Cannabis can be described as a family of medicines rather than one medicine [31]. CBMPs include pharmaceutical preparations that can contain a broad spectrum of the bioactive chemical constituents of the cannabis plant (‘whole-plant’ or ‘full-spectrum’ products), only individual chemical constituents of the plant (isolates), or in a varied combination of constituents. The cannabis plant synthesises many cannabinoids including cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), terpenes, and flavonoids [32]. Cannabinoids act on the endocannabinoid system, a complex widespread neuromodulator system involved in multiple functions throughout the body [33], highlighting the array of potential targets for CBMPs.

The constituents of the cannabis plants are thought to have distinct therapeutic benefits, and there is a further layer of complexity whereby there may be an entourage effect of some constituents [32]. The entourage effect is a pharmacological synergy whereby the entirety of the effect is greater than the sum effects of each individual component of the cannabis extract [34]. This term was first coined in 1998 after in vitro and in vivo observations that various seemingly inactive metabolites could alter the activity of the endocannabinoid system [35]. Currently, most medicinal cannabis research has focused on CBD and THC, and therefore further research is needed into the specific roles of minor cannabinoids and other constituents, as well as the entourage effect [36, 37]. The potential of cannabinoids to have distinct therapeutic benefits has been demonstrated in the context of acute COVID-19 infection, whereby cannabigerolic acid and cannabidiolic acid prevented the entry of SARS-CoV-2 into epithelial cells in vitro [38]. Although there is a limited investigation of the entourage effect in treating Long COVID symptoms, it is necessary to highlight this synergy whereby whole plant CBMPs may offer therapeutic superiority over isolates [36, 39].

Given that the preparation of the CBMP and its constituents will influence the potential effects, the details on the constituent of the CBMPs used in studies throughout this review are provided (when this information is available).

Understanding the medical contexts in which CBMPs are currently used and the existing evidence highlights why CBMPs may offer a potential treatment of Long COVID symptoms. It outlines some of the key overlapping symptoms and conditions CBMPs are used to treat and those commonly reported in Long COVID (Figure 1). It is not exhaustive as Long COVID presents a vast array of symptoms [10], some of which are not included in Figure 1. Similarly, CBMPs are used in the real-world setting for a variety of conditions and symptoms which may not be presented in Figure 1 [40, 41].

CBMPs are typically used to try and manage symptoms to provide symptomatic relief for patients [42]. They are used in chronic complex conditions where patients are often on multiple medications [41], including multiple sclerosis (MS) and fibromyalgia, and patients with these diagnoses commonly have more than one symptom [41, 43]. Due to the nature of the cannabis plant and differing types of CBMPs, the selection of CBMPs is usually individualised and tailored to the patient’s symptoms. Globally, the most common symptoms for which medical cannabis is used are pain, muscle stiffness (spasticity), nausea, fatigue, anxiety, insomnia, mood disorders, and seizures [41, 44, 45]. Some of these symptoms, particularly anxiety, mood disorders, fatigue, and pain are commonly reported in patients with Long COVID [9–12].

Multiple lines of evidence support the potential use of CBMPs in Long COVID (see Figure 2 for an overview of the areas of evidence). Firstly, some of the most commonly reported symptoms of Long COVID include sleep disturbance, fatigue, pain, and anxiety: these symptoms are common to many of the disorders currently being treated with CBMPs. There is burgeoning literature suggesting the efficacy and effectiveness of cannabinoids in treating pain, anxiety/depression, and other symptoms [40, 46–50] while also improving quality of life [40, 46–51]. In the sections below, key evidence for CBMPs use in commonly reported symptoms is discussed.

Increasing RWE from global large-scale databases highlights that patients are successfully using medicinal cannabis to treat pain, anxiety, depression, migraines/headaches, insomnia, post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), nausea, and more see [41] and [40] for summaries from two United Kingdom (UK)-based registries. RWE provides an alternative to controlled trials to study the effects of CBMPs and has a broad range of advantages [43]. RWE offers better ecological validity than randomised controlled trials (RCTs) as it can be acquired from a much larger demographic range of patients and is inclusive of those with significant comorbidities [43]. Furthermore, RWE enables the investigation of a broad range of CBMPs and is therefore more reflective of the variety of CBMPs used by patients [43].

Long COVID is associated with a myriad of symptoms, and therefore these patients present similarities to current medical cannabis patients who typically have co-morbid symptoms and conditions secondary to their primary condition. The multiple suggested effects of CBMPs are thought to contribute to overall improvement in overall quality of life, a key issue in chronic conditions [41]. In the United Kingdom Medical Cannabis Registry, treatment with CBMPs was associated with an improvement in quality of life, sleep- and anxiety-specific symptoms after 12 months in patients with chronic illness [40]. This highlights how CBMPs are already used to manage patients with complex conditions and symptoms in chronic illness, presenting similarity with the complexity of Long COVID.

Meta-analyses demonstrate low to moderate-quality evidence for a role of CBMPs in the reduction of chronic pain [52–55]. The most frequent primary condition in Project Twenty21, a UK based real-world data registry of prescribed cannabis patients, is chronic pain [41]. These chronic pain patients reported high levels of comorbidity; people reported an average of 4.6 comorbid conditions with the most common comorbid conditions being anxiety, depression, insomnia, and stress [41]. These high levels of comorbidity are also reported in the United Kingdom Medical Cannabis Registry [40]. These registries include patients being treated with a broad set of CBMPs: various formulations (oil, capsules, lozenges, and dried flower), preparations (isolated cannabinoids or broad/full spectrum extract), and constituents of cannabinoids/terpenes [40, 41]. Project Twenty21 has demonstrated consistent reductions in pain symptomatology and improvements in quality of life, general health, mood, and sleep among chronic pain patients [56]. Additionally, there was a substantial reduction in the use of prescribed opioids in these patients [56]. Further observational studies of patients using CBMPs have reported improvements in pain [57–62].

Headaches and migraines are other common symptoms of Long COVID [10]. Systematic reviews report reduced frequency [63, 64] and length [63] of migraine headaches after treatment with CBMPs.

Emerging evidence suggests that the immune-inflammatory response triggered by acute COVID-19 infection is associated with the neuropsychiatric symptoms of Long COVID including anxiety, depression, and fatigue [65]. Furthermore, preclinical data show that prolonged, sustained inflammation in COVID-19 animal models correlates with anxiety-like behaviour [66]. Focusing on one component of CBMPs, CBD has been proposed as a potential treatment for anxiety disorders, despite a lack of studies investigating chronic CBD dosing [67]. A systematic review of the concentration effects of CBD reported that the majority (70.3%) of studies found no effect of CBD on anxiety outcomes, however, the authors stated that it would be premature to conclude that CBD does not have anxiety-reducing properties [68]. There are several limitations of the existing literature, including the assessment of anxiety symptomatology, cross-species analysis, and missing pharmacokinetics (PK) data [68]. Studies of particular interest include the use of a 300 mg daily dose of CBD for a period of 4 weeks for the treatment of social anxiety disorder in teenagers which demonstrated a reduction in anxiety measures [69]. Furthermore, a small tolerability clinical trial investigating a full spectrum high-CBD CBMP in 14 patients with anxiety demonstrated improvements in anxiety, mood, sleep, quality of life, and cognition [70]. It is suggested that low doses of THC are anxiolytic and can offer therapeutic benefits, however, THC may be anxiogenic at higher doses [71].

The potential role of CBD in COVID-19-related anxiety and post-traumatic stress symptoms (PTSS) or PTSD, as well as sleep disturbances often concomitantly reported, has been hypothesised and discussed in the context of current evidence [72]. The authors discuss a growing body of small randomized controlled clinical trials using CBD for anxiolytic effects; however, many were in healthy volunteers rather than relevant patient cohorts [72]. RWE highlights the potential value of CBMPs to reduce anxiety symptomatology and improve patients’ well-being and sleep [40, 56] and observational studies of CBMPs have also demonstrated improvements in anxiety [59, 61, 62, 73]. There is a need for further investigation into which CBMPs may offer therapeutic benefits in anxiety, as well as the dosing schedule and treatment duration.

The evidence for CBMPs in the treatment of depression is more limited than for anxiety. A meta-analysis reported that CBMPs did not improve symptoms of depression, however, depression was often recorded as an outcome measure in RCTs with a different primary indication [74]. Observational studies demonstrate the potential role of CBMPs in alleviating depression symptoms in patients, including those seeking treatment for other primary conditions [40, 56, 75, 76].

Fatigue is commonly reported in Long COVID [10] and while there’s a lack of research specifically investigating CBMPs and fatigue, conditions with fatigue as a symptom, such as fibromyalgia can provide potential insights. Fibromyalgia is a pain disorder characterised by chronic widespread pain, fatigue, and sleep disturbance, in the absence of any well-defined underlying organic disease. Although there is limited data from RCTs for CBMPs in fibromyalgia [77], fibromyalgia is a common condition for which patients seek CBMPs in the real-world setting [40]. An observational study investigating CBMP in pain conditions, including 132 patients with fibromyalgia out of 751, reported reductions in fatigue as well as decreases in pain, headaches, fatigue, anxiety, and nausea [62].

Sleep disturbances are commonly reported by Long COVID patients [10]. Meta-analyses report a potential improvement in sleep from CBMPs treatment in chronic pain patient groups [74, 78], particularly noting the effect of nabiximols [74, 78]. RWE from registries and observational studies elucidate a potential role of CBMPs in improving sleep often presented alongside other symptoms [40, 56, 59, 61, 73, 75, 76].

Cognitive dysfunction is commonly reported by Long COVID patients [10]. CBD has the potential to impact brain function [79] and although CBD has been shown to improve cognition in preclinical models of cognitive impairment [80], some uncertainty remains for the potential effects of CBMPs on cognitive function due to the heterogeneity of constituents and limitations across the studies [81]. An improvement in cognition after 4 weeks of treatment with a high-CBD CBMP has been demonstrated [70] and a small clinical trial of the CBMP nabiximols in ADHD demonstrated a trend towards significance in favour of the CBMP for improving cognitive performance and activity level after 6 weeks of treatment [82]. Despite the limited evidence from RCTs for ADHD, CBMPs are currently used in clinical practice for ADHD [40]. An observational study demonstrated cognitive improvements after 3 months of treatment with CBMPs and reported improved task performance accompanied by changes in brain activation patterns within the cingulate cortex and frontal regions that were more reflective of healthy controls from previous studies than at pre-treatment [75]. A further observational longitudinal study demonstrated that CBMPs may improve cognitive function over the course of 12 months [83].

CBD, a key component of many CBMPs, has anti-inflammatory properties [84–87] and the potential role of CBD or high CBD CBMPs as an anti-inflammatory treatment for acute COVID-19 infection has been highlighted [88–90]. Inflammation is one of the hypotheses regarding the aetiology of Long COVID [91] and therefore CBD dominant CBMPs may offer direct benefits for Long COVID patients if this is proven to be the case. In an animal study on asthma, CBD was able to reduce the production of proinflammatory cytokine production, actually reducing airway inflammation [92]. In the same study, CBD also reduced pulmonary fibrosis, a condition where lung tissue becomes damaged and scarred, thickening lung tissue and making breathing more difficult [92], which mirrors COVID-19 symptoms such as serious pulmonary fibrosis [93]. Through in silico investigation, the cannabis derivatives CBD and cannabivarin have been suggested to have the potential to bind to and downregulate central nervous system (CNS) proteins related to Long COVID symptoms [94].

Despite limited research into the potential anti-viral properties of cannabinoids [95], the potential antiviral effects of cannabinoids and terpenes in the context of SARS-CoV-2 virus have been highlighted [96]. The potential anti-viral properties of cannabinoids could be of relevance due to the potential role of EBV in Long COVID. Studies have demonstrated an increased incidence of reactivation of the EBV in patients following SARS-CoV-2 infection [16]. This is hypothesised to be one of the contributing aetiologies of Long COVID [16], and THC has been shown to suppress activation of the EBV in vitro [97].

One current hypothesis is that some of the Long COVID symptoms could be attributed to dysautonomia [98] and the potential connection has become increasingly recognised amongst health care professionals [99, 100]. Dysautonomia refers to a disorder of autonomic nervous system (ANS) function that generally involves failure or excessive activation of the sympathetic or parasympathetic components of the ANS. Several studies indicate a high prevalence of dysautonomia in Long COVID patients [101, 102], including a global survey which reported moderate to severe autonomic dysfunction in 66% of patients [101]. Dani and colleagues [103] have discussed the scientific rationale for an underlying impaired autonomic physiology in Long COVID proposing that virus- or immune-mediated disruption of the autonomic nervous system results in orthostatic intolerance syndromes. Common reported symptoms of dysautonomia in Long COVID include palpitations, fatigue, sleep difficulties, cognitive impairment, breathlessness, and dizziness. Dysautonomia is also observed frequently in other post-viral states and other conditions such as diabetes [104], MS [105], fibromyalgia [106], and Parkinson’s disease [107]. Medical cannabis is used to treat the symptoms of some of these conditions including fibromyalgia and MS [41, 108]. A recent study suggested that Long COVID patients with fatigue may exhibit dysautonomia characterised by dysregulation of heart rate variability, compared to the control group of participants with previous COVID infection but no fatigue [109].