liquid chromatography/mass spectrometry detected 25B-NBOMe (0.089 mcg/mL) 22 hours post ingestion (Isbister et al, 2015a).
e) CASE REPORT: A 19-year-old man ingested an unknown amount of 25B-NBOMe (confirmed by laboratory analysis of serum and urine) and was found by a friend having 'jerking' motions. He was admitted with generalized tonic-clonic jerking movements and hyperpyrexia (temperature 104 degrees F). Immediate treatment included 1 mg of lorazepam and intubation and ventilation. A propofol infusion was started to control agitation. A routine urine drug screen was positive for marijuana. He was successfully extubated on day 3 and maintained on 3 L/min via nasal cannula. His clinical course was further complicated by rhabdomyolysis (creatine kinase peaked at 11,645 on day 5) and mild renal impairment that was treated successfully with IV hydration (Lactated Ringer's at 150 cc/hr). The patient was able to maintain an adequate urine output. His serum creatinine was 0.4 mg/dL by day 5. Initially, the patient was drowsy but responded appropriately to family and staff. By day 6. he had completely recovered (Poklis et al, 2014).
f) CASE REPORT: A 17-year-old teenager, with a history of cannabis use, was admitted with agitation and confusion after taking one pill containing NBOMe. Initial vital signs included tachycardia (140 beats/min), hypertension (215/94 mmHg), and hyperthermia (38.4 degrees C). Seizures and severe sympathomimetic symptoms developed shortly after admission. High doses of diazepam (total 17.5 mg ) were administered to treat sympathomimetic toxicity. The patient was also intubated and sedated with midazolam. Approximately 12 hours later, the patient was fully alert. By day 5, the patient was fully recovered. A urine sample was positive for 25-NBOMe (Tang et al, 2014).
g) CASE REPORT: A 22-year-old man developed visual hallucinations after nasal insufflation of 25I-NBOMe followed by tonic-clonic seizures successfully treated with diazepam. However, further doses of diazepam (total dose: 30 mg) were necessary due to severe agitation and aggressive behavior and hallucinations persisted for 15 hours after drug use. Symptoms resolved completely and he was discharged on the day of admission (Hill et al, 2013).

C) CLOUDED CONSCIOUSNESS

1) WITH THERAPEUTIC USE

a) CASE SERIES (NBOMe): In a review, a series of 25 cases (ie, 25I-NBOMe in 19 cases; 25C-NBOMe in 3 cases; in further 3 cases, exact NBOMe was not identified) of NBOMe exposure were reported to a poison center during 2012 to 2013, confusion (24%) was a frequent adverse event. In the majority of cases (n=21 (84%)), no other substances were used (Wood et al, 2015).

D) SEROTONIN SYNDROME

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 20-year-old man, with a history of depression treated with fluoxetine (20 mg) daily, immediately collapsed following ingestion of 25I-NBOMe powder and had seizures witnessed by paramedics. Diazepam was given in route for severe agitation. Upon arrival, the patient required intubation. Persistent, short-lasting jerky movements thought to be seizures were treated with lorazepam and propofol. Within 5 hours, the patient had evidence of serotonin syndrome (ie, sustained clonus, ocular clonus, fever (38.6 degrees C), tachycardia and an elevated creatine kinase (228 International Units/L). Cyproheptadine was initiated. By day 2, the patient's jerky movements were thought to be related to cerebral irritation versus seizures. The patient continued to improve and was discharged by day 4 clinically improved (Hill et al, 2013).

Hepatic

3.9.2)

A) INCREASED LIVER ENZYMES

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Approximately 6.5 hours after ingesting an estimated 10 g of 25NBOMe, a 31-year-old man, with a history of substance abuse, was admitted with sympathomimetic symptoms (ie, agitation, tachycardia, hypertension, and hyperthermia). His initial symptoms were followed by rhabdomyolysis, impaired renal function and elevated liver enzymes (ALT 463 Units/L, AST 492 Units/L). Early treatment included IV fluids, lorazepam (total dose: 12 mg) and supportive care (ice packs). Creatine kinase peaked at 11,066 Units/L. Sodium bicarbonate was added for urine alkalization. On day 3, the patient demanded to be discharged and left against medical advice. 25B-NBOMe and 25C-NBOMe were detected in urine (Tang et al, 2014).

Genitourinary

3.10.2)

A) ACUTE RENAL IMPAIRMENT

1) WITH POISONING/EXPOSURE

a) SUMMARY: Severe NBOMe toxicity can produce acute renal injury, seizures and rhabdomyolysis (Isbister et al, 2015; Hill et al, 2013; Tang et al, 2014; Poklis et al, 2014)
b) CASE SERIES (25I-NBOMe): Acute renal injury developed in 1 of 7 patients after using 25I-NBOMe (Hill et al, 2013).
c) CASE REPORT: A 29-year-old man injected 3 mL of liquid 25I-NBOMe (concentration unknown) and was admitted with agitation, aggression, and seizures. Initial laboratory studies included an elevated creatinine and respiratory and metabolic acidosis. During the first 24 to 48 hours, anuric renal failure developed. Veno-venous hemofiltration (CVVH) was started on day 1. However, the patient's clinical course remained complicated with worsening renal function, acute respiratory insufficiency and difficulty maintaining adequate ventilation (ie, high ventilatory pressures secondary to acute lung injury and pulmonary abscesses). Despite gradual respiratory improvement with supportive care, CVVH was required for ongoing anuria. Creatinine peaked at 660 micromol/L. A renal ultrasound showed loss of corticomedullary differentiation and hypoechogenicity of the renal parenchyma. By day 27, the patient began to produce urine. On day 43, the patient was discharged with normal renal function and no evidence of chronic sequelae (Hill et al, 2013).
d) CASE REPORT: Approximately 6.5 hours after ingesting an estimated 10 g of 25NBOMe, a 31-year-old man, with a history of substance abuse, was admitted with sympathomimetic symptoms (ie, agitation, tachycardia, hypertension, and hyperthermia). His initial symptoms were followed by rhabdomyolysis, impaired renal function (plasma urea 6.2 mmol/L and plasma creatinine 170 micromol/L) and elevated liver enzymes (ALT 463 Units/L, AST 492 Units/L). Early treatment included IV fluids, lorazepam (total dose: 12 mg) and supportive care (ice packs). Creatine kinase peaked at 11,066 Units/L. Sodium bicarbonate was added for urine alkalization. Acute renal impairment resolved with treatment. On day 3, the patient demanded to be discharged and left against medical advice. 25B-NBOMe and 25C-NBOMe were detected in urine (Tang et al, 2014).
e) CASE REPORT: A 19-year-old man ingested an unknown amount of 25B-NBOMe (confirmed by laboratory analysis of serum and urine) and was found by a friend having 'jerking' motions. He was admitted with generalized tonic-clonic jerking movements and hyperpyrexia (temperature 104 degrees F). Immediate treatment included 1 mg of lorazepam and intubation and ventilation. A propofol infusion was started to control agitation. A routine urine drug screen was positive for marijuana. He was successfully extubated on day 3 and maintained on 3 L/min via nasal cannula. His clinical course was further complicated by rhabdomyolysis (creatine kinase peaked at 11,645 on day 5) and mild renal impairment that was treated successfully with IV hydration (Lactated Ringer's at 150 cc/hr). The patient was able to maintain an adequate urine output. His serum creatinine was 0.4 mg/dL by day 5. Initially, the patient was drowsy but responded appropriately to family and staff. By day 6. he had completely recovered (Poklis et al, 2014).

Acid-Base

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) CASE SERIES (25I-NBOMe): Metabolic acidosis developed in 3 of 7 patients after using 25I-NBOMe (Hill et al, 2013).

1) CASE REPORT: A 29-year-old man presented with agitation, aggression, seizures, tachycardia, hypertension, tachypnea, and fever after the intravenous injection of 3 mL of 25I-NBOMe (unknown concentration). Laboratory results revealed respiratory and metabolic acidosis, elevation of creatine kinase, impaired renal function, and elevated alanine transaminase. A CT scan of the head showed mild cerebral edema. Despite supportive care, he developed anuric renal failure within the next 2 days and he underwent continuous veno-venous hemofiltration (CVVH). His condition deteriorated later with fever, high-oxygen and vasopressor requirements and worsening renal impairment. Acute lung injury and pulmonary abscesses were observed in chest radiographs. Following a complicated hospital course and aggressive supportive care, his condition gradually normalized and he was discharged home 43 days after presentation (Hill et al, 2013).

Hematologic

3.13.2)

A) LEUKOCYTOSIS

1) WITH POISONING/EXPOSURE

a) CASE SERIES (25I-NBOMe): Elevated WBC developed in 2 of 7 patients after using 25I-NBOMe (Hill et al, 2013).

Musculoskeletal

3.15.2)

A) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) SUMMARY: Severe NBOMe toxicity can produce acute renal injury, seizures and rhabdomyolysis (Isbister et al, 2015; Poklis et al, 2014; Hill et al, 2013; Tang et al, 2014).
b) CASE SERIES (25I-NBOMe): Elevated creatine kinase developed in all patients (n=7) after using 25I-NBOMe. The highest level reported was 15424 International Units/L in a 29-year-old man who developed seizure-like activity, acute renal failure and respiratory impairment (ie, acute lung injury and pulmonary abscesses) requiring prolonged intubation and mechanical ventilation. He recovered without sequelae following approximately 6 weeks of intensive care (Hill et al, 2013).
c) CASE REPORT: A 19-year-old man ingested an unknown amount of 25B-NBOMe (confirmed by laboratory analysis of serum and urine) and was found by a friend having 'jerking' motions. He was admitted with generalized tonic-clonic jerking movements and hyperpyrexia (temperature 104 degrees F). Immediate treatment included 1 mg of lorazepam and intubation and ventilation. A propofol infusion was started to control agitation. A routine urine drug screen was positive for marijuana. He was successfully extubated on day 3 and maintained on 3 L/min via nasal cannula. His clinical course was further complicated by rhabdomyolysis (creatine kinase peaked at 11,645 on day 5) and mild renal impairment that was treated successfully with IV hydration (Lactated Ringer's at 150 cc/hr). The patient was able to maintain an adequate urine output. His serum creatinine was 0.4 mg/dL by day 5. Initially, the patient was drowsy but responded appropriately to family and staff. By day 6. he had completely recovered (Poklis et al, 2014).
d) CASE REPORT: Approximately 6.5 hours after ingesting an estimated 10 g of 25NBOMe, a 31-year-old man, with a history of substance abuse, was admitted with sympathomimetic symptoms (ie, agitation, tachycardia, hypertension, and hyperthermia). His initial symptoms were followed by rhabdomyolysis, impaired renal function and elevated liver enzymes. Early treatment included IV fluids, lorazepam (total dose: 12 mg) and supportive care (ice packs). Creatine kinase peaked at 11,066 Units/L. Sodium bicarbonate was added for urine alkalization. On day 3, the patient demanded to be discharged and left against medical advice. 25B-NBOMe and 25C-NBOMe were detected in urine (Tang et al, 2014).

B) CLONUS

1) WITH POISONING/EXPOSURE

a) CASE SERIES (25I-NBOMe): Clonus developed in 2 of 7 patients after using 25I-NBOMe (Hill et al, 2013).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs and mental status.
B) Monitor serum electrolytes and renal function.
C) Obtain ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (ie, delirium, agitation, seizure).
D) Monitor creatinine phosphokinase in patients with prolonged agitation, seizures or coma; monitor renal function and urine output in patients with rhabdomyolysis. Monitor liver enzymes in patients with hyperthermia.
E) Plasma concentrations are not readily available or useful in guiding therapy.
F) These substances are not detected on most urine toxicology screens.

Methods

A)

1) TOXICOLOGY SCREENING

a) In a case report of a man who used 25I-NBOMe, high performance liquid chromatography with tandem mass spectrometry (HPLC/MS/MS) analysis was used to confirm the presence of 25I-NBOMe in serum (Rose et al, 2013). HPLC/MS/MS was also used to detect 25B-NBOMe in the serum and urine of a teenager that developed severe toxicity following self-administration of a drug known as '25B' as reported by a friend (Poklis et al, 2014).
b) In another study high performance liquid chromatography tandem mass spectrometry was used to determine the presence of 2CC-NBOMe and 25I-NBOMe in the serum of severely intoxicated ED patients (Poklis et al, 2013).

2) DRUG SPECIMEN ANALYSIS

a) Liquid chromatograph-time-of-flight mass spectrometer (LC-TOF/MS) confirmed the presence of 25C-NBOMe and a smaller amount of 2CI-NBOMe on blotter paper ingested by a young woman that developed tachycardia and agitated delirium. She had ingested 3 blotter-paper doses that she thought was lysergic acid diethylamide (LSD) along with drinking wine and smoking marijuana at an outdoor event (Armenian & Gerona, 2014).

3) SPECIMEN COLLECTION

a) At present, NBOMe serum testing has limited clinical use; however, it can provide information to confirm a possible exposure and may assist with a diagnosis. Based on one study, it has been suggested that blood collection tubes with serum/plasma separator gels not be used to avoid a false negative test result. If blood is collected in a serum separator gel tube, the serum should be poured off from the gel within one hour and refrigerated to prevent loss of these various agents. In addition, NBOMe has been found as a urine biomarker; however, accurate test results are limited to recent drug use (Poklis et al, 2016).

B)

1) LC-MS/MS (liquid chromatography tandem mass spectrometry) was used successfully to identify 25I-NBOMe in the plasma of 7 patients after the reported use of 25I-NBOMe (Hill et al, 2013).
2) LC-MS (liquid chromatograph-mass spectrometry) was used to confirm and quantify the presence of 25I-NBOMe in the urine of several cases of exposure (Kelly et al, 2012).

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, coma), or persistent tachycardia should be admitted. Patients with coma, seizures, serotonin syndrome or severe toxicity should be admitted to an intensive care setting.

6.3.1.2) HOME CRITERIA/ORAL

A) Severe toxicity has been reported after recreational doses. There is not data to support home management.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (ie, persistent seizures, rhabdomyolysis, serotonin syndrome), or in whom the diagnosis is not clear. Refer patients for substance abuse counseling as appropriate.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Exposed patients should be sent to a healthcare facility for evaluation, treatment and observation.

Monitoring

A)

B)

C)

D)

E)

F)

Oral Exposure

6.5.1)

A) Prehospital gastrointestinal decontamination is not recommended because of the potential for agitation and seizures and subsequent aspiration.

6.5.2)

A) SUMMARY

1) Gastrointestinal decontamination is generally NOT indicated because the patient presents several hours after ingestion when absorption is complete and because the risk of aspiration outweighs potential benefit.

6.5.3)

A) MONITORING OF PATIENT

1) Monitor vital signs and mental status.
2) Monitor serum electrolytes and renal function.
3) Obtain ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (ie, agitation, seizure).
4) Monitor creatinine phosphokinase in patients with prolonged agitation, seizures or coma; monitor renal function and urine output in patients with rhabdomyolysis. Monitor liver enzymes in patients with hyperthermia.
5) Plasma concentrations are not readily available or useful in guiding therapy.
6) These substances are not detected on most urine toxicology screens.

B) PSYCHOMOTOR AGITATION

1) SUMMARY

a) Agitation has been commonly observed following 25I-NBOMe exposure and has required boluses of lorazepam and continuous infusions to treat persistent agitation and/or aggression (Rose et al, 2013). In another case, a patient required multiple doses of diazepam (total 30 mg) to treat persistent agitation following 25I-NBOMe use (Hill et al, 2013).
b) INDICATION

1) If patient is severely agitated, sedate with IV benzodiazepines.

c) DIAZEPAM DOSE

1) ADULT: 5 to 10 mg IV initially, repeat every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
2) CHILD: 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).

d) LORAZEPAM DOSE

1) ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed (Manno, 2003).
2) CHILD: 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 (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).

e) Extremely large doses of benzodiazepines may be required in patients with severe intoxication in order to obtain adequate sedation. Titrate dose to clinical response and monitor for hypotension, CNS and respiratory depression, and the need for endotracheal intubation.

2) DROPERIDOL

a) In a prospective study of droperidol vs lorazepam for the sedation of agitated methamphetamine intoxicated patients both agents were able to control agitation in patients. Droperidol provided more rapid and deeper sedation (Derlet & Duncan, 1996; Richards et al, 1997). It has been observed that the use of lorazepam may require more repeat dosing as compared to droperidol(Richards et al, 1997).
b) Extreme agitation and hallucinations may respond to intravenous droperidol (up to 0.1 milligram/kilogram) (Derlet & Duncan, 1996; Richards et al, 1997; Gary & Saidi, 1978).

1) CAUTION: DROPERIDOL: Based on cases of QT prolongation and/or torsades de pointes in patients receiving droperidol at doses at or below recommended dosing, it should be reserved for use in patients who fail to show an acceptable response to other agents ((Anon, 2001)).
2) A baseline ECG (repeat as indicated) and continuous cardiac monitoring for 3 hours are recommended for all patients receiving droperidol.

3) PHENOTHIAZINES

a) Based on amphetamine or hallucinogenic amphetamine cases, phenothiazines are NOT routinely recommended due to undesirable side effects (orthostatic hypotension and mental status changes) (Grinspoon & Hedblom, 1975; Snyder et al, 1970; Solursh & Clement, 1968).

4) NEUROLEPTICS

a) ZIPRASIDONE: Oral ziprasidone was used to treat episodes of aggressiveness in an 18-year-old man who used 25I-NBOMe (Rose et al, 2013). However, neuroleptic agents can cause QT prolongation and increase the risk of developing ventricular dysrhythmias. Neuroleptics should be avoided in patients with known QT prolongation (Dean et al, 2013).
b) HALOPERIDOL: Haloperidol has been protective in mice against lethality and hyperthermia caused by some but not all hallucinogenic amphetamines (Nichols et al, 1975; Davis & Borne, 1984; Paton et al, 1975). There are no data in humans. The mechanism of action is presumed to be dopaminergic blockade. Because haloperidol lowers seizure threshold and predisposes to hyperthermia, benzodiazepines are preferred.

5) KETAMINE

a) Based on other phenethylamine agents in this class, ketamine has been suggested as an alternative chemical restrained in patients with excited delirium. Benzodiazepines and neuroleptics often have a slow onset of action via the IM route. Ketamine has a rapid onset, predictable ability to induce a dissociated state, and lack of cardiovascular or respiratory depression. However, airway compromise, including laryngospasm and hypoxia may occur following ketamine therapy. In addition, ketamine can cause stimulatory cardiovascular effects resulting in increased tachycardia and hypertension (Dean et al, 2013).

C) SEIZURE

1) 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).

2) 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 .

3) 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).

4) 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).

5) 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).

6) 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).

7) 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).

D) SEROTONIN SYNDROME

1) Serotonin toxicity has been reported in one patient following ingestion of 25I-NBOMe (Hill et al, 2013).
2) SUMMARY

a) Benzodiazepines are the mainstay of therapy. Cyproheptadine, a 5-HT antagonist, is also commonly used. Severe cases have been managed with benzodiazepine sedation and neuromuscular paralysis with non-depolarizing agents(Claassen & Gelissen, 2005).

3) HYPERTHERMIA

a) Control agitation and muscle activity. Undress patient and enhance evaporative heat loss by keeping skin damp and using cooling fans.
b) MUSCLE ACTIVITY: Benzodiazepines are the drug of choice to control agitation and muscle activity. DIAZEPAM: ADULT: 5 to 10 mg IV every 5 to 10 minutes as needed, monitor for respiratory depression and need for intubation. CHILD: 0.25 mg/kg IV every 5 to 10 minutes; monitor for respiratory depression and need for intubation.
c) Non-depolarizing paralytics may be used in severe cases.

4) CYPROHEPTADINE

a) Cyproheptadine is a non-specific 5-HT antagonist that has been shown to block development of serotonin syndrome in animals (Sternbach, 1991). Cyproheptadine has been used in the treatment of serotonin syndrome (Mills, 1997; Goldberg & Huk, 1992). There are no controlled human trials substantiating its efficacy.
b) ADULT: 12 mg initially followed by 2 mg every 2 hours if symptoms persist, up to a maximum of 32 mg in 24 hours. Maintenance dose 8 mg orally repeated every 6 hours (Boyer & Shannon, 2005).
c) CHILD: 0.25 mg/kg/day divided every 6 hours, maximum dose 12 mg/day (Mills, 1997).

5) HYPERTENSION

a) Monitor vital signs regularly. For mild/moderate asymptomatic hypertension, pharmacologic intervention is usually not necessary.

6) HYPOTENSION

a) Administer 10 to 20 mL/kg 0.9% saline bolus and place patient supine. Further fluid therapy should be guided by central venous pressure or right heart catheterization to avoid volume overload.
b) Pressor agents with dopaminergic effects may theoretically worsen serotonin syndrome and should be used with caution. Direct acting agents (norepinephrine, epinephrine, phentolamine) are theoretically preferred.
c) NOREPINEPHRINE

1) PREPARATION: Add 4 mL of 0.1% solution to 1000 mL of dextrose 5% in water to produce 4 mcg/mL.
2) INITIAL DOSE

a) ADULT: 2 to 3 mL (8 to 12 mcg)/minute.
b) ADULT or CHILD: 0.1 to 0.2 mcg/kg/min. Titrate to maintain adequate blood pressure.

3) MAINTENANCE DOSE

a) 0.5 to 1 mL (2 to 4 mcg)/minute.

7) SEIZURES

a) DIAZEPAM

1) MAXIMUM RATE: Administer diazepam IV over 2 to 3 minutes (maximum rate: 5 mg/min).
2) ADULT DIAZEPAM DOSE: 5 to 10 mg initially, repeat every 5 to 10 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 30 milligrams.
3) PEDIATRIC DIAZEPAM DOSE: 0.2 to 0.5 mg/kg, repeat every 5 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 10 milligrams in children over 5 years or 5 milligrams in children under 5 years of age.
4) RECTAL USE: If an intravenous line cannot be established, diazepam may be given per rectum (not FDA approved), or lorazepam may be given intramuscularly.

b) LORAZEPAM

1) MAXIMUM RATE: The rate of IV administration of lorazepam should not exceed 2 mg/min (Prod Info Ativan(R), 1991).
2) ADULT LORAZEPAM DOSE: 2 to 4 mg IV. Initial doses may be repeated in 10 to 15 minutes, if seizures persist (Prod Info ATIVAN(R) injection, 2003).
3) PEDIATRIC LORAZEPAM DOSE: 0.1 mg/kg IV push (range: 0.05 to 0.1 mg/kg; maximum dose 4 mg); may repeat dose in 5 to 10 minutes if seizures continue. It has also been given rectally at the same dose in children with no IV access (Sreenath et al, 2009; Chin et al, 2008; Wheless, 2004; Qureshi et al, 2002; De Negri & Baglietto, 2001; Mitchell, 1996; Appleton, 1995; Giang & McBride, 1988).

c) RECURRING SEIZURES

1) If seizures cannot be controlled with diazepam or recur, give phenobarbital or propofol.

d) PHENOBARBITAL

1) SERUM LEVEL MONITORING: Monitor serum levels over next 12 to 24 hours for maintenance of therapeutic levels (15 to 25 mcg/mL).
2) ADULT PHENOBARBITAL LOADING DOSE: 600 to 1200 mg of phenobarbital IV initially (10 to 20 mg/kg) diluted in 60 mL of 0.9% saline given at 25 to 50 mg/minute.
3) ADULT PHENOBARBITAL MAINTENANCE DOSE: Additional doses of 120 to 240 mg may be given every 20 minutes.
4) MAXIMUM SAFE ADULT PHENOBARBITAL DOSE: No maximum safe dose has been established. Patients in status epilepticus have received as much as 100 mg/min until seizure control was achieved or a total dose of 10 mg/kg.
5) PEDIATRIC PHENOBARBITAL LOADING DOSE: 15 to 20 mg/kg of phenobarbital intravenously at a rate of 25 to 50 mg/min.
6) PEDIATRIC PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 5 to 10 mg/kg may be given every 20 minutes.
7) MAXIMUM SAFE PEDIATRIC PHENOBARBITAL DOSE: No maximum safe dose has been established. Children in status epilepticus have received doses of 30 to 120 mg/kg within 24 hours. Vasopressors and mechanical ventilation were needed in some patients receiving these doses.
8) NEONATAL PHENOBARBITAL LOADING DOSE: 20 to 30 mg/kg IV at a rate of no more than 1 mg/kg/min in patients with no preexisting phenobarbital serum levels.
9) NEONATAL PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 2.5 mg/kg every 12 hours may be given; adjust dosage to maintain serum levels of 20 to 40 mcg/mL.
10) MAXIMUM SAFE NEONATAL PHENOBARBITAL DOSE: Doses of up to 20 mg/kg/min up to a total of 30 mg/kg have been tolerated in neonates.
11) CAUTION: Adequacy of ventilation must be continuously monitored in children and adults. Intubation may be necessary with increased doses.

8) CHLORPROMAZINE

a) Chlorpromazine is a 5-HT2 receptor antagonist that has been used to treat cases of serotonin syndrome (Graham, 1997; Gillman, 1996). Controlled human trial documenting its efficacy are lacking.
b) ADULT: 25 to 100 mg intramuscularly repeated in 1 hour if necessary.
c) CHILD: 0.5 to 1 mg/kg repeated as needed every 6 to 12 hours not to exceed 2 mg/kg/day.

9) NOT RECOMMENDED

a) BROMOCRIPTINE: It has been used in the treatment of neuroleptic malignant syndrome but is NOT RECOMMENDED in the treatment of serotonin syndrome as it has serotonergic effects (Gillman, 1997). In one case the use of bromocriptine was associated with a fatal outcome (Kline et al, 1989).

E) HYPERTENSIVE EPISODE

1) SUMMARY: Hypertension usually resolves once the patient is less agitated (ie, following benzodiazepine administration). Large doses of benzodiazepines have been used in patients following 25I-NBOMe use (Hill et al, 2013; Rose et al, 2013).
2) If severe hypertension associated with end-organ damage persists, use of nitroprusside or a calcium channel blocker is suggested; use of beta-blockers is generally contraindicated since these agents may worsen vasospasm and result in hypertension (Shannon, 2000). As hypertension is generally short lived, a short acting titratable agent is preferred for treating hypertension.
3) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
4) For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives.
5) SODIUM NITROPRUSSIDE/INDICATIONS

a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.

6) SODIUM NITROPRUSSIDE/DOSE

a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).

7) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION

a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

8) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS

a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

9) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS

a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

10) PHENTOLAMINE/INDICATIONS

a) Useful for severe hypertension, particularly if caused by agents with alpha adrenergic agonist effects usually induced by catecholamine excess (Rhoney & Peacock, 2009).

11) PHENTOLAMINE/ADULT DOSE

a) BOLUS DOSE: 5 to 15 mg IV bolus repeated as needed (U.S. Departement of Health and Human Services, National Institutes of Health, and National Heart, Lung, and Blood Institute, 2004). Onset of action is 1 to 2 minutes with a duration of 10 to 30 minutes (Rhoney & Peacock, 2009).
b) CONTINUOUS INFUSION: 1 mg/hr, adjusted hourly to stabilize blood pressure. Prepared by adding 60 mg of phentolamine mesylate to 100 mL of 0.9% sodium chloride injection; continuous infusion ranging from 12 to 52 mg/hr over 4 days has been used in case reports (McMillian et al, 2011).

12) PHENTOLAMINE/PEDIATRIC DOSE

a) 0.05 to 0.1 mg/kg/dose (maximum of 5 mg per dose) intravenously every 5 minutes until hypertension is controlled, then every 2 to 4 hours as needed (Singh et al, 2012; Koch-Weser, 1974).

13) PHENTOLAMINE/ADVERSE EFFECTS

a) Adverse events can include orthostatic or prolonged hypotension, tachycardia, dysrhythmias, angina, flushing, headache, nasal congestion, nausea, vomiting, abdominal pain and diarrhea (Rhoney & Peacock, 2009; Prod Info Phentolamine Mesylate IM, IV injection Sandoz Standard, 2005).

14) CAUTION

a) Phentolamine should be used with caution in patients with coronary artery disease because it may induce angina or myocardial infarction (Rhoney & Peacock, 2009).

15) ALPHA BLOCKERS: Phentolamine and phenoxybenzamine have been shown to block the pressor response in mice.

F) HYPERPYREXIA

1) Hyperpyrexia was reported in 3 of 7 patients exposed to a single dose of 25I-NBOMe (Hill et al, 2013). Severe, life-threatening hyperthermia has not been reported but has been reported with other hallucinogenic amphetamines and is theoretically possible.
2) Core temperature above 40 degrees C may be life threatening and should be treated aggressively with rapid sedation and cooling.
3) External cooling measures should be provided. Accelerate evaporative heat loss by keeping the patient's skin wet with cool water and placing fans in the room. Rapid cooling measures including placing the patient in an ice bath may be required, however this can make access to the patient for resuscitation cumbersome. Monitor temperature every continuously by rectal probe, or every 30 minutes until below 38 degrees centigrade.
4) Administer intravenous benzodiazepines. Large doses may be required. Monitor respiratory adequacy and airway. Be prepared to intubate and ventilate if needed.
5) Intubation with neuromuscular paralysis and sedation may be required in severe cases.

G) TACHYARRHYTHMIA

1) Based on limited case reports of 25I-NBOMe exposure, sedation with benzodiazepines to control agitation has been sufficient to manage both tachycardia and hypertensive episodes (Hill et al, 2013; Rose et al, 2013).

a) CASE REPORT: An 18-year-old man was admitted to the ED with severe agitation and hallucinations following the use of 25I-NBOMe. Initial vital signs included significant tachycardia (heart rate 150s beats per min) and hypertension (blood pressure 150 to 170 mm Hg systolic and 110 mm Hg diastolic). An ECG showed sinus tachycardia. Vital signs normalized approximately 12 hours after admission following an initial bolus and a continuous infusion of lorazepam (1.5 mg/h) (Rose et al, 2013).

H) VENTRICULAR ARRHYTHMIA

1) VENTRICULAR DYSRHYTHMIAS SUMMARY

a) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.

2) LIDOCAINE

a) LIDOCAINE/DOSE

1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.

a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).

2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).

b) LIDOCAINE/MAJOR ADVERSE REACTIONS

1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).

c) LIDOCAINE/MONITORING PARAMETERS

1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).

3) AMIODARONE

a) AMIODARONE/INDICATIONS

1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).

b) AMIODARONE/ADULT DOSE

1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).

c) AMIODARONE/PEDIATRIC DOSE

1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).

d) ADVERSE EFFECTS

1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).

I) RHABDOMYOLYSIS

1) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
2) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
3) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
4) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
5) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).

Enhanced Elimination

A)

1) At the time of this review, it is unknown if hemodialysis or hemoperfusion would be beneficial. At the time of this review, most patients exposed to 25I-NBOMe respond quickly to supportive care with no permanent sequelae (Hill et al, 2013).

Abstracts

Range Of Toxicity

Summary

A)

B)

Minimum Lethal Exposure

A)

1) Based on data gathered by postmortem toxicology reports from 11 States in the US, 17 individuals have died from a combination of 25I-NBOMe, 25C-NBOMe and 25B-NBOMe. Of the 17 deaths, 14 were associated with acute toxicity and 3 were related to accidents or violent behavior due to use of these agents (Drug Enforcement Administration, 2013).
2) There have been reports of deaths related to 2C-I-NBOMe use in the US and a number of deaths in Australia (Nikolaou et al, 2015).
3) CASE REPORTS: 25I-NBOMe was detected in 2 individuals that died following exposure. In the first case, a 21-year-old man took 2 'hits of acid' and smoked cannabis at a rave party. A short time later, he began to hallucinate while being driven home and became very agitated and violent (attacking his friend). His friend left him in the car to get help and upon his return, the patient was unresponsive and resuscitation efforts were unsuccessful. The second case was a 15-year-old girl that drank a clear liquid while attending a rave party. She complained of feeling ill to her friend and than developed flailing of her extremities and became unresponsive. She was driven to the ER by her friend. In the ER, she was asystolic and hyperthermic (39.9 degrees C) and declared dead 18 minutes after arrival. In both cases, the postmortem analysis of heart blood and urine were positive for 25I-NBOMe and cannabis metabolites were detected by a comprehensive toxicology screen. Physical examination revealed only external injuries consistent with physical aggression (Wood et al, 2015).
4) CASE REPORT: A 19-year-old was found lying prone and unresponsive by his friends. He was declared dead at the scene after an unwitnessed fall from a balcony. Postmortem exam was positive for 25I-NBOMe in various biological samples (eg, heart and peripheral blood, urine, brain) (Wood et al, 2015).

Maximum Tolerated Exposure

A)

1) TYPICAL DOSE: 25I-NBOMe: The active dose has been reported to be as low as 50 to 250 mcg; a typical dose ranges from 500 to 800 mcg (Halberstadt & Geyer, 2014).
2) CASE SERIES (2C-I-NBOMe): In a series of 10 patients that had ingested and/or insufflated 2C-l-NBOMe, the most common symptoms were tachycardia, hypertension, agitation and hallucinations (Nikolaou et al, 2015).

B)

1) CASE REPORT: A 17-year-old boy, with a history of cannabis use, was admitted with agitation and confusion after taking one pill containing NBOMe. Initial vital signs included tachycardia (140 beats/min), hypertension (215/94 mmHg), and hyperthermia (38.4 degrees C). Seizures and severe sympathomimetic symptoms developed shortly after admission. High doses of diazepam (total 17.5 mg ) were administered to treat sympathomimetic toxicity. The patient was also intubated and sedated with midazolam. Approximately 12 hours later, the patient was fully alert. By day 5, the patient was fully recovered. A urine sample was positive for 25-NBOMe (Tang et al, 2014).
2) CASE REPORT: Approximately 6.5 hours after ingesting an estimated 10 g of 25NBOMe, a 31-year-old man, with a history of substance abuse, was admitted with sympathomimetic symptoms (ie, agitation, tachycardia, hypertension, and hyperthermia). His initial symptoms were followed by rhabdomyolysis, impaired renal function (plasma urea 6.2 mmol/L and plasma creatinine 170 micromol/L) and elevated liver enzymes (ALT 463 Units/L, AST 492 Units/L). Early treatment included IV fluids, lorazepam (total dose: 12 mg) and supportive care (ice packs). Creatine kinase peaked at 11,066 Units/L. Sodium bicarbonate was added for urine alkalization. Acute renal impairment resolved with treatment. On day 3, the patient demanded to be discharged and left against medical advice. 25B-NBOMe and 25C-NBOMe were detected in urine (Tang et al, 2014).
3) CASE REPORT: A 29-year-old man presented with agitation, aggression, seizures, tachycardia, hypertension, tachypnea, and fever after the intravenous injection of 3 mL of 25I-NBOMe (unknown concentration). Laboratory results revealed respiratory and metabolic acidosis, elevation of creatine kinase, impaired renal function, and elevated alanine transaminase. A CT scan of the head showed mild cerebral edema. Despite supportive care, he developed anuric renal failure within the next 2 days and he underwent a continuous veno-venous hemofiltration (CVVH). His condition deteriorated later with fever, high-oxygen and vasopressor requirements and worsening renal impairment. ARDS and pulmonary abscesses developed, requiring prolonged mechanical ventilation and respiratory support. Following a complicated hospital course and aggressive supportive care, his condition gradually normalized and he was discharged home 43 days after presentation (Hill et al, 2013).
4) CASE REPORT: A 20-year-old man, with a history of depression and taking fluoxetine (20 mg) daily, immediately collapsed following ingestion of 25I-NBOMe powder and had witnessed seizures by paramedics. Diazepam was given in route for severe agitation. Upon arrival, the patient required intubation. Persistent, short-lasting jerky movements thought to be seizures were treated with lorazepam and propofol (an increase in the infusion rate). Within 5 hours, the patient had evidence of serotonin syndrome (ie, sustained clonus, ocular clonus, fever (38.6 degrees C), tachycardia and an elevated creatine kinase (228 International Units/L). Cyproheptadine was initiated. By day 2, the patient's jerky movements were thought to be related to cerebral irritation versus seizures. The patient continued to improve and was discharged by day 4 clinically improved (Hill et al, 2013).
5) 25I-NBOMe: An 18-year-old man was admitted to the ED with severe agitation and hallucinations after using 25I-NBOMe. He also developed significant tachycardia and hypertension. Following initial treatment with lorazepam (2 doses of 2 mg), the patient became alert and cooperative. Vital signs normalized approximately 12 hours after admission following a continuous infusion of lorazepam. However, agitation and restlessness continued to be present when the patient was awake. At 24 hours, the lorazepam infusion was increased and restraints were also necessary. By the following day, the infusion was discontinued, but the patient continued to have intermittent episodes of aggressiveness. An oral antipsychotic (ziprasidone) was started after psychiatric evaluation. A urine toxicology screen was positive for cannabinoids only and a positive blood ethanol level of 25 mg/dL (Rose et al, 2013).
6) 25I-NBOMe: A 21-year-old man developed agitation, hallucinations, tachycardia, and fever after insufflating about 0.1 g of 25I-NBOMe powder. He recovered gradually following supportive care (Hill et al, 2013).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) 25I-NBOMe

a) In a case report of a man who used 25I-NBOMe, the concentration was 0.76 ng/mL in the patient's serum using high performance liquid chromatography with tandem mass spectrometry (HPLC/MS/MS) analysis. He recovered following supportive care (Rose et al, 2013).
b) In another study, high performance liquid chromatography tandem mass spectrometry was used to determine the presence of 2CC-NBOMe and 25I-NBOMe in the serum of intoxicated ED patients. Of 2 severely 25I-NBOME intoxicated patients, serum concentrations were 250 and 2780 pg/mL, respectively (Poklis et al, 2013).

2) 25B-NBOMe

a) A 16-year-old teenager ingested "acid" on blotting paper (thought to be LSD) and developed multiple seizures prior to admission. Upon admission, he had a fourth seizure and was intubated and ventilated and received IV sedation. He was successfully extubated the next day. A blood sample using high performance liquid chromatography/mass spectrometry detected 25B-NBOMe (0.089 mcg/mL) 22 hours post ingestion (Isbister et al, 2015a).

3) 25C-NBOMe

a) A 27-year-old man developed hallucinations and became violent and aggressive after taking "acid" (thought to be LSD). His hallucinations continued for 24 hours. A blood sample was analyzed using high performance liquid chromatography/mass spectrometry detected 25C-NBOMe (0.164 mcg/mL) about 15 hours after ingestion (Isbister et al, 2015a).

Pharmacology Toxicology

Toxicologic Mechanism

A)

B)

1) N-benzyl substituted phenethylamine 2C derivatives act as potent 2A (5-HT2A) receptor agonists. These agents are psychoactive substances that are related to the phenethylamines of the 2C and 2D series of designer drugs. Similar to these compounds, the N-benzyl series act as serotonergic hallucinogens and are increasingly being used as recreational drugs (Hill et al, 2013; Halberstadt & Geyer, 2014). Although the mechanism of action of phenethylamines (including the N-benzyl derivatives) is not completely understood, it is thought that all hallucinogens share a common site of action on central 5-HT2 receptors. Following N-benzyl derivative intoxication, patients have presented with either a sympathomimetic syndrome, serotonin toxicity, hallucinogenic effects, or a combination of all of these clinical effects (Hill et al, 2013; Rose et al, 2013; Halberstadt & Geyer, 2014).

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PHENETHYLAMINE DESIGNER DRUGS-N-BENZYL SERIES

Classification | Detailed evidence-based information

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Specific Substances

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Treatment Overview

Range Of Toxicity

Summary Of Exposure

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General Bibliography