A systematic PubMed search covering the period from April 2013 to June 2023 was conducted by EDANZ (https://www.edanz.com, accessed on 10 November 2023) using the following MESH terms, keywords, and search strings:

• MESH terms: THC, tetrahydrocannabinol, dronabinol;
• Keywords: THC, d9-THC, delta-tetrahydrocannabinol, tetrahydrocannabinol, dronabinol;
• PubMed syntax: (THC, tetrahydrocannabinol, dronabinol [MeSH Terms]) OR (Dronabinol, OR THC OR tetrahydrocannabinol OR *tetrahydrocannabinol) AND (inhale* OR *mucosal* OR oral OR sublingual*).

Relative to administration routes, only oral and inhaled routes of administration were considered. Only clinical trial publications investigating the effect of purified THC were considered. This resulted in a list of articles that were further screened and manually searched for eligible content using the title and the abstract, yielding 24 filtered articles (refer to Table 2). A narrative evaluation of 9 studies that represent the generic limitations and weaknesses of THC trial design is presented and incorporated into the tabulated summary along with the 24 identified trials. The tables organize the trials by clinical indication or diagnosis.

• (van den Elsen et al., 2017 [14]).

This was a repeated crossover, double-blind, randomized controlled trial (RCT) of 12 weeks duration on the efficacy and safety of twice daily (bid) doses of oral THC in 18 patients with dementia (doses were placebo, 0.75, and 1.5 mg bid). The diagnosis of dementia included “possible” or “probable” Alzheimer’s disease, vascular (multi-infarct) dementia, or mixed dementia. Effects on dementia-associated mobility impairment focused on validated objective and quantitative balance and gait assessments. It was concluded that, in the doses given, THC had a “benign adverse effect profile” and was well tolerated.

Functional impairment is a core symptom of Alzheimer’s disease or any dementing illness and is often measured by a loss of ability to perform activities of daily living. The essential objective of the study was to demonstrate sustained improvement in specific functional capabilities reflected in patients’ mobility status. Diagnostic precision may not be crucial here, but modifiers such as “possible” or “probable” do not convey underlying pathology.

The principal challenge in interpreting trends toward deterioration or improvement during a study of brief duration is teasing intervention effects from the rapid waxing and waning cycle of symptoms. It is noteworthy that Anderson et al. (2017) [28] concluded that for Alzheimer’s patients, the variability in measurements between individuals implies that it will always be difficult to detect even a good treatment effect in a trial of years duration, especially with a small sample size. Additionally, longer durations for trials increase the likelihood of detecting an effect.

Neuropsychological functioning is impacted in a progressive and hierarchical manner associated with cognitive decline, but it has been and remains conventional wisdom among those who study and manage Alzheimer’s disease that substantial variability from one day to the next may remain among the most affected individuals (Arrighi et al., 2013 [29]; Heston, 1997 [30]; Meehan et al., 2002 [31]).

Moreover, individual symptoms evolve differently over the course of dementia. Notwithstanding the general impression that the overall level of neurological and psychopathology increases with dementia severity, the severity level tends to wax and wane, often with severe fluctuation over time. For this reason, longitudinal studies are required to achieve significant insights into the putative post-intervention trajectory of Alzheimer’s disease during the course of the disease (Scassellati et al., 2020 [32]).

Depression and anxiety are integral to the spectrum of dementia, both as a consequence of the disease itself as well as from the patients’ subjective awareness of losses. Following the ideal approach to geriatric research, a rigorous study ought to utilize selected and serially administered depression and mental status measures to attempt to tease out the contributions of tauopathy versus psychosocial variables. The constellation of symptoms often concurs and frequently waxes and wanes in the course of the disease. However, they may serve as prodromal indicators and may influence clinical presentation on any given day. Again, depression and anxiety are risk factors for dementia, but they are not just comorbidities or sequelae. The neurological and psychiatric crosstalk between depression, anxiety, and Alzheimer’s disease generally and ideally requires a long lens or sampling frame to characterize a patient’s baseline and any change in baseline that could be attributed to an intervention (Tanaka et al., 2021 [33]; Tarawneh et al., 2012 [34]).

It is important to note that fluctuating symptoms, even over the course of a day, are not unusual; thus, a dramatic sensorial or motoric improvement may be temporally associated with an intervention but is more likely to be causally linked to the natural history or presentation of Alzheimer’s disease from one day or one week to the next (Donovan et al., 2022 [35]; Mack et al., 2022 [36]; Tarawneh et al., 2012 [34]).

Despite its limitations, Van den Elsen et al.’s study is significant. Abnormal gait is prevalent in established dementia; may discriminate Alzheimer’s from other neurodegenerative disorders; and can also predict progression from normal cognition, cognitive complaints, and mild cognitive impairment (MCI) to dementia syndromes. Quantitative gait parameters, particularly the variability in the stride-to-stride fluctuations, are sensitive markers of neurological dysfunction and are associated with future mobility disability and incident dementia (Downey et al., eds 2017 [37]).

The notion that gait variability may be a putative marker of cognitive–cortical deterioration in neurodegenerative disorders has diagnostic and prognostic implications. In light of data suggesting chronic ultra-low-dose THC is associated with significant augmentation of memory and other aspects of cognition in animal models and in older adults with dementing illness (Bilkei-Gorzo, 2017 [38]; Sarne et al., 2011 [39] and 2018 [40]; Calabrese & Rubio-Casillas, 2018 [41]), the finding that mobility and gait stability are not likely to acutely deteriorate with THC on board represents reassurance about safety.

• (van Amerongen et al., 2018 [9]).

This “accelerated proof-of-concept study” consisted of 2 phases: a crossover challenge (dose-finding) phase and a 4 week, parallel, randomized placebo-controlled treatment phase. A total of 24 patients (12 in the placebo group and 12 in the treatment group) with progressive multiple sclerosis (MS) and moderate spasticity were enrolled. There were equal numbers of males and females in each group. The aim was to identify any clinical impact and establish an effective dose while minimizing adverse events.

With a combination of objective and subjective measures, i.e., providing convergent validity, it was concluded that the complex interplay of psychoactive effects and analgesia notwithstanding, it appeared that the oral formulation of THC had a stable pharmacokinetic profile, had few adverse events, and appeared to augment the treatment of spasticity and pain associated with MS.

Apart from the very small sample size and brief study duration, an entire constellation of potential confounds was ignored, and this fact is especially salient in the setting of chronic disease, in which personality or coping style is known to have significant impacts on illness behavior and progression; personality traits have long been known to contribute to the phenomenology of disease states and disease progression (Turiano, 2012 [42]; Sutin et al., 2013 [43]).

The way in which patients cope with and express symptoms, especially over the course of chronic disease, is often significantly mediated by a discrete coping style or personality, and this set of variables must be accounted for. Early “Type A” literature linked an aggressive style to cardiovascular outcomes, such as heart attack and stroke (Williams et al., 1980 [44]). More recently, hostility was again suggested as the driving characteristic of the association between “Type A” behavior and cardiovascular disease (MacDougall, Dembroski, Dimsdale, & Hackett, 1985 [45]). Other work demonstrated that specific personality traits are associated with illness severity, duration, and prognosis. For example, higher neuroticism and lower conscientiousness have been found to predict aggregate morbidity (Chapman et al., 2013 [46]) and self-rated health (Turiano et al., 2012 [42]). The same traits are also associated with increased risk for specific diseases (Goodwin & Friedman, 2006 [47]), such as Alzheimer’s disease (Terracino et al., 2014 [48]). Among those living with HIV, disease progression is slower for more open, extraverted, and conscientious individuals (Ironson et al., 2008 [49]).

• (Carley et al., 2018 [26]).

This was a small, double-blind, randomized placebo-controlled dose escalation pilot trial looking at the effect of two doses of oral dronabinol vs. placebo in a total of 73 patients with moderate to severe obstructive sleep apnea (OSA) over a 6-week study period. A total of 17 patients received a placebo; 19 received 2.5 mg of dronabinol, and 20 patients received 10 mg 1 h before bedtime. This trial is the largest and longest randomized controlled trial of any putative primary drug treatment for OSA. Despite this fact, the authors readily acknowledge that the study likely remains underpowered to detect simultaneous clinically meaningful effects at multiple endpoints.

• (Bisaga et al., 2015 [17]).

This work represented an 8-week double-blind, randomized, placebo-controlled trial of opiate-dependent subjects in the detoxification and naltrexone induction phases of management. Enrolled subjects had previous cannabis smoking experience. A total of 20 subjects were randomized to placebo, and 40 received 30 mg of dronabinol orally and daily. Outcomes included a subjective assessment of opioid withdrawal with a focus on insomnia and anxiety.

The development of tolerance and the impact on long-term efficacy were not addressed here, and this is a potential threat to the validity of conclusions about clinical utility. Beyond the small sample size and the fact of inter-subject variability, the principal hurdle is the relatively brief duration of the study in the face of a clinical process that typically requires months, if not years, of multi-modal therapies.

• (Almog et al., 2020 [50]).

This was a randomized, three-arm double-blind, placebo-controlled, crossover trial of inhaled THC via a novel metered-dose device in 24 patients with significant chronic neuropathic or radicular pain or pain associated with chronic regional pain syndrome (CRPS). Apart from the small sample size, the pitfalls of subjective self-assessment, and the preponderance of male subjects, the challenge here is that of chronic pain. Gender, socioeconomic status, educational level, and, most importantly for the experience of pain, coping style or personality traits are potentially significant confounds that, in future studies, should be assessed on some level. Chronic pain is a complex phenomenon that embraces physical, emotional, and social components that are inextricably tied to the somatosensory cortex as well as cognitive and affective processing (Marchand, 2020) [51]. Other potentially significant intervening variables that should be collected and folded into data interpretation include sleep disturbance, fatigue, appetite, and nutritional status.

• (Weizman et al., 2018 [6]).

This was a randomized, placebo-controlled trial of sublingual THC oil in 15 patients with chronic radicular pain. In addition to looking at the impact of the intervention on the subjective assessment of pain, the authors utilized functional MRI (fMRI) to explore simultaneous neural correlates of cannabis-induced analgesia associated with a single oral dose of THC vs. placebo. What may be most interesting about this work is that putative THC analgesia in chronic pain appears to be mediated through brain areas that underly effective processing of pain as well as supraspinal pain modulation, potentially addressing an imbalance in pain processing dynamics that may occur in chronic pain states.

Women were excluded from this study due to concern regarding menstruation-induced fluctuations in pain sensitivity. In addition, larger-scale studies are mandated not only to assure statistical power but also to look at any generalizable effects on diverse populations. The authors themselves suggested that future investigations should include other related chronic conditions to better understand whether the results represent a pervasive neuronal mechanism of cannabinoid effects on chronic pain or are unique to neuropathic pain states.

• (Toth et al., 2012 [52]).

This was a 5-week double-blinded trial of 26 subjects with diabetic peripheral neuropathy (DPN) randomized to nabilone or placebo groups (13 placebo and 13 nabilone) in a flexible-dose study. The authors reported that a flexible dose of nabilone 1–4 mg/day orally was effective in relieving DPN symptoms, improving disturbed sleep, and enhancing quality of life. They also subjectively assessed the overall patient status. Nabilone was well tolerated and successful as an adjuvant in patients with DPN, benefiting secondary outcome measures of associated features of the syndrome, including anxiety, depression, sleep efficacy, and subjects’ evaluation of quality of life.

Again, conclusions are weak because the study is underpowered, i.e., it suffers primarily from a small sample size, by the authors’ own admission. Moreover, DPN is a chronic waxing and waning condition, and prolonged treatment with serial assessments over months to years is typically required for definitive results. Dosing of nabilone was performed based upon individual subject tolerability and efficacy, but further dose-finding studies may be more appropriate for determining safety and efficacy if doses higher than 4 mg per day are to be considered. In addition, the authors state that this study was performed to study the adjuvant potential of nabilone in subjects already receiving pharmacotherapeutic management of neuropathic pain from established diabetes; the use of concomitant medications leads to difficulty in teasing out the individual effect of nabilone. Future studies to assess the efficacy of nabilone monotherapy would require a washout of medications, with a focus on the primary efficacy of nabilone for chronic diabetic neuropathic pain.

• (Grant et al., 2011 [24]).

This was a 12-week uncontrolled pilot study of dronabinol (dose ranging from 2.5 to 15 mg/day) in 12 female patients with a diagnosis of the compulsive hair-pulling disorder, trichotillomania. The authors reported that dronabinol appeared to promote statistically significant reductions in trichotillomania symptoms in the absence of negative constitutional or subjectively assessed cognitive effects. However, larger placebo-controlled studies incorporating validated and widely used cognitive measures are warranted given the small sample and open-label design.

The exclusively female sample may also be a significant confound; the interaction between the gonadal hormones and pain perception is intricate and not well understood. Several clinical pain conditions show significant variation in symptom severity across the menstrual cycle, though there does not appear to be a consensus on whether the menstrual cycle influences experimental pain sensitivity in healthy individuals (Iacovides et al., 2015 [53]).

• (Malik et al., 2017 [54]).

This was a 28-day pilot study of oral dronabinol (5 mg twice daily) in 13 patients (11 female and 2 male) with non-gastroesophageal reflux and non-cardiac chest pain. These were patients who were diagnosed with odynophagia, hypersensitivity, and pain associated with esophageal dysmotility and who were essentially refractory to mainstream management. The etiology of the challenging symptom picture was attributed to several hypersensitivity mechanisms that include altered autonomic activity, amplified cerebral processing of visceral sensory input, abnormal mechanophysical properties, sustained longitudinal muscle contractions, psychological abnormalities, and increased mucosal mast cells. Improvement was reported in both objective and subjective indices of swallow, esophageal function, and pain. A possible contribution to study outcomes from psychiatric variables was seen as unlikely in light of the results on anxiety and depression inventories.

Threats to validity lie primarily with the small sample size and the brief duration of the study. Assessment of any intervention for broadly defined or vaguely described syndromes that are often diagnoses of exclusion is seen as intrinsically weak. While study subjects appeared to improve with dronabinol, sustained and significant changes should be demonstrated in a larger, appropriately powered sample over a more meaningful study duration and, ideally, in subjects with documented and specific pathologic diagnoses.