The proof is in the pudding: patient engagement in studying cannabidiol in mild cognitive impairment

Active patient engagement (PE) in which patients function as genuine partners in clinical trials – particularly in drug development – has gained enormous importance in recent years. Currently, PE is considered the gold standard in all phases of study design due to the growing awareness of the discrepancy between patient needs and research practice [1]. It is generally accepted that joint action between patient partners and academic researchers is crucial for enhancing the focus on patient-centered healthcare [1]. Zvonareva et al. [2] proposed a framework for conceptualizing the varying degrees of PE in drug research delineating four levels: consultation, involvement, collaboration, and patient-controlled. However, PE remains uncommon in the context of drug research trials. While a variety of disease areas are encompassed by trials that incorporate PE activities, many disease areas remain devoid of such activities in the context of drug research [2]. By actively engaging patient partners in determining how to conduct trials, it is more probable that unmet clinical needs will be addressed and that participant recruitment and adherence will be facilitated.

To the best of our knowledge, PE has not yet been applied in the design of a randomized controlled trial (RCT) investigating the effectiveness and safety of a compound in individuals with mild cognitive impairment (MCI). Mild cognitive impairment is defined as a decline in cognitive abilities that is significantly below what would be expected for an individual’s age and level of education. Frequently regarded as an intermediated phase between normal cognitive aging and dementia, MCI differs from dementia in that it is not accompanied by substantial limitations in activities of daily living (ADL) [3]. Nevertheless, MCI represents a notable alteration in health status and is associated with an elevated risk of progression to dementia with a progression rate of approximately 70% within five years [4]. Moreover, MCI is frequently associated with Alzheimer’s disease (AD), with 40–60% of individuals aged 58 and above diagnosed with MCI also exhibiting underlying AD pathology [5, 6]. A meta-analysis conducted by Jansen and colleagues [7] indicates that the prevalence of AD pathology is 20–30% higher in individuals with MCI compared to those with non-impaired cognition or subjective cognitive impairment, supporting the notion that MCI constitutes a risk condition for AD.

In many cases, direct PE is no longer feasible after the disease progresses and transitions into AD because medical decisions have to be made by patients’ legal representatives on behalf of the individual at this stage [8]. In contrast, people with MCI retain full legal competence. In light of the significant challenges posed by AD to both individuals and society [9], an evidence-based pharmacological treatment for MCI is urgently needed but is currently unavailable [10]. The fact that MCI is easy to diagnose provides the unique chance to implement a treatment that could potentially delay or reduce the probability of progression to AD.

The cannabinoid known as cannabidiol (CBD) has been identified as a promising candidate for slowing down the progression of MCI and therefore delaying the transition to AD due to its neuroprotective and anti-inflammatory properties [11]. In addition, CBD is safe and generally well-tolerated, largely due to its lack of untoward psychoactive sequelae. To date, only a limited number of studies have actively incorporated PE when examining the efficacy and safety of cannabis-based medicines across various indications [12]. Remarkably, approval of highly purified CBD (Epidiolex^®) to treat seizures in two rare forms of epilepsy (Lennox-Gastaut syndrome and Dravet syndrome) in 2018 was significantly initiated by the fact that the mother of Charlotte, a little girl with Dravet syndrome, had self-initiated adjunctive therapy with a high concentration of CBD from the tetrahydrocannabinol (THC) strain of cannabis to reduce the frequency of Charlotte’s seizures [13]. This case study impressively illustrates the benefits of engaging patients and their relatives or caregivers in initiating new pharmacological therapy strategies.

As part of our planned RCT investigating the effectiveness and safety of CBD in individuals with MCI, we aimed to directly involve patient partners in all steps of the study. To this end, we administered an online survey to individuals diagnosed with MCI who had participated in a recent trial at our center [14]. With this approach, we aimed to design an RCT that employs the most pertinent outcomes for participants, offers a more convenient approach to adverse events (AEs), and considers practical aspects such as acceptance of additional and invasive investigations.

Here, we present the results of the first online survey administered to people with MCI exploring their views on matters of convenience and their preferences regarding the setup of a clinical trial.

This survey aimed to incorporate PE when setting up an RCT to investigate the effectiveness and safety of CBD in treating MCI. In our sample, people with MCI considered improvement in cognitive abilities to be the most important clinical outcome. This finding is consistent with the ICD-11 diagnostic criteria, which identify cognitive impairment as the central symptom of MCI [19]. To conduct patient-relevant research, our findings support the use of a cognitive assessment tool as the primary endpoint, while also considering additional patient-relevant outcomes – such as quality of life, sleep, and activities of daily living – as key secondary endpoints.

In clinical routine settings, the diagnosis of MCI is made on the basis of the results of clinical assessments such as the Montreal Cognitive Assessment [16] or Mini-Mental-State-Examination [20]. According to German guidelines for the diagnosis of AD [10], it is strongly recommended that either a lumbar puncture for cerebrospinal fluid (CSF) analyses or positron emission tomography (PET) imaging are additionally performed to collect and examine AD biomarkers, including amyloid plaques, neurofibrillary tangles, and neurodegeneration [10]. However, PET imaging is extremely expensive [21], has only limited availability, is time consuming, and is therefore hardly possible in the context of larger RCTs, while lumbar puncture is invasive and may cause side effects [22‐24]. We were therefore interested in whether people with MCI would be willing to accept a lumbar puncture as an additional investigation in an RCT using CBD. Non-surprisingly, only one fifth of participants indicated their willingness to undergo CSF analyses and another third of patients asked for further information (although written patient information on lumbar puncture was already included in the survey). By contrast, blood sampling was much more accepted by this group of participants, suggesting that, as an alternative to CSF analyses, plasma levels of AD biomarkers should be used to confirm a diagnosis of MCI, although, until now, promising plasma biomarkers for AD (e.g., phosphorylated tau 217; p-tau217) have still been slightly less sensitive than CSF analyses and PET imaging [25]. Additional advantages of blood sample analyses are generally lower costs and general accessibility [26].

With respect to AEs, people with MCI have indicated persistent diarrhea and severe fatigue as AEs that have led to study drop out. This information is important, as the most common side effects of high dose treatments of CBD are diarrhea, nausea, fatigue, and headache, among others [27‐29]. So far, no RCTs have been available to investigate the efficacy and safety of CBD in people with MCI. Accordingly, the optimal dose of CBD is also unknown. Based on effects of CBD in other psychiatric indications, it can be assumed that higher doses may be more effective [30]. However, the results of this survey clearly indicate that, in an RCT, the dose titration of CBD should consider the importance of AEs, such as diarrhea and severe fatigue.

Interestingly, in general, participating in an RCT to test the use of CBD seems to be highly attractive to people with MCI. In addition, our results emphasize the need for involvement and informed decision-making, as more than half of the participants requested additional information before participating in the study. As most of the individuals expressed their willingness to participate even if given a placebo, a placebo-controlled trial for CBD appears to be feasible.

Although our study provided valuable insights into PE for planning a trial to test the use of CBD to treat MCI, it is important to acknowledge the limitations of our study. First, due to the inability to match responses with participants, our sample description included individuals who did not participate in the survey, thus rendering it an inaccurate representation of those who indeed completed it. Second, the survey assessments were hypothetical, making different decisions (e.g., regarding treatment discontinuation due to certain side effects) in an actual study possible. Third, our sample consisted of individuals who had already participated in a non-pharmacological trial for MCI, and so they were familiar with the study procedures. Thus, the sample may have been biased because of their general willingness to participate in a clinical trial, and such willingness may have influenced their responses to some extent.

In summary, this study is the first to incorporate PE into a trial on the use of CBD for MCI, as there are currently no existing PE activities in this area. It provides valuable insights into the concerns, aims, and needs of people with MCI and offers initial implications for planning and conducting future studies involving this population. Our main message is to encourage the incorporation of PE activities in the drug research process, not only to reflect the goals and needs of patients but also to improve the quality of research.