Ketamine therapy can reduce risk for suicide and depression in treatment-resistance patient. It is also used to treat chronic pain syndromes [1]. Adverse effects of ketamine infusion include blurred vision, nausea and vomiting, hepatotoxicity, headache, and cystitis. However, the effect of ketamine infusion on blood glucose remains unclear. Here, we report a case of hypoglycemia associated with the infusion of ketamine.

Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

A 36-year-old Thai man with type 1 diabetes mellitus (T1DM), he has had T1DM since he was 14-year-old and he had good adherence to diabetic treatment. Two years prior to admission, his work condition has changed, leading to a progression of depression. Since then, he had multiple episodes of moderate to severe hyperglycemia; therefore, his endocrinologist referred him to a psychiatrist for treatment of depression. He had unsuccessful treatments of escitalopram, agomelatine, mirtazapine, sertraline, lurasidone, bupropion, cariprazine, and quetiapine, hence ketamine infusion therapy was suggested due to treatment resistant depression.

His medical history included T1DM and dyslipidemia. His current medications were insulin degludec (14 units/d), ezetimibe/simvastatin (10/20 mg/d), agomelatine (50 mg/d), etifoxine (200 mg/d), flunitrazepam (1 mg/d), and clonazepam (0.5 mg/d). Diabetic and lipid control medications had been taken regularly at stable dose for more than 6 months prior to ketamine infusion. His hemoglobin A1C test was 6.5%. The patient’s serum renal, hepatic functions, and complete blood count were normal. He did not use any other substances including alcohol.

This article describes the first three ketamine sessions which he was admitted on the psychiatric ward. The patient received ketamine through a continuous intravenous infusion pump at 0.5 mg/kg diluted in normal saline for 40 minutes. Vital signs and level of consciousness were monitored every 10 minutes during ketamine infusion and every 15 minutes for another 2 hours. The first ketamine infusion therapy was started three hours after the regular meal. Vital signs were monitored before starting ketamine. Body temperature (BT), 36.9°C; heart rate (HR), 72 bpm; respiratory rate (RR), 20 breaths per minute; blood pressure (BP), 131/73 mmHg; oxygen saturation in room air (O₂Sat), 100%. His point-of-care testing for blood glucose (POCT-BG) was 171 mg/dl. The last insulin dose was administered the night before the intervention with the same dosage as previous. The patient’s conditions were stable until 1 hour after ketamine infusion when he reported dizziness, palpitation and concern that he had become hypoglycemic. He displayed no signs of confusion and reported no symptoms such as blurred vision, stomach pain, or fruity-smelling breath. His vital signs were stable; BT 36.9°C; HR 70 bpm; RR 20 breaths per minute; BP 128/63 mmHg; O₂Sat, 98%, however, his POCT-BG was 68 mg/dl. He was treated according to the ‘Siriraj Hospital guideline for adult patients with insulin administration’. According to this guideline, patients experiencing hypoglycemia are assessed for symptoms and POCT-BG level. Subsequently, they are administered 30 ml of a sweet drink mixed with 100 ml of water, or injected with 50% glucose at a dose of 20−50 ml, followed by dexterous intravenous fluid as directed by the doctor. In this particular instance, the patient received a sweet drink as part of the treatment protocol. Consequently, his POCT-BG increased to 124 mg/dl and he felt more relaxed.

On day two, the second dose of ketamine was administered with the same protocol. Before ketamine administration, his vital signs were stable; BT 36.5°C; HR 82 bpm; RR 20 breaths per minute; BP 121/70 mmHg; O₂Sat, 100%. His POCT-BG was 138 mg/dl. After this dose, he reported that he felt like his depression had improved because he did not think about death and had plans to living well. Four hours after ketamine infusion, he reported fatigue, sweating, and palpitation. His POCT-BG was 46 mg/dl while his vital signs were stable. After receiving sweeten liquid according to the guideline, his POCT-BG increased to 113 mg/dl.

The third dose of ketamine was administered the next day. His vital signs before ketamine infusion were stable; BT 36.3°C; HR 68 bpm; RR 20 breaths per minute; BP 139/72 mmHg; O₂Sat, 100%. His POCT-BG was 125 mg/dl. Two hours after ketamine therapy, his POCT-BG dropped to 63 mg/dl, so he received care according to the protocol and his POCT-BG increased to 168 mg/dl. Physical examination was performed before discharge, his vital signs were stable; BT 36.5°C; HR 62 bpm; RR 20 breaths per minute; BP 124/68 mmHg; and O₂Sat, 100%.

During 1 year, he received ketamine infusion therapy for 11 times (including first three times as described) and his POCT-BG has shown in Table 1. His post-ketamine POCT-BG was lower than 70 mg/dl for 4 times (36%). His blood glucose always decreased after expose to ketamine, while his POCT-BG pre and post-ketamine were higher. POCT-BG range before and after ketamine were 100−277 and 46−167 mg/dl, respectively. Taking into account the non-ketamine exposure, the blood glucose range was examined at a time point similar to that of ketamine POCT-BG. The range was 47−324 and 56−450 mg/dl. The mean difference of average POCT-BG were; non-ketamine, 6.78 mg/dl; and ketamine, −93.18 mg/dl.

This case report describes hypoglycemia, less than 70 mg/dl [2], in a patient with T1DM who had recently received ketamine. Considering the temporal interval of roughly 12 hours since the final insulin administration, the likelihood of active medication effect is minimal. Furthermore, his symptoms do not align with those typically associated with diabetic ketoacidosis, a potential complication arising from the patient’s diabetes. The causality of adverse drug reactions was assessed using the Naranjo algorithm score [3] that hypoglycemia is probably related to ketamine. Although hypoglycemia occurred in only 36% of his ketamine administrations, blood glucose almost always decreased after ketamine infusion. Taking into account the factors predisposing to hypoglycemia, the patient did not change his daily activities before and during ketamine treatment. He did not drink alcohol or take any other substances. He took the same dose of his medications, including insulin, for one year. Therefore, ketamine infusion therapy could cause lower blood glucose in patient with T1DM.

The evidence suggests that ketamine affects to blood glucose. Ketamine might have dual effect on blood glucose in rabbits. At the low dose (0.17 mg/kg), glucose level increased significantly, while at higher dose (1−2 mg/kg), the blood glucose was lower [4]. The mechanism that might explain ketamine-induced hypoglycemia is ketamine mediated through opioid receptors and β-adrenoreceptors after blockade of α₂-adrenoceptors. In contrast, diabetic rats were at risk of ketamine-induced hyperglycemia [5]. One possible mechanism is that ketamine might activate the hypothalamic-pituitary-adrenal (HPA) axis, increasing corticosterone. Then, the positively changed corticosterone level was increased in blood glucose. However, there is an evidence that ketamine reduces depressive symptoms in rats without affecting the blood glucose level [6].

There is a lack of knowledge about the interaction between ketamine and insulin, particularly in relation to the occurrence of hypoglycemia in diabetic patients. Although the exact mechanisms underlying ketamine-induced hypoglycemia remain unclear, we hypothesize that the patient with depression and T1DM could have higher baseline physical stress than the general population. Previous studies have reported that depression was likely caused by impaired HPA axis and subsequent elevation of glucocorticoids [7], as well as poor controlled diabetes also increased HPA activity [8]. Therefore, both conditions amplify the effects of psychophysical stressors. While ketamine rapidly reduced his psychological stress, it may have also increased the biological reactivity of the HPA axis, reducing the blood glucose. While, this single case report is not conclusive, we suggest that careful observation of glucose levels in patients with T1DM who receive ketamine infusion for depression is indicated.

The authors would like to thank the patient who gave consent to share his case.

No potential conflict of interest relevant to this article was reported.

Conceptualization: Keerati Pattanaseri. Data acquisition: Keerati Pattanaseri. Formal analysis, Writing—original draft: Juthawadee Lortrakul. Writing—review & editing: Keerati Pattanaseri, Juthawadee Lortrakul.