Can Naloxone Be Used to Treat Synthetic Cannabinoid Overdose?

To the Editor

Synthetic cannabinoids, commonly known as K2 or Spice, have emerged as a recreational drug and an inexpensive alternative to cannabis (1). Currently, there is no antidote for synthetic cannabinoid overdose/overintoxication, and clinical care typically only includes symptom management. However, naloxone, a drug used to treat opioid overdose, might prove beneficial (2,3). Naloxone is a nonselective opioid antagonist increasingly used by medical personnel and laypersons to reverse overdose due to the use of opioid analgesics and heroin (4).

Why might an opioid receptor antagonist affect a drug that acts on the cannabinoid receptor? Studies show that opioid and cannabinoid receptors are colocalized in multiple brain regions where they may exist as heterodimeric systems. Both receptors also have cross-modulatory pharmacologic effects, including cross-agonism, -antagonism, -sensitization, and -tolerance (5,6). Accordingly, several studies suggest that opioid receptor antagonists might counter the effects of cannabinoid agonists (2,7).

In April 2015, synthetic cannabinoid-related emergency department visits increased dramatically in New York City. In response, the New York City Department of Health and Mental Hygiene conducted a public health investigation to gain a better understanding of the circumstances, presenting symptoms, and severity of synthetic cannabinoid overdose. Twenty-seven medical charts were identified from citywide emergency department records and reviewed; 15 met the eligibility criteria for inclusion: patient was admitted to the hospital April 10–20, 2015, and synthetic cannabinoid use was documented in the medical record. The medical chart review identified four cases with documentation of improved symptomology after the administration of naloxone (Table 1). In each of these cases we found evidence of increased responsiveness and/or normalized vital signs after naloxone administration. These four cases were of particular interest because there was no evidence of recent opioid use (either by self-report or in drug toxicology) that would account for symptom improvement after naloxone administration.

Table 1.

Summary of Medical Details From Four Cases of Suspected Synthetic Cannabinoid Overintoxication

Sex	Race	Age, Years	Location	Chief Complaint	Symptoms	Naloxone Administered By	Response to Pain	Self-Reported Drug Use	Drug Toxicology	BAC (mg/dL)	Presenting Vitals (EMS)				Final Vitals (ED)				Outcome	Mental Health Hx
											HR/beat/min	O2 Sat, %	RR, breaths/min	BP, mm Hg	HR, beats/min	O2 Sat, %	RR/breaths/min	BP, mm Hg
M	B	30	Street	Altered mental status	Lethargy/sleepiness, nonresponsiveness to verbal stimuli, respiratory depression, mild respiratory acidosis, vomiting, seizure, chest pain	EMS	Responsive	SynCan	Negative (amphetamine and cannabis were not tested)	NR	116		6	128/80	60	98	19	127/74	Discharged	SCZD
F	B	36	Shelter	Nonresponsive	Drowsiness, sluggishness, nonresponsiveness to verbal stimuli, tachycardia, vomiting, confusion, lethargy/sleepiness, loss of consciousness, intoxication	EMS	Responsive	SynCan	Not performed	0		80	16	114/73	61	100	16	99/54	Admitted	None
M	W	61	Street	Nonresponsive, seizure	Lethargy, intoxication, nonresponsiveness to verbal stimuli, rapid breathing, tachycardia, loss of consciousness	EMS	Responsive	SynCan, alcohol	Negative	18	141	87	30		89	98	16	106/59	Admitted, left AMA	Alcohol abuse
M	NR	46	Home	Nonresponsive, confusion	Nonresponsiveness to verbal stimuli, borderline hypotension, confusion, elevated CO2, lactic acidosis	EMS	Non-responsive	SynCan, alcohol	Negative	46						95			Admitted	None

AMA, against medical advice; B, black; BAC, blood alcohol content; BP, blood pressure; ED, emergency department; EMS, emergency medical services; F, female; HR, heart rate; Hx, history; M, male; NR, not reported; RR, respiratory rate; Sat, saturation; SCZD, schizophrenia; SynCan, synthetic cannabinoid; W, white.

In New York City, first responders have been trained to administer naloxone in instances of suspected opioid use or respiratory depression. Although these cases tentatively suggest that the administration of naloxone led to symptom improvement, this conclusion should be made with caution. In each of these cases a number of treatment interventions may have been used aiding in resolution of adverse symptoms. In addition, little is known about the time course of synthetic cannabinoid overdose, and symptoms may have improved without medical intervention. Finally, in two of the four cases there is evidence of alcohol use. Opioid antagonists also block alcohol-mediated effects, which may account for some degree of symptom improvement (8).

Another interesting finding from these cases is the shared clinical presentation of synthetic cannabinoid overdose to opioid overdose (9). The co-occurrence of symptoms such as loss of alertness, unconsciousness, and decreased respiratory measures may further demonstrate the interrelatedness of endogenous opioid and cannabinoid systems and may add credibility to the potential utility of naloxone in cases of synthetic cannabinoid overdose. Again, we stress caution in drawing conclusions from only four cases. In addition, because synthetic cannabinoids include hundreds of different chemical compounds, their chemical composition and resultant neuropharmacology is varied. Therefore, the efficacy of naloxone to improve symptoms after synthetic cannabinoid use may vary depending on the exact synthetic cannabinoid compound(s) involved. Despite these limitations, these case results provide a basis to initiate further investigation into how clinicians might address the adverse health consequences of a class of drugs with no presently known antidote.