The present report describes a case of severe cannabinoid toxicosis in a ferret that was diagnosed with an over‐the‐counter human urine test and was successfully treated with ILE administration and supportive care. This case illustrates that ingestion of cannabinoid candy can produce severe neurologic signs in ferrets, such as markedly decreased mentation, absent gag reflex, anisocoria, bradycardia, hypothermia, hypotension, and hypercapnia.

The severe hypercapnia present in this patient warranted mechanical ventilation or high‐flow nasal oxygen therapy; our facility does not have these capabilities to treat patients weighing < 1 kg. Manual ventilation could be considered; however, in this case, it was declined by the owners. Due to the inability to ventilate the patient, it was decided to provide oxygen therapy via oxygen cage at 40% FiO₂ to increase PAO₂. Hypoxemia due to hypoventilation can be improved with supplemental oxygen by increasing PAO₂ even if the hypoventilation remains uncorrected [8]. The PvCO₂ improved significantly within 14 h, decreasing from 126.7 to 69.3 mmHg.

Due to the severity of clinical signs and poor response to initial medical management, including several doses of hyperosmolar therapy to reduce suspected intracranial edema, and the owners' consideration of euthanasia based on the lack of clinical improvement, dexamethasone sodium phosphate was administered with the aim of minimizing intracranial edema. However, a controversial approach, recent human studies suggest a benefit from the use of corticosteroids in some cases of acute brain injury due to their neuroprotective effects [9, 10, 11]. These effects are based on affecting downstream apoptotic pathways and decreasing neuronal cell death, reducing tumor necrosis factor alpha production, limiting the inflammatory‐mediated response, and acting on prosurvival signals [10]. Also, dexamethasone exerts neuroprotection via activation of phosphorylated Akt, similar to the effects seen in hypothermia treatment [10]. Adverse effects of dexamethasone, such as gastrointestinal ulceration and polyuria, could have further compromised the ferret; however, there is no published evidence of these adverse effects in ferrets. This ferret's clinical improvement was obvious only after the intralipid administration, which occurred several hours after corticosteroid administration. Thus, the effect of corticosteroids in this case was unclear, and they most likely did not impact the ferret's clinical improvement.

Although normal in this case, electrolyte disturbance should be considered as a potential cause of the neurological signs or a worsening factor, especially in the event of hypokalemia and hypomagnesemia. Clinical signs of hypokalemia are rare in other species and can include neuromuscular weakness, ventral flection of the neck, stiff hindlimbs, wide‐based stance, and hypermetria of the forelimbs [12]. Severe cases can result in respiratory arrest from neuromuscular weakness. Severe hypomagnesemia can also lead to muscle weakness, neurological signs, abnormal behavior, and sudden death [12]. Magnesium concentrations were not measured in this ferret becuase the blood volume required would have exceeded the total blood volume extraction recommended for this species within 24 h [13]. Empirical supplementations could be considered in cases where prolonged anorexia was present or anticipated.

The LD₅₀ for cannabinoids has not been established in ferrets, dogs, or cats [3]. In one study, the LD₅₀ of cannabinoids administered intragastrically and by inhalation to rats was found to be 36–40 mg/kg [14]. In dogs, the minimal toxic or lethal dose of delta‐9‐THC is 3 g/kg when taken orally, which is 1000 times greater than the dose that causes behavioral disorders [3]. In the present report, the maximum ingested dose could have been 30 mg (40 mg/kg) of each one of the two compounds present in the candy (THC and cannabidiol [CBD]). However, since another ferret in the household was also affected, the dose ingested by the ferret in this report was likely lower than 40 mg/kg of THC and CBD. In dogs, the onset of clinical signs of marijuana toxicosis typically occurs within 30–90 min of exposure and can last up to 96 h [3]. In this ferret, it was not possible to determine how soon the clinical signs appeared after exposure because the owner did not know when the ferret ingested the cannabinoid‐containing candy or when the ferret started showing clinical signs of intoxication.

It is unclear what the cause of the ferret's high fluid requirements is, but it was likely multifactorial. It is possible that fluid losses (urine output) were underestimated since a urinary catheter was not placed and the urine output was not measured. An underestimation of the degree of dehydration is also possible since the patient's clinical signs may have started hours before presentation. Repeated doses of mannitol could have contributed to increased urine output, which clinicians were likely not matching. Also, the lack of oral water intake because of the ferret's altered mental state has to be considered. Other potential causes could include CBD‐induced hypotension as seen in other species [15], or CBD caused endothelium‐dependent vasorelaxation of the mesenteric arteries via CB1 activation, which has been reported in people [16].

In dogs, over‐the‐counter drug tests for marijuana are known not to be adequately sensitive because of the relatively low concentrations of THC‐COOH in dog urine, which is the cannabinoid metabolite detected by over‐the‐counter tests [4]. Other causes of false negative results include sampling urine too soon after cannabinoid exposure; sample handling and storage problems, since THC binds to rubber stoppers and glass; consumption of synthetic cannabinoids; and overhydration [17]. In this ferret, the positive urine results may be explained by a higher elimination rate of THC‐COOH in urine relative to dogs. Considering that this ferret weighed < 1 kg, it is also possible that the ingested dose per kg of body weight was much higher in this ferret than what is typically observed in dogs. Although the possibility that the urine result could have been a false positive has to be considered, the history, clinical signs, and response to treatment strongly suggest that this was indeed a case of cannabinoid toxicosis. An example of a possible cause for a false positive result would be the treatment with nonsteroidal anti‐inflammatory drugs [18]; however, this ferret was not treated with such medications. Other modalities of cannabinoid detection and quantification exist, such as liquid chromatography–tandem mass spectrometry [19] or gas chromatography [20], which can be considered in cases where urine testing is negative, but a high suspicion remains.

Lack of evidence of traumatic injuries on radiographs and CT did not support the hypothesis of trauma. The CT was not performed until approximately 14 h after admission since this modality is only available during routine hours in our hospital. Later, the history of missing cannabinoid candy and the positive urine test supported the diagnosis of cannabinoid intoxication.

In veterinary medicine, only acute cannabinoid toxicosis has been described, and the treatment for this condition is similar to what is recommended for people. Emesis induction and activated charcoal administration can be considered to prevent absorption of ingested cannabinoids still present in the gastrointestinal tract [21]. These approaches were not used for this ferret because the ferret's neurological deficits were a contraindication for emesis induction and oral administration of activated charcoal. Treatment with extracorporeal therapy should be considered in extreme intoxications such as this case [22]. However, due to the small size of this patient (0.75 kg), this treatment option would be extremely challenging, if not impossible.

Cannabinoids are highly lipophilic, are distributed in adipose tissue, liver, lungs, and spleen after absorption from the gastrointestinal tract, and are slowly redistributed into the plasma before excretion in the feces and urine [23]. ILE has been described as an effective treatment for toxicosis caused by lipophilic substances such as calcium channel blockers, bromethalin, avermectin parasiticides, baclofen, bupropion, loperamide, permethrin in cats, and sertraline [3]. It has been hypothesized that an expanded intravascular lipid phase acts to sequester lipophilic toxin within it, thus reducing the effect site concentration and toxicosis until the compound is metabolized and excreted [24]. In the ferret described in this report, ILE was administered as soon as the diagnosis of cannabinoid toxicosis was confirmed by the urine test. In this case, no clinical improvements were seen until after the second ILE treatment (total dose 31 mL/kg). Conversely, in the only reported ferret treated with ILE, a much lower dose (total dose 9 mL/kg) was effective for olanzapine toxicosis [25]. The large volume of lipid emulsion required in the present ferret may be explained by differences between the toxic compounds (olanzapine vs. cannabinoids) and/or the ingestion of a very high dose of cannabinoids by this ferret.

Potential adverse effects of ILE administration in small animals can include pancreatitis secondary to persistent lipemia, hypersensitivity reactions, fat overload syndrome, and lipid emboli, as well as sepsis [26]. Lipemia was subjectively diagnosed in the ferret reported here immediately after administration of the first dose of ILE; however, 4 h later, gross evidence of lipemia was no longer observed. Consequently, treatment with ILE in this ferret did not cause obvious complications.

In conclusion, severe cannabinoid toxicosis in this ferret was successfully managed with supportive care and ILE. The history of possible trauma delayed the diagnosis of cannabinoid toxicosis. Considering that cannabinoid‐containing products are now widely available in North America, it is essential to consider cannabinoid toxicosis as a differential in pets with signs of diffuse dysfunction of the central nervous system. More studies are needed to provide essential information that can help diagnose cannabinoid toxicosis in ferrets and determine whether over‐the‐counter urine tests can be routinely used to detect THC‐COOH concentrations in ferret urine.