Assessing Cognitive Function over Time in Patients with Refractory Chronic Migraine Who Received Ketamine Infusions: A Prospective, Observational Study

Abstract

Background

Ketamine infusions are used in the inpatient setting for refractory chronic migraine but are associated with neurotoxicity in rodents at high doses and memory deficits in illicit users. The relationship between ketamine infusions and cognitive function in refractory chronic migraine patients after infusions is unknown. We aimed to determine if patients receiving ketamine infusions for refractory chronic migraine experience changes in cognitive function as assessed by the telephone Montreal Cognitive Assessment.

Methods

Adults 18 years or older who were diagnosed with refractory chronic migraine and met criteria for hospitalization with an elective ketamine infusion were recruited for this prospective observational study. All patients had Migraine Disability Assessment grade IV (severe disability) and had previously failed an inpatient treatment with at least one other intravenous infusion. Baseline assessments included current and average pain levels, monthly migraine days, depression history, medications, and initial assessments of the telephone Montreal Cognitive Assessment, Migraine Disability Assessment, and Headache Impact Test-6. Patients were admitted to a dedicated headache unit within 1 month of baseline assessments to undergo a 5-day continuous ketamine infusion to a maximum rate of 1 mg/kg/h. The aforementioned assessments were then repeated at 1, 6, and 12 months. The primary outcome was the change over time in the telephone Montreal Cognitive Assessment, which was analyzed using generalized estimating equations adjusted for age and sex.

Results

A total of 23 patients were analyzed. The mean age was 44.8 $\pm$ 11.5 years, and 87% were female. A history of depression was present in 82.6%. The estimated marginal mean telephone Montreal Cognitive Assessment score changed from 18.8 $\pm$ 0.7 to 19.9 $\pm$ 0.7 at 1 month (p < 0.001), 19.2 $\pm$ 0.8 at 6 months (p = 0.390), and 18.3 $\pm$ 0.9 at 12 months (p = 0.382). Only the change at 1 month reached the minimal clinically important difference of 1 point. Monthly migraine days decreased from a baseline of 27.1 $\pm$ 1.6 to 24.4 $\pm$ 2.1 at 1 month (p = 0.08), 22.4 $\pm$ 2.3 at 6 months (p = 0.05), and 22.3 $\pm$ 2.2 at 12 months (p = 0.026).

Conclusion

The study suggests that measurable cognitive impairment did not occur over the course of the 1-year study period in most patients with refractory chronic migraine after receiving a ketamine infusion. However, a few patients experienced worsening telephone Montreal Cognitive Assessment scores, and furthermore, the small sample size and lack of a control group prevent any definitive conclusions. Larger follow-up studies would further establish the safety of ketamine treatment in headache or pain.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40263-025-01252-x.

Key Points

Cognitive outcomes during the 12 months after a multiday ketamine infusion, as measured by the Montreal Cognitive Assessment, did not significantly worsen on average.

Current pain ratings decreased at 1 month compared to baseline, which coincided with a slight improvement in the average telephone Montreal Cognitive Assessment score.

Because a few outliers did experience worsened cognitive function after treatment, additional studies are needed to define which patients are at risk.

Introduction

Ketamine is an N-methyl-D-aspartate (NMDA)-receptor antagonist approved for use as a dissociative anesthetic, but frequently used off-label for indications such as refractory depression, neuropathic pain, complex regional pain syndrome, and refractory chronic migraine (RCM), a subset of chronic migraine with disabling symptoms with inadequate response to standard therapies [1]. Ketamine possesses anti-inflammatory effects and interacts with other receptors, including dopaminergic, muscarinic, nicotinic, sigma, and voltage-gated calcium channels [2, 3]. Ketamine has been shown to provide relief in treatment-resistant depression [4], and some studies suggest that it may be effective for RCM [5–7].

Despite this, there have been persistent concerns related to neurotoxicity in rodents that received ketamine. Vacuolation within the cytoplasm of neurons in specific regions of the rat brain, including the cingulate and retrosplenial cortices, has been noted after exposure to high concentrations ($\ge$ 40 mg subcutaneously), raising the concern for neurotoxicity [8].^. While neurotoxicity cannot be directly monitored in humans, the affected regions of rat brains—the retrosplenial and cingulate cortices—serve complex functions in humans that include memory, navigation, contextual learning, and narrative comprehension [9, 10].

There have also been reports of memory deficits and cognitive dysfunction related to ketamine in humans. Ketamine affects episodic memory and spatial working memory in humans, and some authors have expressed concern that this might continue even after cessation of use [11]. In a randomized, double-blind study of human volunteers, Rowland et al. administered ketamine or placebo and found that ketamine impaired learning of spatial and verbal information [12]. Impaired cognitive function has been reported in chronic frequent users of ketamine, defined in one study as using the drug at least 4 times per week [13]. The ”frequent” ketamine users in that study had been using the drug illicitly for an average of 6.67 years. The cognitive effects of subanesthetic ketamine infusions used for RCM and other challenging patient populations have not been well studied. Considering the rapid and widespread use of subanesthetic ketamine infusions for migraine, depression, and chronic pain, studies are needed to minimize potential harm.

The primary objective of this observational study was, therefore, to assess changes in cognitive function over time in RCM patients treated with multiday ketamine infusions to better understand if clinical doses of the drug are associated with cognitive impairment and, if present, the duration of impairment. To achieve this, we performed serial Montreal Cognitive Assessments (MOCAs) in the patients up to 12 months after treatment and compared all assessments to baseline.

Methods

This was a prospective, observational pilot study and was approved by the Thomas Jefferson University institutional review board on April 22, 2021 (Control #21D.412). All patients provided written informed consent. This study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments, with the exception that it was not registered due to its observational design. Study enrollment took place from 9/2021 through 7/2022, with the final 12-month follow-up being completed on 9/2023. Inclusion criteria included adults, ages 18–75 years, who met the International Classification of Headache Disorders (ICHD)-3 diagnostic criteria for chronic migraine [14]. Patients had to have refractory disease, which was defined for the purpose of this study as having failed adequate trials of at least three preventive treatments with established effectiveness in migraine for at least 2 months at optimal or maximum-tolerated dose, as well as multiple classes of abortive treatments with established efficacy in migraine [15]. Additional RCM criteria for the patients included the failure of at least one multiday infusion therapy, such as dihydroergotamine or lidocaine, which is consistent with the most severe (grade IV) of the refractory criteria proposed by Silberstein et al. [1] To be included, patients also needed to be scheduled for an inpatient hospitalization, with a consult with the acute pain management service for ketamine infusion. The use of ketamine was not considered a study intervention because it is part of the care of RCM patients at our center. Exclusion criteria were previous ketamine infusion, pregnancy, previously diagnosed cognitive impairment or dementia, history of stroke, multiple sclerosis, psychotic disorders, Parkinson’s disease, chronic kidney disease, chronic liver disease, and poorly controlled hypertension. Patients with other concurrent headache disorders were excluded if that headache disorder was the patient’s predominant cause of morbidity. For example, if the patient’s primary diagnosis was hemicrania continua or cluster headache rather than RCM, they were excluded. Given the significant disability of the study population and the refractory nature of the disease, other preventive medications were continued. A sample size of 24 patients was planned a priori based on available funding and resources.

Data Collection, Assessments, Outpatient Management, and Inpatient Treatment

Baseline data collected included demographics, history of depression, benzodiazepine use at the time of enrollment, previous intranasal ketamine use, baseline pain level (0–10 numerical rating scale [NRS] with 0 being no pain and 10 being the worst pain imaginable), and the number of migraine days in the previous 30 days. A migraine day was defined as a day in which the patient experienced at least 4 h of continuous pain of at least moderate intensity and had migraine features or required specific migraine treatment, consistent with the published definition as used in clinical trials [16]. The metric of monthly migraine days (MMD), as opposed to monthly headache days, was used as it better describes the symptoms experienced by the typical RCM population.

Participants were scheduled for a telephone interview to complete a baseline telephone MOCA (t-MOCA), Migraine Disability Scale (MIDAS), and Headache Impact Test (HIT-6) prior to hospitalization. All necessary permissions were obtained. The t-MOCA is a validated instrument consisting of 22 questions that assess language and recall abilities and has been shown to be effective at detecting mild cognitive impairment in multiple populations [17–19]. The t-MOCA was originally developed for people with visual impairments, as it removes items that require visual abilities or the use of a writing instrument, but is also an ideal option for telephone assessment [20]. The scores range from 0 to 22, with 22 indicating the best possible score; the test covers verbal fluency, orientation, digit span, attention, calculation, repetition, abstraction, and recall [21]. Scores of 18–19 and below suggest mild cognitive impairment and warrant further testing [22]. The minimal clinically important difference for the standard MOCA is 1 point [23].

Study personnel completed a 1-h training module and received certification for administering the t-MOCA to study participants. The study personnel who administered the t-MOCA were not the attending physicians directly treating the patients.

All participants were contacted prior to and 1 month, 6 months, and 12 months after their respective date of hospitalization to complete t-MoCA assessments. Twenty-three patients included in the study analysis were present for all study timepoints. Reminders were sent by email to study personnel to complete the virtual encounters, and study participants were contacted a maximum of three times to complete the post-treatment assessments. Patients were selected on the criteria that they could operate a telephone independently and had fluency in English. The memory index score (MIS), which is a subset of the t-MOCA assessment, is scored on a range from 0 through 15, with 15 representing perfect word recall, and it is focused specifically on memory [21].

We measured the impact of RCM using two validated questionnaires: the MIDAS and the HIT-6 [24, 25]. Both MIDAS and HIT-6 assessments were administered via telephone at baseline and 1 month, 6 months, and 12 months after hospitalization.

Patients were scheduled for inpatient treatment, including a ketamine infusion, within 1 month of enrollment.

Ketamine Treatment Protocol and Admission

The treatment took place in a dedicated headache unit within an acute care hospital. Neither patients nor data collectors were blinded to treatment status. A baseline headache pain level was recorded at the time of admission. Patients were admitted for a planned 5 days of continuous intravenous (IV) ketamine infusion, or approximately 120 h. Outpatient preventive medications were continued, but abortive medications were stopped during their admission. Ketamine infusions were started at 10 mg/h per hospital protocol and titrated up by 5–10 mg/h every 4 h until intolerable adverse effects (AEs) occurred, or 1 mg/kg/h was reached. Hospital protocols dictate that the maximum ketamine rate to be administered to patients is 1 mg/kg/h outside of an intensive care unit setting. Unless contraindicated because of baseline low blood pressure, all patients also received a clonidine 0.2-mg transdermal patch for the duration of the ketamine infusion to mitigate AEs, including ketamine-induced hypertension and psychomimetic effects. Additional medications administered during hospitalization included ketorolac, magnesium sulfate, and methylprednisolone. Patients were monitored on telemetry, and ketamine was managed by the acute pain management service. If severe AEs occurred, the infusion rate was decreased to the previously tolerated rate, and a low dose of benzodiazepine was administered at the discretion of the treating team. Severe AEs were defined as generalized anxiety/panic attack, hallucinations, nightmares, intractable or medically refractory nausea or vomiting, blurry vision, malignant hypertension (> 180/110), tachycardia (defined as persistent elevation > 100 beats per minute), elevated liver function tests, or excessive sedation. We assessed each patient for AEs throughout hospitalization daily by the neurology and pain management services, with nursing checks every 4 h. If severe or intolerable AEs occurred more than once, the treating team paused or stopped the infusion at their discretion. Admissions were planned for 5 hospital days but varied slightly based on time of admission and the patient’s clinical course. Unless intolerable AEs occurred that necessitated stopping the infusion, we continued ketamine until the time of discharge.

We assessed pain at least once daily using the 0–10 NRS. Pain and MMD were also assessed via the telephone calls at 1, 6, and 12 months. Patient responses were based upon recall and not a headache diary.

Outcomes and Statistical Analyses

The primary outcome was the change over time in the mean t-MOCA score for the cohort. Secondary outcomes included changes over time in MIDAS and HIT-6, changes in pain ratings, and changes in the number of migraine days in the previous month.

Data were analyzed using SPSS, v. 29 (IBM Corp., Armonk, NY, USA). Categorical data were presented as number (%). Numerical descriptive data were presented as means ± standard deviation (SD) if normally distributed or as medians (interquartile range [IQR]) if highly skewed and were analyzed using the Student t test if normally distributed or the Wilcoxon signed rank test if non-normally distributed. Data were tested for normality using the Shapiro-Wilk test. The treatment effect on cognitive function was analyzed by generalized estimating equations (GEEs), which model the longitudinal effect averaged over repeated measures. Separate GEE models (gamma with log link) were fitted to each dependent variable, including MMD, current pain intensity, average pain intensity over past month, HIT-6, MIDAS, t-MOCA, and MIS from baseline to 12 months (four time points). Unstructured covariance was used, and the clustering unit was each individual patient. The main effect of the treatment type was assessed and adjusted for age and sex. Uncorrected estimated marginal means (EMMs) and β estimates (95% confidence intervals [CIs]) were presented for each time point, along with standard errors (SEs) for t-MOCA, MIDAS, and HIT-6 data. Missing data were treated as random without carrying over. The adequacy of the data was verified to meet the assumptions of the testing and modeling conducted. The statistical significance level was set at p < 0.05 (two-sided test).

As this was a pilot study, no formal power analysis was performed.

Results

Demographics and Baseline Data

A total of 26 patients were screened and subsequently enrolled. One patient who signed informed consent was later discovered to have a diagnosis of cluster headache and was therefore excluded from analyses. One additional patient did not receive ketamine as originally planned, and another declined to participate after initially agreeing; both were excluded, leaving a total of 23 patients for analysis. Enrollment of participants was staggered, and all patients were contacted at baseline and 1 month, 6 months, and 12 months after their hospitalization. Nine of the 23 patients received one additional multiday ketamine infusion and hospitalization during their 12-month observation period. For these patients, ketamine infusion and pain data were analyzed and reported only for the first (index) hospitalization.

The mean $\pm$ SD age of the cohort was 44.8 ± 11.5 years, and 20 of the 23 patients were female (87%). The median (IQR) number of MMD at baseline was 30 (2), indicating substantial daily pain. The baseline pain level at the time of admission was 5.8 ± 2.6; the average pain level over the previous month was 6.7 ± 1.6. Eight of the 23 patients (34.8%) had previously taken intranasal ketamine as an abortive agent for refractory migraine symptoms on an outpatient basis. The prescribed dosing for the intranasal ketamine was 10 mg per spray, with each patient instructed to use 1–2 sprays per nostril every 15 min as needed, with a maximum of 20 sprays per day, 40 sprays per week, which is consistent with a previous publication from our group [26]. In this population, RCM patients use an average of six sprays of intranasal ketamine per use day, with a median of 10 days of spray use per month [26]. Baseline patient characteristics and pain data are shown in Table 1.

Table 1.

Patient characteristics and baseline pain

Characteristic
Mean age (SD) in years	44.8 (11.5)
Sex, n (%)
Male	3/23 (13)
Female	20/23 (87)
Race and ethnicity, n
Non-Hispanic White	18
Non-Hispanic Black	1
Non-Hispanic Asian	1
Hispanic	1
Other or mixed	2
Median weight [IQR] in kg	69.8 [21.7]
Smoker, n (%)
Current	0 (0)
Former	11/23 (47.8)
Current alcohol use, n (%)	7/23 (30.4)
History of depression, n (%)	19/23 (82.6)
Outpatient opioid use, n (%)	3/23 (13)
Outpatient benzodiazepine use, n (%)	12/23 (52.2)
Outpatient beta blocker use, n (%)	5/23 (21.7)
Previous intranasal ketamine use, n (%)	8/23 (34.8)
Median [IQR] number of migraine days at baseline	30 [2]
Baseline mean (SD) pain, 0–10	5.8 (2.6)
Average mean pain (SD) over previous month, 0–10	6.7 (1.6)

IQR interquartile range, SD standard deviation

The mean $\pm$ SD baseline t-MOCA prior to admission was 19.2 $\pm$ 1.9. The median (IQR) baseline MIS was 13.0 (3.0). The mean $\pm$ SD baseline MIDAS was 191.0 $\pm$ 100.4, consistent with very severe disability [24]. The mean $\pm$ SD baseline HIT-6 was 68.7 $\pm$ 4.7, which is consistent with participants having severe impacts on daily activities [25].

Hospital Outcomes and Ketamine Infusion Data

The mean $\pm$ SD length of stay for all patients was 5.0 $\pm$ 0.7 days, while the duration of ketamine infusion was 4.7 $\pm$ 0.7 days. The mean $\pm$ SD maximum ketamine rate administered was 52.8 $\pm$ 12.1 mg/h. Benzodiazepines were administered to 22 of the 23 patients during admission. This includes 12 patients who received their home benzodiazepine regimen and ten who were started on a low-dose benzodiazepine to treat psychomimetic side effects. Clonidine was administered to 21 of the 23 patients to mitigate the psychomimetic effects of ketamine and prevent ketamine-induced hypertension. The median (IQR) pain level on the day of admission was 7.5 (2.8), which decreased to 2.0 (3.0) by the end of treatment (p < 0.001). The lowest median pain rating during infusion was 2.0 (4.0). AEs occurred in 14 of the 23 patients and included anxiety, increased liver function tests, nausea and vomiting, psychomimetic effects (hallucinations, nightmares, or dissociative effects), sedation, visual changes, or “other” (Table 2). Five patients experienced AEs that required a decrease or discontinuation of the infusion. An 84-kg female patient who experienced blurry vision and slurred speech required a rate decrease from 60 to 55 mg/h, after which the symptoms resolved. A 98-kg female patient whose maximum infusion rate was 60 mg/h required early discontinuation of her infusion after her liver function tests were abnormal. A 65-kg female patient experienced emotional lability when her infusion was at 35 mg/h and necessitated a temporary rate decrease but tolerated 35 mg/h later in her admission. A 95-kg male patient whose maximum infusion rate was 45 mg/h experienced severe nausea and dizziness that required a rate decrease to 30 mg/h, after which he tolerated the infusion well. Lastly, a 142-kg male patient whose maximum infusion rate was 50 mg/h experienced hallucinations that only partially improved after his infusion was decreased to 30 mg/h. His infusion eventually was discontinued early because of persistent hallucinations.

Table 2.

Adverse effects during inpatient migraine treatment

All adverse effects, N = 23	N (%)
Anxiety	5 (21.7)
Increased liver function tests	3 (13.0)
Nausea and vomiting	2 (8.7)
Psychomimetic effectsa	2 (8.7)
Sedation	1 (4.3)
Visual changes	3 (13.0)
Otherb	7 (30.4)

Adverse effects requiring infusion decreases or discontinuation	N (%)	Action taken
Visual changes and slurred speech	1 (4.3)	Decrease
Increased liver function tests	1 (4.3)	Discontinuation
Emotional lability	1 (4.3)	Decrease
Nausea and dizziness	1 (4.3)	Decrease
Hallucinations	1 (4.3)	Discontinuation

^aIncluded hallucinations, nightmares, and dissociative experiences

^bIncluded slurred speech (2 patients), dizziness (2 patients), urinary retention (1 patient), grogginess (1 patient), and constipation (1 patient)

t-MOCA, MIDAS, HIT-6, and Pain Outcomes over Time

The analyses of t-MOCA scores using GEE showed that the baseline EMM with SE was 18.8 $\pm$ 0.7. This increased to an EMM of 19.9 $\pm$ 0.7 at 1 month (β = 0.058, 95% CI 0.035–0.081; p $<$ 0.001), which was statistically significantly higher and greater than the minimal clinically important difference. At 6 months, the EMM was 19.2 $\pm$ 0.8 (β = 0.023, 95% CI − 0.029 to 0.074; p = 0.390), and at 12 months, the EMM was 18.3 $\pm$ 0.9 (β = − 0.023, 95% CI − 0.076 to 0.029; p = 0.382), indicating no statistically significant change from baseline. An additional analysis of t-MOCA controlling for age, sex, and current pain intensity was performed. In that analysis, the baseline EMM with SE was 19.3 $\pm$ 0.6, which increased to 20.4 $\pm$ 0.6 (β = 0.055, 95% CI 0.028–0.082; p < 0.001) at 1 month. At 6 months, the EMM was 19.6 $\pm$ 0.7 (β = 0.020, 95% CI − 0.035 to 0.075; p = 0.472), and at 12 months, the EMM was 20.0 $\pm$ 1.0 (β = 0.035, 95% CI − 0.037 to 0.106; p = 0.340). Only the mean t-MOCA at 1 month was greater than the minimal clinically important difference. However, when analyzing individual patient changes in the t-MOCA, some patients did demonstrate worsening of scores over time that exceeded the minimal clinically important difference (Figure 1). Because of dropouts and patients lost to follow-up, the number of patients analyzed for the primary outcome was 22, 20, and 19 at 1, 6, and 12 months, respectively.

Fig. 1.

Individual participant t-MOCA scores over 12 months. As a result of drop-outs, at 1 month, N = 22, at 6 months, N = 20, and at 12 months, N = 19. t-MOCA telephone Montreal Cognitive Assessment

The MIS scores followed a similar pattern and are shown in Table 3. MIDAS scores progressively decreased over time from baseline, indicating less disability, and are shown in Table 3. However, most remained in the severe disability category throughout the study. HIT-6 scores demonstrated no statistically significant changes from baseline over time and are shown in Table 3. Additional outcomes over time, including changes in current and average pain and MMD, are shown in Table 3.

Table 3.

Changes to t-MOCA, MIDAS, HIT-6, pain, and monthly migraine days over time, adjusted for age and sex

Outcome	Baseline	1 month	P value	6 months	P value	12 months	P value
MOCA
EMM (SE)	18.8 (0.7)	19.9 (0.7)	< 0.001	19.2 (0.8)	0.390	18.3 (0.90)	0.382
β estimate		0.058		0.023		− 0.023
95% CI of β		0.035–0.081		− 0.029 to 0.074		− 0.076 to 0.029
Memory index score
EMM (SE)	12.3 (0.6)	13.2 (0.5)	< 0.001	12.4 (0.7)	0.791	12.2 (0.8)	0.920
β estimate		0.077		0.010		− 0.006
95% CI of β		0.032–0.121		− 0.066 to 0.087		− 0.120 to 0.109
MIDAS
EMM (SE)	208.6 (26.7)	190.0 (23.1)	0.213	166.3 (20.4)	0.021	149.7 (20.8)	0.002
β estimate		− 0.094		− 0.227		− 0.332
95% CI of β		− 0.241 to 0.054		− 0.419 to − 0.035		− 0.540 to − 0.123
HIT-6
EMM (SE)	68.6 (2.5)	67.2 (3.3)	0.47	63.3 (4.3)	0.062	64.9 (4.3)	0.260
β estimate		− 1.390		− 5.358		− 3.692
95% CI of β		− 5.16 to 2.38		− 10.981 to 0.264		− 10.123 to 2.738
Current pain (0-10)
EMM (SE)	7.0 (0.7)	5.9 (0.6)	0.011	6.7 (0.5)	0.393	6.9 (0.6)	0.747
β estimate		− 0.176		− 0.049		− 0.024
95% CI of β		− 0.041 to − 0.310		− 0.161 to 0.063		− 0.170 to 0.122
Average pain (0-10)
EMM (SE)	6.2 (0.4)	5.9 (0.4)	0.241	6.3 (0.5)	0.750	5.1 (0.5)	0.010
β estimate		− 0.042		0.014		− 0.197
95% CI of β		− 0.111 to 0.028		− 0.072 to 0.100		− 0.346 to − 0.048
Monthly migraine days
EMM (SE)	27.1 (1.6)	24.4 (2.1)	0.08	22.4 (2.3)	0.05	22.3 (2.2)	0.026
β estimate		− 0.107		− 0.191		− 0.195
95% CI of β		0.012 to − 0.227		0.0 to − 0.382		− 0.023 to − 0.367

P values are compared to baseline

CI confidence interval, EMM estimated marginal mean, HIT-6 Headache Impact Test, MIDAS Migraine Disability Assessment, t-MOCA telephone Montreal Cognitive Assessment, SE standard error

Discussion

In this study, we found that the mean t-MOCA for the cohort showed a small improvement from baseline to 1 month and no statistically significant changes at 6 and 12 months after adjusting for age and sex. The results were similar when adjusting for the current pain level and MMD. These findings are preliminary, given the small sample size and observational nature of our study. These results match our clinical observations as well as existing evidence documenting stable cognitive function after ketamine infusions for other indications, such as complex regional pain syndrome [27] and treatment-resistant depression [28]. The reasons for the improvement in the t-MOCA observed at 1 month are speculative but could be due to increased mental clarity and ability to concentrate because of migraine improvement [29].

Rodent studies have demonstrated an association between NMDA-receptor antagonists and neurotoxicity [8, 30–32]. However, a more recent study from Morris et al. [33] reported that no neurotoxicity occurred in rats given up to 20 mg/kg of IV ketamine in a single dose (the human equivalent is about 3.2 mg/kg), suggesting that at lower doses, this does not occur. The dosing strategy used in our headache center involves a multiday infusion of low-dose ketamine without bolus doses, and this is a major difference from the large, single-dose administration technique used in the rat studies to date. It is not currently known if continuous infusions over multiple days produce neurotoxicity in rats.

The effects of illicit ketamine use on memory and cognition have been described in several reports. One study of illicit ketamine users performed cognitive testing 12 months apart in 150 individuals divided equally into five groups: frequent ketamine users, infrequent ketamine users, abstinent users, polydrug controls, and non-users of illicit drugs. In this study, cognitive deficits were largely observed only in frequent ketamine users, in whom increasing ketamine use throughout the 12-month testing period correlated with worsening performance on spatial working memory and pattern recognition memory tasks, as well as worsening psychological health, resulting in higher rates of dissociative and delusional symptoms [13]. “Frequent” ketamine use in that study was defined as more than 4 times per week. While it is difficult to quantify the doses being used on the street, it is likely that they exceed the 10-mg sprays used in our practice. The concerns over spatial working memory impairment are reiterated in a study of 11 ketamine users compared to polydrug controls, which showed ketamine users had significantly less hippocampal complex activation in a spatial memory task when navigating to a learned object location [34]. The risks related to medically prescribed ketamine in patients with refractory conditions under clinical supervision appear to be much lower, but few long-term studies have been performed [35].

Cognition is multifaceted and influenced by many factors, including education level, comorbid conditions, genetics, medications and recreational substances, and physical activity. Although the t-MOCA is an effective tool to screen for mild cognitive impairment [36], it does not provide a comprehensive neurocognitive evaluation, and other manifestations of neurotoxicity could have been missed. Additional assessments using functional magnetic resonance imaging could add important details to these results and provide a more thorough evaluation of brain changes. The resources required for a more comprehensive evaluation greatly exceeded those available for this study.

Despite the overall lack of statistical change in mean t-MOCA scores for the cohort, individual responses varied, including some with worsening of scores. We were unable to identify specific factors that contributed to the worsening of t-MOCA scores in a few patients, but the timing of the assessments in relation to the migraine severity may have played a role. It has been previously suggested that poor sleep and depression, both of which occur often during severe migraine days, are factors associated with cognitive decline in migraineurs [37]. These factors may have caused a worsening of cognitive function on that particular day that led to a lower t-MOCA score, but this is speculative.

One additional factor worth noting was that 21 of the 23 patients in the study received a clonidine 0.2-mg transdermal patch for the duration of the ketamine infusion, which is part of our institutional protocol for multiday ketamine infusions to minimize psychomimetic AEs from ketamine. Jevtovic-Todorovic and colleagues have demonstrated that clonidine can prevent neurotoxicity induced by the NMDA antagonist MK-801 in rodents [38]. While clonidine’s effects on cognitive changes have not been well studied in humans, the results of our study should be interpreted in that context. We argue that clonidine should be used routinely for patients receiving elective multiday ketamine infusions, considering it has few serious AEs other than its anti-hypertensive effects.

Limitations

This study had several limitations. First, there was a relatively small study sample size. Dropouts further impacted our small sample size, and the number analyzed at each time point was lower than the previous one. It is possible that the patients who dropped out were different from those who remained in the study, which could have introduced nonresponse bias. Furthermore, scores may be impacted by learning effect as the participants grew familiar with the assessment on repeat administrations. A second limitation is that because of the challenge of arranging for the follow-up sessions, some patients were interviewed on severe migraine days, which could have affected the scores. After adjustment for age, sex, and current pain, the EMM t-MOCA difference between baseline and follow-up times was greater than the minimal clinically important difference of 1 point at 1 month only but remained steady through 12 months. The adjusted EMM t-MOCA values at 6 and 12 months were slightly greater than the unadjusted values, suggesting that perhaps pain was influencing the responses in a few patients. Third, eight of the patients had previously used intranasal ketamine as an outpatient rescue medication prior to admission, which could have affected our results. Furthermore, although no intranasal ketamine was used during the ketamine infusion, participants were allowed to continue intranasal ketamine during the follow-up period. The use of intranasal ketamine as an abortive medication prior to and after the ketamine infusion is a potential confounding factor for this study. A future study could focus on studying changes in specifically the abortive intranasal ketamine subgroup population. Fourth, our sample was largely white and female, which may not be representative of all RCM patients. Additionally, our metric of MMD, although a better representation of disease in the RCM population, was different to the metric of monthly headache days that is used in many similar studies. Furthermore, a year is a relatively short period of time to monitor cognitive changes and may not be sufficient to detect more rare or insidious cognitive effects. Our study lacked a control group to account for confounding factors, which is a common challenge of studies on RCM patients, as the high degree of disability in this population necessitates aggressive medical treatment. Lastly, we were unable to assess the safety of ketamine in the patients who got an additional infusion during the study period. This is an area in need of additional research.

Conclusions

In this prospective study of patients with RCM treated with multiday ketamine infusions, the mean t-MOCA remained unchanged from baseline at 6 and 12 months after a slight improvement at 1 month. There was no broad signal of worsening cognition, suggesting that IV treatment with ketamine does not cause long-term impairment in this time period. Our study did not detect an overall trend toward worsening cognitive function, but some individual patients did experience worsened t-MOCA scores. Future studies should include larger sample sizes, minimize variability in concurrent medications and ketamine dosing, and include a control group, if possible, to better understand the factors associated with changes in cognitive function after ketamine infusions.

Supplementary Information

Below is the link to the electronic supplementary material.

Funding

This work was supported by patient philanthropy and Miles for Migraine.

Declarations

Conflict of Interest

Dr. Vinokur has nothing to disclose. Dr. Schwenk has nothing to disclose. Dr. Alabad has nothing to disclose. Dr. Hamilton has nothing to disclose. Within the past 24 months, Dr. Yuan has received funding from the American Headache Society; institutional support for serving as an investigator from Teva, AbbVie, Ipsen, Parema, Shiratronics, Johnson & Johnson, Pfizer, and Lundbeck; consultant/advisory board fees from Salvia, Pfizer, AbbVie, and Cerenovus; and royalties from Cambridge University Press and MedLink Neurology. Dr. Fallon has nothing to disclose. Within the last 24 months, Dr. Marmura has received honoraria for consultations from Lundbeck. He has received research funding for his role as principal investigator from Teva, Lundbeck, and AbbVie.

Authors' Contributions

Marianna Vinokur: Conceptualization, data curation, investigation, methodology, formal analysis, validation, writing—original draft, and writing—review and editing. Eric Schwenk: Conceptualization, data curation, formal analysis, investigation, methodology, project administration, supervision, writing—original draft, and writing—review and editing. Sawsan Alabad: Data curation, investigation, methodology, and writing—review and editing. Winston Hamilton: Data curation, investigation, methodology, and writing—review and editing. Hsiangkuo Yuan: Conceptualization, data curation, formal analysis, investigation, methodology, project administration, supervision, validation, writing—original draft, and writing—review and editing. Samuel Fallon: Data curation, investigation, and writing—review and editing. Michael Marmura: Conceptualization, data curation, funding acquisition, investigation, methodology, project administration, validation, writing—original draft, and writing—review and editing. All authors have read and approve the final submitted manuscript, and agree to be accountable for the work presented here.

Availability of Data and Material

Data are available upon reasonable request.

Ethics Approval

This study was approved by the Thomas Jefferson University institutional review board on April 22, 2021 (Control #21D.412). All patients provided written informed consent. This study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments, with the exception that this study was not registered due to its observational design.

Consent to Participate

Informed consent was obtained from all individual participants included in the study via either telephone or in person screening. All participants signed written consents prior to study participation. All signed written consent records are stored in Thomas Jefferson University Hospital.

Consent for Publication

Not applicable.

Code Availability

Not applicable.