Is the Grass Really Greener? Cognitive Function After Discontinuation of Cannabis

Author(s)
Lindsey Trotter, PharmD
Sean Smithgall, PharmD, BCACP
Nicole Slater, PharmD, BCACP

Reviewed By
Nicole Hahn, PharmD, BCACP
Jacquelyn L. Bainbridge, PharmD., BCPP

Citation
Feinstein A, Meza C, Stefan C, Staines W. Coming off cannabis: a cognitive and magnetic resonance imaging study in people with multiple sclerosis. Brain 2019; 142: 2800–12.

The Problem

 

Cannabis use is a hot topic among patients and in healthcare circles. Cannabis is used by an estimated 20% of multiple sclerosis (MS) patients to ameliorate symptoms such as spasticity, pain, and insomnia.¹ Unfortunately, both MS and regular cannabis use can negatively impact cognition. ^2,3  More patients with MS may be inclined to use cannabis as more countries and states legalize it.  Determining whether cognitive impairment can be reversed upon discontinuation of cannabis can help to distinguish its beneficial and harmful effects in patients with MS.²  It might also provide insights regarding the reversibility of cognitive impairment when cannabis is used for recreational purposes. 

 

What’s Known

 

MS is an immune-mediated, neurodegenerative disease commonly characterized by highly variable sensory symptoms but frequently involve the face and extremities.⁴  Relapsing-remitting MS (RRMS) is the most common form with periods of partial or full recovery; however, patients may have residual or permanent symptoms that persist between relapses.⁵  Cannabis is often used by MS patients for both its therapeutic and psychoactive effects. These effects are primarily attributed to two pharmacologically active constituents found in cannabis plants in varying concentrations, cannabidiol (CBD) and tetrahydrocannabinol (THC).⁶  Based on the ratio of CBD to THC, central and peripheral cannabinoid receptors are activated to variable degrees, and this leads to patients experiencing feelings of well-being (seen with lower doses) or psychosis (seen with higher amounts of THC).  Regular cannabis use can also cause impaired memory and cognitive processing slowed locomotor function, reduce muscle spasticity, and promote sleep.⁶  Depending on the product and duration of use, there is persuasive evidence that cannabis use can reduce spasticity and pain in patients with MS.  However, cannabis use has questionable benefits on bladder function and appears to have no benefit for tremors or involuntary movement disorders.⁶ Evidence regarding the impact of regular cannabis use on cognitive impairment in patients with MS is conflicting.^7,8

 

What’s New

 

In a recent study conducted in Ontario, Canada, investigators recruited 40 patients from an MS clinic to participate in a parallel, open-label study. Patients were required to have started cannabis after their diagnosis of MS, used cannabis at least four times per week over many years, and have cognitive impairment, defined as a failure on two or more cognitive domains on the Brief Repeatable Neuropsychological Battery (BRNB), a validated instrument commonly used to detect cognitive impairments (see Table 1).  In addition to the BRNB, magnetic resonance imaging (MRI) studies were performed at baseline and at 28 days.

 

Table 1: Cognitive Domains and Associated BRNB Tests

Domain	Test
Verbal Memory	Selective Reminding Test, Long-Term Storage (SRT-LTS)
Visual Memory	10/36 (Spatial Total Recall Test)
Auditory Processing Speed	Paced Auditory Serial Addition Test (PASAT)
Visual Processing Speed	Symbol Digit Modalities Test (SDMT)
Executive Functioning	Controlled Oral Word Association Test (COWAT)

Patients were assigned to either continue cannabis use (CC) or withdraw cannabis (CW).  Patients in the CW group were asked to abstain from cannabis use for 28 days. Cannabis withdrawal symptoms were assessed with the Cannabis Withdrawal Scale (CWS). The Hospital Anxiety and Depression Scale (HADS) was used to assess symptoms of depression and anxiety. In addition, MRI with concurrent cognitive testing measured brain lesions size and mental processing speed.

 

Patients were excluded if they had another CNS disease, a significant mental illness, an intellectual disability, a recent neuropsychological assessment within the past 18 months, steroid use within the past three months, vision of less than 20/70, or a positive urine drug screen for an illicit substance other than cannabis.

 

The two groups were similar. Patients approximately 40 years of age and reported using around 2 grams of cannabis per day at baseline. Of note, the duration of disease differed between the two groups (CC = 9.61 years vs. CW = 5.62 years). The investigators set the p-value for statistical significance at < 0.01 to control for multiple comparisons.

 

Primary outcomes for the study were changes in BRNB testing scores, MRI imaging (structural and functional), withdrawal symptoms based on CWS, and change in anxiety and depression based on HADS from baseline to 28 days compared within and between the CC and CW groups.

 

One patient in the CW group was dismissed due to cannabis use during the abstinence period. Results showed that cognitive performance did not differ at baseline between the CC and CW groups; however, between-group and within-group results at 28 days differed for all cognitive domains with significant improvements observed only in the CW group.  Conversely, the CC group showed a decline in visual memory from baseline to 28 days.

 

Withdrawal symptoms and changes in anxiety and depression did not differ between or within groups from baseline or at 28 days. The authors concluded that there was no significant increase in withdrawal symptoms or worsening of reported anxiety or depression. None-the-less, two patients in the CW group requested appointments to address insomnia that had worsened after discontinuation of cannabis. Structural MRI results did not differ between or within groups from baseline or at 28 days. Conversely, functional MRI results showed significantly more brain activation in the CW group at 28 days in four brain regions.

 

Our Critical Appraisal

 

This innovative study attempted to evaluate the effects of cannabis-withdrawn on cognitive function. The strengths of this study include the use of validated neuropsychiatric instruments to assess cognitive impairment (BRNB) as well as anxiety and depression (HADS-A/D).  Furthermore, the investigators used serial versions of the BRNB to avoid familiarity with the original test administered at baseline. 

 

There are several study limitations including a small sample size, unblinded investigators, short duration of follow-up, and differences in baseline demographics. The small number of participants increases the probability that findings are due to chance.  The disease duration between groups was different, albeit this difference was not significant based on the investigator defined threshold (CW duration 5.62 years vs. 9.61 years; p = 0.03). The investigators noted that disease duration emerged as an independent predictor of performance on the SDMT portion of cognitive testing, suggesting this could potentially be an important confounder.  Additionally, two CW patients (10% of group participants) were given a hypnotic medication for insomnia before the 28-day CWS retest. When applying this study to patient care, a longer follow-up would be necessary to determine if MS symptoms worsened (e.g., spasticity) or withdrawal symptoms emerged.  Worsening of MS symptoms are not likely to have developed in the 28-day study period. Likewise, the designated study timeline was based on THC being fully cleared at 28 days, but that leaves little time after drug clearance to evaluate the emergence of anxiety or depression. Unfortunately, the investigators don’t report the participants’ cannabis use history (amount, duration, frequency, and reasons for use) and other medications taken for MS symptom management. These factors are all potential confounders that may have influenced the results. Despite these many limitations and potential confounders, the significant improvement in cognitive function measured using validated tools and objectives tests suggests that discontinuing cannabis use can have a positive impact.

 

The Bottom Line

 

Studies involving cannabis are difficult due to legal restrictions, stigma, and product variability. Much of the evidence supporting the use of cannabis for MS-related symptoms are subjective, conflicting, and lack rigor.  However, studies have shown that cannabis can cause cognitive impairment and, coupled with the fact that MS can independently impact cognition, makes this population particularly vulnerable to this harmful effect. Patients may choose to use cannabis use for any number of reasons, but we often lack data regarding the benefits and risks. These data provide us with some tangible evidence that discontinuing cannabis use can have a positive impact on cognitive impairment. While the study was conducted in patients with MS, the results may apply to other adults who chronically use cannabis.  The good news — cognitive impairments associated with chronic cannabis use appear to be reversible. Despite the hype about medical marijuana, the grass may not be greener when it comes to continued cannabis use in patients with MS.

 

The Key Points

 

• Cannabis use has become more common as more countries and states legalize marijuana use.  Practitioners need more data about the benefits and risks of marijuana use and potential adverse effects when it is discontinuation.
• Evidence supports the use of cannabis in patients with MS to reduce pain and spasticity but benefits for other MS-related symptoms are questionable. 
• Chronic cannabis use has been associated with cognitive impairments and these symptoms are also prevalent in patients with MS.  Stopping cannabis use may lead to significant improvements in cognition.
• Future studies need to evaluate the impact of cannabis discontinuation on MS symptoms, not just cognition.

FINAL NOTE:  This program will be available for recertification credit through the American Pharmacists Association (APhA) Ambulatory Care Review and Recertification Program.  To learn more, visit https://www.pharmacist.com/ambulatory-care-review-and-recertification-activities.