Cognitive Pharmacological

Amantadine is a synthetic antiviral agent and dopamine agonist used for the treatment of influenza A and dyskinesia associated with parkinsonism, although the mechanism of action is still unclear. Amantadine has also been used off-label, including for the treatment of MS-related fatigue ("Drug monograph: Amantadine," 2021).

Discussion

Cohen et al. (2019) conducted a phase II RCT in which participants were randomized to receive either amantadine or placebo for four weeks. Cognitive function was included as a secondary endpoint and was assessed using the BiCAMS at baseline and at two and four weeks. This study did not identify any betweengroup differences in cognitive function at either follow-up time point.

One study examined the effects of amantadine or pemoline on CI in PwMS compared to placebo (Geisler et al. 1996). Pemoline is a central nervous system (CNS) stimulant which has subsequently been associated with hepatic failure. Participants were assessed at baseline and six weeks later. There was no significant difference in the change in cognition outcomes over six weeks between the amantadine, pemoline, and placebo groups, with the exception of change scores on the written version of SDMT, favouring the amantadine-treated group. The written version of the SDMT is not validated in persons with MS for the assessment of cognitive impairment because of a reliance on motor function.

Conclusion

There is level 1a evidence that amantadine compared to placebo may not improve cognitive function (two randomized controlled trials; Cohen et al. 2019, Geisler et al. 1996).

There is level 1b evidence that pemoline compared to amantadine or placebo may not improve cognitive function (one randomized controlled trial; Geisler et al. 1996).

Amphetamine is a CNS stimulant. Amphetamines are used in other disorders to treat impaired processing speed and have been shown to improve symptoms in adults and children with attention-deficit hyperactivity disorder (ADHD) (Rhodes, Coghill, & Matthews, 2004). Amphetamines for ADHD may improve attention span, the ability to follow directions or complete tasks, decrease distractibility, and decrease impulsivity. Mixed amphetamine salts, extended release (MAS-XR; trade name Adderall XR), an extended release version of Adderall IR (immediate release), are composed of equal amounts of the sulfate salts of dextroamphetamine, amphetamine, d-amphetamine, and d-,I-amphetamine aspartate monohydrate, resulting in a 3:1 ratio of d to I-isomers of amphetamine (McGough et al., 2003). It is approved for the treatment of ADHD in children, adolescents, and adults. Similarly, lisdexamfetamine dimesylate is an inactive amphetamine prodrug that is converted to lysine and d-amphetamine. It is currently approved for the treatment of both children and adults diagnosed with ADHD and was developed to provide extended steady clinical effect.

Discussion

Four studies were found which investigated the use of amphetamines for CI in PwMS. One study (Morrow & Rosehart, 2015) compared single doses of 5mg and 10mg of an extended-release form of a dextroamphetamine and amphetamine combination tablet (trade name: Adderall XR) with placebo. The 10mg treatment group significantly improved on the SDMT compared to placebo (5.2±4.5 vs. 0.6±4.4; p=0.043; effect size of 0.47 in favour of treatment). However, there was no significant improvement on the Paced Auditory Serial Addition Test (PASAT) in either treatment group when compared to placebo, regardless of baseline impairment on the PASAT.

A small pilot study examining l-amphetamine, the isomer of d-amphetamine, found a significant difference between the placebo group and the highest dose l-amphetamine (45mg) group on measures of processing speed, but not on measures of memory (Benedict et al., 2008). However, a larger, multi-center placebo-controlled study of l-amphetamine (30mg) did not find any significant between-group differences on these same measures of processing speed, but did find significant differences in favour of the treatment group on similar measures of memory (Morrow et al., 2009). A secondary analysis of the same dataset (Sumowski et al., 2011) suggested that baseline CI level may affect response to treatment. Among those with memory impairment at baseline, Sumowski et al. (2011) found significant interactions whereby l-amphetamine improved memory more than placebo in terms of performance on the California Verbal Learning Test (CVLT-II) delayed recall (p=0.02), and the Brief Visuospatial Memory Test-Revised (BVMT-R) delayed recall (p=0.012) and total recall.

A randomized placebo-controlled pilot study of lisdexamfetamine dimesylate, a prodrug that is metabolized to lysine and d-amphetamine, demonstrated improvements among participants on the SDMT by 4.6 points in the treatment group compared to 1.3 points in the placebo group after eight weeks (Morrow et al., 2013). There was also an increase in performance on the CVLT-II, a measure of verbal learning and memory, in the lisdexamfetamine group compared to the placebo group (4.7 vs. -0.9). As with Morrow & Rosehart (2015), the PASAT was not significantly different between the two groups following intervention (p=0.11). However, the PASAT is known to have a significant practice effect and a strong component of working memory in addition to processing speed which may have contributed to the lack of treatment effect on the PASAT (Brochet et al., 2008; Drake et al., 2010; Nagels, D'Hooghe M, Kos, Engelborghs, & De Deyn, 2008).

Amphetamines or products with similar mechanisms are of interest in the treatment of CI, but these products are not widely used in clinical practice. Clinical practice patterns of amphetamine use in PwMS may be explained by the lack of strong evidence to support their benefit, the paucity of data with respect to the long-term safety of amphetamine use, as well as little clinical experience with amphetamines to date.

Conclusion

There is level 1b evidence that mixed amphetamine salts, extended release compared to placebo may improve visual processing speed, but not auditory processing speed (one randomized controlled trial; Morrow & Rosehart 2015).

There is level 1b evidence that lisdexamfetamine dimesylate compared to placebo may improve visual processing speed, and verbal learning and memory, but not auditory processing speed, visuospatial memory, or subjective impact on daily activities (one randomized controlled trial; Morrow et al. 2013).

There is level 1b evidence that l-amphetamine compared to placebo may improve verbal and visuospatial memory (one randomized controlled trial; Morrow et al. 2009; Sumowski et al. 2011).

There is level 1b evidence that l-amphetamine compared to placebo may not improve auditory processing speed, visual processing speed, or subjective ratings of cognition (one randomized controlled trial; Morrow et al. 2009).

Methylphenidate is a CNS stimulant similar to amphetamines and indicated for use in ADHD. Stimulants may lead to improved attention span and ability to follow directions or complete tasks, decreased distractibility, and decreased impulsivity ("Drug monograph: Methylphenidate," 2020).

Discussion

One study has investigated methylphenidate for CI in MS. Harel et al. (2009) reported a significant within group improvement pre-post on the PASAT with a single 10mg dose of methylphenidate, while no significant change was reported pre-post for the placebo group. No between group comparisons were provided for this RCT. Therefore, the trial provides lower-level evidence in favour of methylphenidate. Methylphenidate use in PwMS is limited due to the short duration of action and neuropsychiatric side effects.

Conclusion

There is level 4 evidence that methylphenidate compared to placebo may improve auditory processing speed in persons with relapsing-remitting MS (one randomized controlled trial; Harel et al. 2009).

Dalfampridine, also known as slow-release fampridine, is a slow-release formulation of 4-aminopyridine (Morrow et al., 2017). It is a neuronal potassium channel blocker that reduces potassium re-entry into axons during the action potential and increases conduction of the nerve impulse across demyelinated segments ("Drug monograph: Dalfampridine," 2018). Prior to the approval of slow-release fampridine, or in areas where it is not available, fampridine as an immediate-release formulation has been studied, although its use has been limited by adverse events, including seizures (Goodman et al., 2009). In this section, both formulations of fampridine (immediate and slow-release) are included.

Discussion

Nine studies have examined the effect of dalfampridine, slow-release fampridine, or 4-aminopyridine on cognitive impairment in PwMS.

Five RCTs have examined the effect of slow-release fampridine or dalfampridine compared to placebo. A trial by Jensen et al. (2016) did not find any significant treatment effects between slow-release fampridine and placebo groups on the SDMT after four weeks of treatment. Morrow et al. (2017) performed a RCT crossover examining the effect of slow-release fampridine on cognitive fatigue and auditory processing speed in MS. After four weeks, results showed a significant treatment by time interaction for both outcomes, with further evaluation indicating a greater improvement in both cognitive fatigue and auditory processing speed in favour of the placebo compared to the active medication. De Giglio et al. (2019) found a positive effect of slow-release dalfampridine on visual and auditory processing speed after 12 weeks of treatment, as measured by the SDMT and PASAT, respectively, but not for other cognitive functions. However, Satchidanand et al. (2020) did not observe any differences on cognitive measures after 12 weeks of treatment with dalfampridine, including the SDMT and PASAT. Finally, Broicher et al. (2018) conducted an open-label and randomized placebo-controlled crossover study to assess the long-term effect of slow-release fampridine on cognitive performance over a period of two years. The authors classified the SDMT as a test to evaluate primarily the psychomotor speed domain rather than primarily visual processing speed. Presumably the written version of the SDMT was utilized and this version has not been validated in PwMS. Compared to placebo, significant fampridine-induced improvements were limited to phasic alertness, while other measures of attentional, processing speed, and executive function remained unchanged.

One small RCT by Arreola-Mora et al. (2019) examined the effect of immediate release 4-aminopyridine compared to placebo over a duration of 20 weeks in participants with relapsing-remitting MS (RRMS), using an extensive battery of neuropsychological tests to assess cognitive function. Results demonstrated that 4-aminopyridine significantly improved some cognitive processes, including attention span, executive function, graphical praxias, and visuospatial skills, but not others. Of note, significant improvements were observed in the placebo group compared to the 4-aminopyridine group on four tests, which may have been due to a placebo effect. Whether this positive result is due to the immediate release formulation use or weight-based dosing (dalfampridine has only one prescribed dose) is not known.

Finally, three studies examined dalfampridine or slow-release fampridine using an uncontrolled pre-post design. Bakirtzis et al. (2018) found that participants treated with slow-release fampridine demonstrated a significant and clinically meaningful improvement on the SDMT after six and 12 months, but did not demonstrate changes in terms of visual or verbal memory. Similarly, Jensen et al. (2014) found that participants demonstrated a statistically significant and potentially clinically meaningful improvement on the SDMT after four weeks of treatment with slow-release fampridine. Korsen et al. (2017) examined the effect of dalfampridine on cognitive function, using the PASAT as the cognitive outcome measure. Similar to the visual processing speed results of Bakirtzis et al. (2018) and Jensen et al. (2014), there was a significant improvement in performance on the PASAT following a treatment duration of approximately two weeks.

Conclusion

Donepezil is an acetylcholinesterase inhibitor, selectively inhibiting this enzyme to improve the availability of acetylcholine, and is approved for the treatment of Alzheimer's disease ("Drug monograph: Donepezil," 2020).

Discussion

Three studies were found which investigated the use of donepezil for CI in MS. A small uncontrolled 12-week study found that participants improved at four and/or 12 weeks on most cognitive measures apart from the Brief Test of Attention, as well as improving on the Clinical Global Impression of Change score (Greene et al., 2000). Krupp et al. (2004), in a small, randomized placebo 24-week pilot study, found a significant benefit of donepezil over placebo on a verbal learning and memory measure (Selective Reminding Test; SRT). However, in a larger multicenter placebo-controlled trial using many of the same outcome measures, there was no benefit noted on either subjective or objective cognitive measures, including the SRT (Krupp et al., 2011).

Conclusion

Erythropoietin exerts a neuroprotective effect in the brain and might address pathophysiological mechanisms in progressive forms of MS (Brines & Cerami, 2005; Schreiber et al., 2017).

Discussion

In a phase II study evaluating the effects of high dose erythropoietin on progressive forms of MS (Schreiber et al., 2017), cognitive measures were included as primary and secondary outcomes. The study did not find any benefit of erythropoietin on any of the outcomes, including cognitive measures, compared to placebo.

Conclusion

There is level 1b evidence that erythropoietin compared to placebo may not improve cognitive impairment in persons with primary or secondary progressive MS (one randomized controlled trial; Schreiber et al. 2017).

It has been hypothesized that fluoxetine and prucalopride may have a positive effect on phosphocreatine metabolism which is believed to be altered in progressive MS (Cambron et al., 2018).

Discussion

Cambron et al. (2018) randomized participants with RRMS to receive either fluoxetine, prucalopride, or placebo for six weeks. Cognitive function was included as a secondary endpoint according to the CVLT-II, SDMT, and Controlled Oral Word Association Test assessed at baseline and six weeks. At the end of the trial, there were no differences in cognitive function on any outcome measures between treatment groups. However, the study was not powered to evaluate these clinical parameters.

Conclusion

Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist and is approved for the treatment of Alzheimer's disease ("Drug monograph: Memantine," 2020). It blocks overstimulated NMDA receptors and is thought to prevent neurotoxicity normally caused by a massive glutamate release.

Discussion

Two studies have examined the effects of memantine on CI in PwMS. In the first study, participants were treated with memantine or placebo for 16 weeks. The were no significant differences between the two groups at the end of the study on objective cognitive measures; interestingly, the family members reported a significantly greater subjective improvement in the placebo group compared to the treatment group (Lovera et al., 2010). A second study in 2016 compared memantine to placebo over 52 weeks and also did not find any significant differences on cognitive measures between groups (Peyro Saint Paul et al., 2016).

Conclusion

There is level 1a evidence that memantine compared to placebo may not improve cognitive impairment (two randomized controlled trials; Peyro Saint Paul et al. 2016; Lovera et al. 2010).

Modafinil is a non-amphetamine CNS stimulant with wakefulness-promoting properties. Armodafinil is the R-enantiomer of modafinil. Both are used to promote wakefulness and decrease somnolence in numerous medical disorders ("Drug monograph: Modafinil," 2020).

Discussion

Studies with either modafinil or armodafinil have been mixed in terms of improving cognitive function in PwMS. Bruce et al. (2012) performed a double-blind crossover study with armodafinil in which participants were tested after a single dose of the drug and placebo, separated by one week. This study found a significant difference on a delayed verbal recall measure with armodafinil compared to the placebo treatment, but no other between-group differences were found for any other cognitive measures. In 2016, Ford-Johnson et al. published a crossover study in which participants were randomly assigned to either modafinil or placebo for two weeks, followed by the alternative treatment after a one-week washout period. There was a significant difference on a measure of working memory favouring the modafinil group. In this study, no other between-group differences were found for any of the other cognitive tests, including no between group differences on the CVLT-ll evaluating verbal memory. Several factors may explain why verbal memory improved after a dose of armodafinil in the armodafinil study, but did not improve in the modafinil study. These factors include different outcome measures utilized to assess verbal memory, different trial designs, and different drug products. Armodafinil contains the R-enantiomer of modafinil while modafinil contains a racemic mixture of R- and S-modafinil.

Conclusion

For studies on pemoline see section 3.1.1 of this module.

For studies on prucalopride see section 3.1.7 of this module.

Rivastigmine is a cholinesterase inhibitor with both acetylcholinesterase and butylcholinesterase activity, and is approved for the treatment of dementia associated with Alzheimer's disease and Parkinson's disease ("Drug monograph: Rivastigmine," 2020).

Discussion

Three studies have examined the effects of rivastigmine on cognition in PwMS. The first study examined memory measures after 12 weeks of rivastigmine treatment compared to placebo. There was no significant difference on the average Wechsler Memory Scale general memory score between the two groups at the end of the study (Shaygannejad et al., 2008). Another prospective randomized placebo-controlled study of rivastigmine for 16 weeks, followed by 12 months of open label treatment, also did not find any significant differences between the rivastigmine and placebo groups on measures of cognitive function (Maurer et al., 2013). A small pre-post randomized placebo-controlled study, included participants with MS as well as normal controls, found a significant 9.9% improvement in visual processing speed in PwMS treated with rivastigmine compared to baseline (p=0.043), while MS participants who received placebo did not demonstrate a significant change from baseline. However, direct between-group statistical comparisons were not reported. Although this study was initially designed as an RCT it only reports within group pre-post results, which provides lower quality evidence (Huolman et al., 2011).

Conclusion

Simvastatin is a prodrug requiring hydrolysis for activation. Once hydrolyzed, it generates mevinolinic acid and interferes with the activity of the enzyme HMG-CoA reductase to reduce the quantity of mevalonic acid, a precursor of cholesterol, thereby reducing total and low-density lipoprotein cholesterol ("Drug monograph: Simvastatin," 2021).

Discussion

One study has examined the effect of simvastatin on cognitive impairment in PwMS (Chataway et al. 2014), for which a secondary analysis of cognitive outcomes was undertaken and published (Chan et al. 2017). Participants with secondary progressive MS (SPMS) were randomized to receive either simvastatin or matching placebo for 24 months. A neuropsychological test battery covering a broad range of cognitive domains was administered at baseline and at 12 and 24 months. At the end of treatment, changes in the overall cognitive profile were similar between groups on most cognitive domains, with a significantly better treatment effect only on frontal lobe (executive) function in the simvastatin group compared to placebo.

Conclusion

There is level 1b evidence that simvastatin compared to placebo may improve executive function, but not other cognitive functions, in persons with secondary progressive MS (one randomized controlled trial; Chan et al. 2017).

Achillea millefolium, commonly known as yarrow, is a widely used medicinal plant. Achillea millefolium contains flavonoids including apigenin and luteolin, which are believed to be the pharmacologically active compounds (Applequist & Moerman, 2011). Based on animal studies, these compounds may have neuroprotective effects against cognitive decline (Liu et al., 2014; Patil et al., 2014).

Discussion

One study has examined the effect of Achillea millefolium as an add-on therapy for CI in PwMS. Ayoobi et al. (2019) randomized participants with RRMS to either one of two doses of Achillea millefolium (250mg or 500mg per day) or placebo for a duration of 12 months. For the study, dried extract was processed from the flowering branches of the plant. Achillea millefolium had been used in complementary medicine for abortion. Therefore, study exclusion criteria included pregnant women or those contemplating pregnancy. Cognitive function was included as a secondary endpoint and was assessed using the word-pair learning test, PASAT, Wisconsin Card Sorting Test, Mini-Mental Status Examination, and Tower of London Test. The Achillea millefolium groups demonstrated significantly improved performance in the word-pair learning test, PASAT, and Wisconsin Card Sorting Test compared to placebo following nine to 12 months of treatment. However, the study was not powered to evaluate these clinical parameters and further research using a larger sample size may be warranted.

Conclusion

There is level 1b evidence that Achillea millefolium as an add-on therapy compared to placebo may improve auditory processing speed and verbal learning and memory in persons with relapsing-remitting MS, but not general cognition or executive functioning at 12 months (one randomized controlled trial; Ayoobi et al. 2019).

Boswellia serrata and Boswellia papyrifera are types of frankincense, a resinous extract secreted from Boswellia tree species (Archier & Vieillescazes, 2000). Boswellia acts as an anti-inflammatory by inhibiting 5-lipoxygenase (Zengion & Yarnell, 2011).

Discussion

Sedighi et al. (2014) examined the effects of Boswellia papyrifera on cognitive function in participants with RRMS, compared to placebo for two months. At the end of the study, there was a significant improvement in the treatment group compared to the placebo group for visuospatial memory (BVMT-R). Another group examined the effects of Boswellia serrata for two months compared to placebo. There was a significant difference in change over time between the treatment and the placebo group for verbal memory and learning (CVLT-II) and visuospatial memory (BVMT-R), but not for other measures of cognitive function (Majdinasab et al., 2016).

Conclusion

Ginkgo biloba (GB) is a supplement derived from the leaves of the Ginkgo biloba Linne tree ("Ginkgo Biloba Leaf Extract," 1998). GB contains ginkgolides that inhibit platelet-activating factor, which modulates presynaptic glutamate release. Thus, GB could antagonistically modulate glutamate excitotoxicity and improve cognition (Lovera et al., 2012). Although GB is frequently used among PwMS, there is limited information on the benefits of GB in this clinical population (Yadav et al., 2006).

Discussion

Three studies have examined the effect of GB on cognitive function in MS. In 2007, Lovera et al. compared cognitive function in participants with MS treated with GB or a placebo for 12 weeks. At the end of the 12 weeks, there was no significant difference in the change over time between the two groups, with the exception of the Stroop Color-Word Test (interference susceptibility and mental flexibility). However, after applying the Bonferroni correction for multiple comparisons, there was no significant difference between GB and placebo on cognitive function. Lovera et al. then conducted a larger follow up study (2012) with a similar design to the previous study. In this larger study, there was no significant difference noted on any of the cognitive outcomes over the 12-week study period. One other small, uncontrolled open label trial found an improvement on a memory measure in participants with MS after eight weeks of GB (Noroozian et al., 2011).

Conclusion

Melatonin is a hormone that plays an important role in modulating several physiological functions. It has been suggested that melatonin may also have an immunomodulatory effect and may therefore modulate the immune response in MS (Roostaei et al., 2015).

Discussion

Only one study was found which examined the potential effects of melatonin on CI in PwMS. Participants were randomized to either placebo or melatonin for 12 months. There was no significant difference in mean change on the PASAT between groups. The authors also included the Modified Fatigue Impact Scale and reported that the cognitive fatigue subscale significantly improved in the melatonin group compared to the placebo group (p=0.006) (Roostaei et al. 2015). The measurement and evaluation of interventions addressing cognitive fatigue is beyond the scope of this module. However, cognitive fatigue does affect cognitive functioning in people with MS and warrants further systematic evaluation.

Conclusion

There is level 1b evidence that melatonin compared to placebo may not improve auditory processing speed in persons with relapsing-remitting MS but may improve self-reported cognitive fatigue (one randomized controlled trial; Roostaei et al. 2015).

Naturopathic medicine aims to stimulate an individual's self-healing capacities using various therapeutic modalities and can be practiced as either a complement or an alternative to conventional medicine. Often, a combination of treatments is applied and adjusted as necessary for a patient's condition (Shinto & Calabrese, 2003).

Discussion

Only one study was found which examined the potential effect of naturopathic medicine as an intervention for CI in PwMS. Shinto et al. (2008) performed a well designed randomized but unblinded study in which participants were randomized to usual care, usual care plus naturopathic treatment specifically tailored for PwMS, or usual care plus MS educational visits with a nurse. Treatment with all three arms of the study took place over six months. At the end of the study, there was a trend towards benefit with the naturopathic intervention on the non-cognitive outcomes, but no effect was noted on the cognitive outcomes.

Conclusion

There is level 1b evidence that naturopathic medicine combined with usual care compared to MS education plus usual care or usual care alone is not more effective for improving cognitive impairment in persons with relapsing-remitting MS (one randomized controlled trial; Shinto et al. 2008).

Tryptophan is a naturally occurring essential amino acid and precursor for serotonin ("Drug monograph: Tryptophan," 2021). It has been suggested that CI in MS may be mediated by serotonergic dysregulation (Boadle-Biber, 1993; Cowen & Sherwood, 2013); as such, increasing the availability of tryptophan may normalize serotonin metabolism and in turn neuropsychological dysfunction (Lieben et al., 2018).

Discussion

One study has examined the effect of dietary tryptophan enrichment on cognitive function in PwMS. Lieben et al. (2018) conducted a RCT crossover in which participants received mixtures containing a whey-based protein alone or with additional tryptophan (in a low, medium, or high ratio) in a randomized order. Cognitive assessments were performed three hours after dietary intake, including the Affective Memory Test, Trail Making Test, and Stroop Color-Word Task. Following dietary intake, the low tryptophan condition demonstrated significant improvements on the Affective Memory Test compared to the whey-only condition, but there were no differences between dose conditions in terms of performance on the Trail Making Test or overall Stroop Color-Word Task. The effect of a tryptophan-enriched diet was irrespective of the presence of depressed mood. However, baseline values of cognitive performance were not measured prior to dietary intake; as such, a potential placebo effect cannot be ruled out. A further limitation of this study is that longer-term effects of dietary tryptophan enrichment on cognition were not examined.

Conclusion

There is level 1b evidence that a tryptophan-enriched whey-based diet compared to a whey-based diet alone may acutely improve memory, but not processing speed, or cognitive flexibility and interference (one randomized controlled trial; Lieben et al. 2018).

Vitamin D deficiency has been associated with cognitive dysfunction (Llewellyn, Langa, & Lang, 2009), providing support for a role of vitamin D supplementation in cognitive functioning and beyond bone homeostasis (Darwish et al., 2017).

Discussion

One study by Darwish et al. (2017) examined the effects of replenishing Vitamin D on cognitive function in PwMS who were deficient at baseline. Participants were divided into two groups, one labelled Vitamin D deficient who were supplemented for three months, and the other labelled Vitamin D sufficient who continued their usual treatment. Whether the two groups were significantly different at baseline was not discussed. The deficient group demonstrated a statistically significant improvement on mild CI (Montreal Cognitive Assessment) and visuospatial memory (BVMT-R) over the three-month treatment period, while the sufficient group improved significantly on visuospatial memory. However, this was analyzed using repeat measures t-tests and the change over time between the two groups was not examined.

Conclusion

There is level 4 evidence that vitamin D may improve mild cognitive impairment and visuospatial memory, but not visual processing speed, or cognitive interference and mental flexibility (one pre-post study; Darwish et al. 2017).

There is level 1b evidence that Achillea millefolium as an add-on therapy compared to placebo may improve auditory processing speed and verbal learning and memory in persons with relapsing-remitting MS, but not general cognition or executive functioning at 12 months (one randomized controlled trial; Ayoobi et al. 2019).

There is level 1a evidence that amantadine compared to placebo may not improve cognitive function (two randomized controlled trials; Cohen et al. 2019, Geisler et al. 1996).

There is level 1b evidence that pemoline compared to amantadine or placebo may not improve cognitive function (one randomized controlled trial; Geisler et al. 1996).

There is level 1b evidence that mixed amphetamine salts, extended release compared to placebo may improve visual processing speed, but not auditory processing speed (one randomized controlled trial; Morrow & Rosehart 2015).

There is level 1b evidence that lisdexamfetamine dimesylate compared to placebo may improve visual processing speed, and verbal learning and memory, but not auditory processing speed, visuospatial memory, or subjective impact on daily activities (one randomized controlled trial; Morrow et al. 2013).

There is level 1b evidence that l-amphetamine compared to placebo may improve verbal and visuospatial memory (one randomized controlled trial; Morrow et al. 2009; Sumowski et al. 2011).

There is level 1b evidence that l-amphetamine compared to placebo may not improve auditory processing speed, visual processing speed, or subjective ratings of cognition (one randomized controlled trial; Morrow et al. 2009).

There is level 1b evidence that Boswellia serrata compared to placebo may improve verbal memory and learning, and visuospatial memory, but not visual processing speed, executive function, verbal fluency, auditory processing speed, or spatial processing, in persons with relapsing-remitting MS (one randomized controlled trial; Majdinasab et al. 2016).

There is level 1b evidence that Boswellia papyrifera compared to placebo may improve visuospatial memory, but not verbal memory and learning or visual processing speed, in persons with relapsing-remitting MS (one randomized controlled trial; Sedighi et al. 2014).

There is level 1a evidence that dalfampridine compared to placebo may not improve verbal learning and memory, visuospatial memory, or executive function after 12 weeks of treatment (two randomized controlled trials; De Giglio et al. 2019; Satchidanand et al. 2020).

There is level 1b evidence that dalfampridine compared to placebo may not improve verbal fluency after 12 weeks of treatment (one randomized controlled trial; De Giglio et al. 2019).

There is level 1b evidence that slow-release fampridine compared to placebo may not acutely improve auditory processing speed (one randomized controlled trial; Morrow et al. 2017) or visual processing speed (one randomized controlled trial; Jensen et al. 2016) or attention, with the exception of improving phasic alertness (one randomized controlled trial; Broicher et al. 2018).

There is level 1b evidence that immediate release 4-aminopyridine compared to placebo may improve working memory, verbal fluency, executive function and visuospatial skills, but not other cognitive functions, in persons with relapsing-remitting MS (one randomized controlled trial; Arreola-Mora et al. 2019).

There is level 4 evidence that slow-release fampridine may not improve visuospatial or verbal memory long-term (one pre-post study; Bakirtzis et al. 2018).

There is conflicting evidence regarding whether dalfampridine compared to placebo improves visual and auditory processing speed after 12 weeks of treatment (two randomized controlled trials; De Giglio et al. 2019; Satchidanand et al. 2020).

Level 1b

Level 2

Level 4

Conflicting evidence

There is level 1a evidence that donepezil compared to placebo may not improve spatial memory, visual processing speed, auditory processing speed, or verbal fluency (two randomized controlled trials; Krupp et al. 2004; Krupp et al. 2011).

There is level 1b evidence that donepezil compared to placebo may not improve executive function or spatial processing (one randomized controlled trial; Krupp et al. 2011).

There is level 1b evidence that donepezil compared to placebo may not improve problem solving (one randomized controlled trial; Krupp et al. 2004).

There is level 1b evidence that erythropoietin compared to placebo may not improve cognitive impairment in persons with primary or secondary progressive MS (one randomized controlled trial; Schreiber et al. 2017).

There is level 1b evidence that fluoxetine compared to placebo may not improve cognitive impairment in persons with relapsing-remitting MS (one randomized controlled trial; Cambron et al. 2018).

There is level 1a evidence that Ginkgo biloba compared to placebo may not improve auditory processing speed, verbal memory and learning, or verbal fluency (two randomized controlled trials; Lovera et al. 2012; Lovera et al. 2007).

There is level 1b evidence that Ginkgo biloba compared to placebo may not improve visual processing speed (one randomized controlled trial; Lovera et al. 2007).

There is conflicting evidence regarding whether or not Ginkgo biloba compared to placebo improves cognitive interference and mental flexibility (two randomized controlled trials; Lovera et al. 2012; Lovera et al. 2007).

There is level 1b evidence that melatonin compared to placebo may not improve auditory processing speed in persons with relapsing-remitting MS but may improve self-reported cognitive fatigue (one randomized controlled trial; Roostaei et al. 2015).

There is level 1a evidence that memantine compared to placebo may not improve cognitive impairment (two randomized controlled trials; Peyro Saint Paul et al. 2016; Lovera et al. 2010).

There is level 1b evidence that modafinil compared to placebo may improve working memory on the WAIS-III letter-number sequencing, but not visual processing speed or verbal memory and learning (one randomized controlled trial; Ford-Johnson et al. 2016).

There is level 1b evidence that armodafinil compared to placebo may improve verbal memory, but not visuospatial memory, cognitive interference and mental flexibility, verbal fluency, auditory processing speed, or sustained attention and impulsivity (one randomized controlled trial; Bruce et al. 2012).

There is level 1b evidence that naturopathic medicine combined with usual care compared to MS education plus usual care or usual care alone is not more effective for improving cognitive impairment in persons with relapsing-remitting MS (one randomized controlled trial; Shinto et al. 2008).

There is level 1b evidence that pemoline compared to amantadine or placebo may not improve cognitive function (one randomized controlled trial; Geisler et al. 1996).

There is level 1b evidence that prucalopride compared to placebo may not improve cognitive impairment in persons with relapsing-remitting MS (one randomized controlled trial; Cambron et al. 2018).

There is level 1a evidence that rivastigmine compared to placebo may not improve memory or general cognitive impairment (two randomized controlled trials; Mäurer et al. 2013; Shaygannejad et al. 2008).

There is conflicting evidence regarding whether or not rivastigmine compared to placebo improves processing speed (two randomized controlled trials; Huolman et al. 2011; Mäurer et al. 2013).

There is level 1b evidence that simvastatin compared to placebo may improve executive function, but not other cognitive functions, in persons with secondary progressive MS (one randomized controlled trial; Chan et al. 2017).

There is level 1b evidence that a tryptophan-enriched whey-based diet compared to a whey-based diet alone may acutely improve memory, but not processing speed, or cognitive flexibility and interference (one randomized controlled trial; Lieben et al. 2018).

There is level 4 evidence that vitamin D may improve mild cognitive impairment and visuospatial memory, but not visual processing speed, or cognitive interference and mental flexibility (one pre-post study; Darwish et al. 2017).