Clinical Benefits and Safety of Medical Cannabis Products: A Narrative Review on Natural Extracts

Key Summary Points

Introduction

Until relatively recently, clinical use of medicinal cannabis and allied cannabis-based or related medicinal products (called here CBMPs) was rather restricted, chiefly to use of a small number of licensed medications in specific indications [1–4]. Such agents are now increasingly studied for their therapeutic effects in a diverse range of clinical conditions and symptoms [5–7], and interest and use are expanding, particularly for managing neuropathic and chronic non-cancer pain [8–11], symptomatic relief in multiple sclerosis (MS) [12, 13], in supportive cancer care and in palliative care [14–17]. In part, this reflects legislative evolutions surrounding recreational cannabis use and a global shift in positive attitudes towards use of medicinal cannabis/CBMPs by medical professionals [18–21] and by patients [22–31]. As a reminder, recreational cannabis use has been formally legalized in some countries, e.g., Canada, Uruguay, and Malta, and across many jurisdictions within the United States (US), with more regulated legal supply also allowed in e.g., Switzerland and the Netherlands [32]. Furthermore, recreational cannabis use has been decriminalized (i.e., the removal of criminal penalties) in more than 30 countries, including Australia and Israel [33]. This has been accompanied by legislative changes allowing broader regulated use of medicinal cannabis in many countries such as the United States, Canada, Israel, and Australia [21, 34–37]. Within Europe, although access to medicinal cannabis remains more restricted, prescribed use is allowed in a number of countries including Italy, France, Germany, the United Kingdom (UK), Greece, the Netherlands, Denmark, and Luxembourg [38–40].

Consequently, medical cannabis and CBMPs are increasingly used by patients with a wide range of chronic medical conditions for symptom relief and to improve quality of life (QoL). In the US, the proportion of patients hospitalized with chronic pain reporting cannabis use doubled between 2011 and 2015, while in Canada, one large survey of patients living with chronic pain reported the prevalence of cannabis use for pain management was 30.1% [22, 23]. Surveys of patients with cancer conducted in the US, Canada, and in Europe reported use in between 13% and 70% of patients [24–28]. Principal reasons of this use was relief of various physical symptoms (e.g., pain or nausea and vomiting during active anticancer therapy) and also for broader psychological support (reducing anxiety/stress or improving mood and sleep) [24, 25, 41]. Note that although patients may report use for a potential anti-cancer effect [24, 27], with some supportive preclinical data [42–45], there are a lack of clinical data for any such benefit [42, 45]. Medical cannabis and CBMP use has also been described in patients with MS. A recent survey conducted in more than 3000 patients within the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry found that 31% reported cannabis use at some point of their health pathway to treat their MS symptoms, with 20% reporting current use [31]. Surveys conducted in Canada, Spain, and France also reported use in between 19% and 23% of patients with MS [29, 46]. In these patients, use of medical cannabis or CMBPs was chiefly for symptomatic relief, mainly pain, spasticity, and sleep disruption, with greater use observed in patients with more severe symptoms [29, 31, 46–48].

These observational data require clinicians to be fully informed on benefits and risks to help decision-making when considering prescribing medical cannabis or CBMP, and to provide appropriate patient guidance. However, clinician surveys conducted across a range of countries indicate that knowledge is often inadequate, with clinicians often uncomfortable in patient discussions and enquiries [49–52]. There is thus a clear need for improved training and education of HCPs to help inform patients about medical cannabis and CBMPs.

As outlined below, such uncertainty around medicinal cannabis and CBMPs arises from a number of factors, including firstly the diverse range of agents and preparations used and the accompanying terminology, and secondly the interpretation of the relevant literature. The two principal bioactive components within Cannabis sativa and most medicinal cannabis preparations and CBMPs are delta-9-tetrahydrocannabinol (∆9-THC), the primary highly psychoactive component, and cannabidiol (CBD), considered as low psychoactive and non-intoxicating [53]. Other components include terpenes and flavonoids, as yet mainly investigated in the preclinical setting [54], and cannabigerol (often used as a nutritional supplement) although clinical data are limited [55, 56]. Medical cannabis and CBMPs vary in their constituent ∆9-THC and CBD components and concentrations, and in their source, i.e., whether derived from natural botanical extracts (‘phytocannabinoids’) or as manufactured synthetic analogs (‘synthetic cannabinoids’) [53]. These are available either as licensed medical agents [1–4], or within a diverse range of prescribed ‘medical cannabis’ and CBMPs (often given under conditional, regulated medicinal use, e.g., in patient registries) [57–60]. Note that a variety of terms are used in the supporting literature, and to some extent in the present review. There is no single standard definition. Here we chiefly use ‘medical cannabis’ in the context of those preparations containing ∆9-THC and/or CBD, and where the study authors use this same terminology in their reporting. Similarly, for CBMPs, in this review we focus on ∆9-THC and/or CBD preparations, again where the study authors use similar terminology. While to some extent these terms (medical cannabis and CBMPs) can be interchangeable, it remains important to specify the nature of each (in terms of their 9-THC and CBD components) to provide the necessary context to the clinical effects we report.

The existing evidence base for benefit and risks associated with medical cannabis and CBMPs use is large and extensively evaluated, with a recent umbrella review reporting across 101 metanalyses of clinical studies [61]. Alongside this, there has been a dramatic increase in the number of clinical studies evaluating medical cannabis and CBMPs in recent years [62]. The sheer volume of existing and emerging data, often involving diverse agents utilizing different ∆9-THC and CBD combinations (sometimes at uncertain concentrations and unclear dosing details), can be difficult to interpret [61, 63]. Indeed, this is often cited by poorly experienced physicians when trying to provide patient guidance [20, 64]. One concern relates to product safety, in particular the potential for adverse effects and any potential for dependance or addiction associated with the ∆9-THC component [39, 65, 66].

The aim of the present narrative review is to synthesize the current knowledge regarding some benefits of medical cannabis and CBMPs and the safety including all potential risks associated with their use. In this, our focus will be on phytocannabinoid preparations incorporating ∆9-THC and CBD derived as natural extracts, rather than synthetic ∆9-THC agents (dronabinol, nabilone) [1, 2]. Also, while a natural purified CBD oil extract (Epidiolex®) is currently used for seizure control in some pediatric seizure disorders [3], our review will focus on medical cannabis and CBMPs use in adults. Hence, the focus will be on certain medical conditions including pain, multiple sclerosis, cancer and palliative care, but not epilepsy.

Search Strategy

To inform the review, an electronic search of PubMed was performed between 11 and 13 March 2023 using different combinations of MeSH terms and keywords with Boolean operators to identify and retrieve articles spanning three areas of interest: (1) efficacy of phytocannabinoids in neuropathic pain, spasticity and cancer symptoms; (2) safety profile of these cannabinoids in these conditions; and (3) addictive potential in all indications and comparative safety of medical versus recreational cannabis. The process is fully described in the Supplementary Appendix and Supplementary Table 1. Additionally, subsequent ad hoc searches, along with continued citation chasing and snowball sampling, was used to remain up to date with emerging literature. Although comprehensive, this approach is not formally systematic and is not presented or reported as such, since the aim is to identify the most relevant literature to ultimately develop a broad current overview of efficacy and safety for clinical use of natural extracts of cannabis among cannabis products. This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.

Overview on the Medical Use of Cannabis Natural Extracts

Benefits in Pain Management

Benefits in Multiple Sclerosis

Efficacy in MS spasticity has been extensively investigated in RCTs and longitudinal studies evaluating nabiximols, with a wealth of real-world data [4, 7, 12, 13, 90, 103]. These indicate substantial benefit. Up to 40% of those patients showing an initial response (considered as those with ≥ 20% improvement in their baseline spasticity NRS score within 4 weeks) will achieve durable responses. Continued treatment (mean dosages of 6–7 sprays/day) results in sustained improvement (≥ 30% improvement from baseline NRS) for response) [4, 7, 12, 90, 103]. A recent post hoc analysis of two RCTs (GWSP0604 [142] and SAVANT [143]) found that use of nabiximols as an adjunct to baclofen led to a significant, sustained reduction in spasticity NRS scores over 12 weeks, and reduced average daily spasm count by 19–35% compared with placebo [144]. A systematic review of real-world observational studies evaluating nabiximols found that the proportion of patients achieving ≥ 20% reduction from baseline spasticity NRS scores ranged from 41.9% to 82.9% after 4 weeks, with benefits maintained over 6–12 months [13]. Spasticity improvement was also accompanied by improvement in pain intensity scores [131].

There are at present limited data from patient registry data for patients with MS [116, 145]. Some insight can be gained from reports of real-world use in patients with MS, with surveys recently conducted in the United States, Canada, and in Europe (Spain, France) reporting current use of medicinal cannabis products in between 20% and 50% of patients surveyed, chiefly to alleviate spasticity symptoms [31, 46–48, 146]. Although outcome data are not always described, and details on product type are lacking, improvement in spasticity symptoms are reported in 70% of respondents in Canada and in France, with over 75% of French respondents also reporting improvement in pain and in sleep [47, 48]. In summary, there is evidence from randomized and observational studies for improvement in spasticity symptoms in some patients with MS using CMBPs.

Additional Symptomatic Benefits

Beyond the use of CBMPs to alleviate specific symptoms (e.g., chronic pain, spasticity), there is some evidence for a benefit in a broader range of symptoms in chronic pain, cancer, and MS such as chemotherapy-induced nausea or vomiting (CINV), anxiety, depression, and sleep disturbance. Much of this can be drawn from reports of real-world use within cannabis registries, although again with the caveat that as these often utilize a range of products with different ∆9-THC and CBD quantities.

Registry reports indicate benefits in reducing nausea, as measured by patient-reported improvement and a concomitant reduction in anti-emetic agent use. For example, reports from the Israel registry, which utilizes mainly inhaled ∆9-THC-rich preparations, indicate substantial improvements in nausea (as measured by the number of patients reporting reduced or cessation of symptoms and reduced use of anti-emetics) in patients with chronic pain and also within the palliative cancer care setting [57, 58]. In patients with cancer, symptom improvement was reported by 91% of patients after 6 months, with 67% discontinuing anti-emetic use [57]. This registry also reports improvements in psychological symptoms, where 84% of patients with cancer reported improvement in anxiety and depressive symptoms, and approximately 25% reporting stopping anxiolytic medications [57].

Benefits of a reduction in anxiety is also widely reported from registries using CBMPs. In the German pain registry, 84% of patients with neuropathic pain receiving nabiximols reported ≥ 50% improvement in anxiety scores [133]. Recent reports from the UKMCR on individuals with generalized anxiety disorder have shown that use of either ∆9-THC-rich, balanced or CBD-rich preparations in individuals with generalized anxiety disorder led to significant improvement in the EQ-5D-5L depression and anxiety subscale scores and in Generalized Anxiety and Depression-7 (GAD-7) scores after 3 months, with greatest benefit in those receiving CBD-rich oil preparations [147]. Other reports from this registry have shown a reduction in these outcomes after 3 months in patients with chronic pain receiving ∆9-THC-rich and/or CBD predominant preparations [121, 123, 124]. In Australia, the AECeR reports that use of combined oral CBMPs (approximately 2:1 ratio for CBD and ∆9-THC) for 12 months led to small improvements in Depression Anxiety Stress Scale scores, with these observed as early as 3 months, and sustained over 24 months [116]. Data from Canada suggests that in addition to pain relief, use of CBD-predominant products in patients with cancer is also associated with improved ESAS-r anxiety and depression symptoms scores over 12 months [125, 126], and that use of exclusively CBD-rich products can reduce anxiety and depression scores in patients with chronic non-cancer pain [138]. Beyond these data, studies evaluating any benefit of CBMPs for overt depression are sparse. One recent case series from the UKMCR reporting on patients with a primary diagnosis of depression receiving a mixture of ∆9-THC-rich and CBD-rich products reported statistically significant reductions in Patient Health Questionnaire-9 (PHQ-9) scores at 1, 3, and 6 months as well as improvements in EQ-5D-5L anxiety/depression subscale scores and GAD-7 scores [148].

Patients often take CBMPs for sleep improvement, but the literature on the place of cannabinoids in sleep disturbance is conflicting [149]. Some reviews conclude that cannabinoids have a limited effect [150, 151], and indeed may adversely impact sleep and may trigger or exacerbate insomnia, in particular ∆9-THC-rich products [149, 151]. Systematic reviews with meta-analysis of RCTs spanning a range of ∆9-THC products have concluded that there is some benefit in individuals with chronic pain [152, 153]. These found significant improvements in sleep quality in those with chronic neuropathic pain and also cancer-associated pain, although these were considered relatively small, involving < 10% of patients [152, 153]. Data from studies evaluating sleep improvement with nabiximols as a secondary outcome show inconsistent findings. Some benefit is reported in patients with MS and cancer-associated pain [140, 154, 155], and longer-term observational data from the German Pain e-Registry reports improved sleep in 70% of patients with neuropathic pain [133]. Similarly, a small Australian study evaluating ∆9-THC and CBD doses (each at 25 mg daily) reported that 49.3% of patients reported a meaningful improvement in sleep over 3 months [134]. Note that this study also reported improved fatigue in 39% [134]. For CBD alone, results are inconsistent, although one recently reported RCT evaluating CBD found that 15 mg of CBD taken at night reduced self-reported sleep disturbance over 4 weeks [156]. Sleep improvement is anyway widely reported in cannabis registry cohorts. In Israel, sleep improvement (less disturbance) was reported in 87% of patients with cancer (receiving predominantly inhaled ∆9-THC-rich preparations), and with reduced use of sedative medications [57]. Similar findings were subsequently reported across a larger cohort, involving both patients with chronic pain and with cancer (with 89% reporting improved sleep) [58]. In patients receiving chiefly CBD-predominant regimens such as those with chronic pain included in the AECeR (median total daily oral dose of 10 mg ∆9-THC and 22.5 mg CBD), a significant sustained reduction in sleep disturbance of approximately 35% was observed over 24 months [116]. Data from the UKMCR also show improved sleep, as measured using the Sleep Quality Scale (SQS), with this reported across a large patient cohort with a range of chronic conditions receiving ∆9-THC-rich and/or CBD-predominant preparations [60]. Sleep improvement was also observed in several specific conditions including chronic pain [121, 123, 124], generalized anxiety disorder, and depressive illness [147, 148].

Overall, clinical evidence and observations strongly suggest that CBMPs may improve sleep quality in a substantial number of patients, mainly those using these treatments for the improvement of other symptoms in chronic cancer and non-cancer pain and MS.

Impact on Quality of Life and Well-being

The benefits of CBMPs in alleviating specific symptoms we describe above have an impact on patients’ QoL. This can be assessed using formal QoL instruments e.g., EQ-5D-5L and EQ-5D-5L VAS, while further insight can be gained from instruments evaluating a more holistic benefit such as the Patient Global Impression of Change (PGIC). Relatively few randomized or controlled studies evaluating CBMPs formally evaluate QoL, with systematic reviews concluding that the evidence from such studies for any impact is relatively weak, even when symptom improvements are observed, with a rather small impact on physical function and little if any on mental well-being [102, 157]. For most randomized studies evaluating nabiximols in MS, the observed benefit in spasticity and pain outcomes is not accompanied by significant improvements in overall QoL scores; in some, improvement in physical functioning scores is observed, the greatest improvements in overall QoL measures being restricted to patients considered as treatment responders [158]. More supportive data for nabiximols in improving well-being is seen in observational studies. In the German pain registry, 55% of patients with neuropathic pain reported ≥ 50% improvement in physical QoL and 24% reported similar improvement in mental well-being. Using the PGIC, 76% reported that their overall situation was “much better” or “very much better” after 12 weeks (Table 2) [133].

A greater understanding of the impact on QoL and patient well-being can be gained from studies reporting from cannabis registries. The UKMCR routinely reports on EQ-5D-5L and PGIC outcomes in patients receiving an array of ∆9-THC-rich, balanced, and CBD-dominant products (which can make identification of the relative impact of ∆9-THC and CBD challenging, although in general patients received greater ∆9-THC dosing) [60, 121–124, 148]. The broad pattern, however, is that in addition to the symptom improvement described above, significant improvements in overall EQ-5D-5L scores (and most instrument subscales) as well as improved GAD-7 scores are observed, sustained over as much as 12 months of follow-up, along with supportive PGIC scores [60, 121–124, 148]. Although improvement was greater in those individuals declaring current consumption of recreational cannabis, benefit was also reported in otherwise cannabis-naïve individuals [60]. In those prospective registry studies from Israel (chiefly using ∆9-THC-rich inhalation formulations), QoL was measured using a five-point Likert scale. These report significant increases in the proportion of patients reporting good QoL after 6 months of receiving cannabis preparations [57, 58]. In the study reporting specifically on patients with cancer, while only 18.7% of patients reported good quality of life prior to treatment initiation, after 6 months this proportion increased to 69.5% [57]. A similar finding was observed in the later study reporting on use for chronic pain in cancer (approximately 50% in each category), with the proportion reporting good QoL increasing from 12.9% at baseline to 69.9% at 6 months [58].

Benefits are also evident for CBD-predominant products. Australian registry data in patients with chronic pain receiving a range of products (although chiefly delivering greater CBD doses) report improved quality of life (SF-36) scores sustained over 24 months, with particular improvement in mental health items [116]. Another retrospective case series study from Australia specifically evaluated QoL in a large cohort (> 3000 patients). While patients received a mix of products, balanced and CBD or ∆9-THC-predominant, which varied across the study, the overall pattern over 2 years was chiefly CBD (approx. 70 mg daily) with lower ∆9-THC doses (titrated up to approx. 20–25 mg daily). This study found substantial improvements from in QoL (SF-36) for all physical and mental domains sustained over 2 years, with the greatest effect observed for mental and emotional well-being [159]. Improved EQ-5D-5L and ESAS-r well-being scores are also reported in chronic pain and cancer cohorts in Canada receiving mixed or CBD-rich CBMPs, although such improvements were relatively small [125, 126, 138].

Safety Profile and Adverse Effects

Therapeutic benefits of medical cannabis and CBMPs must be considered in the context of any potential negative impact, considering not only the conventional safety profile but also regarding any ‘addictogenic’ potential. Systematic evaluations of safety are often reported across different CBMPs products and formulations given to different patient populations [11, 107, 160, 161]]. While this brings some uncertainty when drawing specific conclusions, some broad observations can be made. Most studies and observational data report a relatively high prevalence of AEs, indeed in as much as over 90% individuals in longer-term studies, although this varies widely [11], and generally less frequent in registry cohorts: 34% in Israel over 6 months [58], 37% within the AECeR over 2 years [116], and 17% over 12 months within the larger UKMCR cohort [60]. In most instances, AEs are mild to moderate and transient, and serious AEs are uncommon [37, 160]. A recent systematic review of longitudinal observational studies reporting on long-term (up to 18 months) safety of medical cannabis and CBMPs reported that discontinuation due to AEs ranged from 0 to 27%, while the prevalence of serious AEs was 1.2% (95% CI, 0.1–3.1%) [11]. The most common AEs, occurring in up to 20% of patients, are dizziness, drowsiness/sedation or fatigue, dry mouth, nausea, and gastrointestinal upset [37, 95, 160]. Other effects such as euphoria, dysphoria, confusion, or cognitive impairment are less common, occurring in between 1% and 10% of subjects [11, 91, 92, 162, 163].

Most side effects are principally associated with ∆9-THC and are dose-dependent [37, 95, 160]. One recent systematic evaluation of synthetic ∆9-THC cannabis-based medications (nabilone and dronabinol) in placebo-controlled trials found that dizziness, drowsiness, dry mouth, and headache were most frequently reported, with a far-greater prevalence compared with placebo [162]. Although less common, there is a recognized association between tachycardia and Δ9-THC [37, 160, 164]. For nabiximols, randomized and observational studies and also longer-term registry data indicate a common pattern of AEs, although prevalence varies across studies: dizziness (1–22%), nausea (4–20%), fatigue (1–9%), and drowsiness (1–12%), most were considered mild or moderate and transient [91, 92, 163, 165]. Safety evaluations of CBD given at dosing up to 600 mg daily in clinical trials indicate gastrointestinal upset as the main AE, reported in up to 60% of individuals, principally diarrhea and nausea/vomiting [83, 85, 166]. Others include drowsiness (17%), fatigue (11%), and reduced appetite (16%) [166]. We should mention that elevated liver enzymes are observed in individuals taking higher CBD doses (including children for seizure control) [83]. However, this relates to far higher CBD dosage than that used in routine practice (e.g., in cancer registries, with daily dosing of between 10 and 240 mg); most studies evaluating CBD dosing of up to 600 mg daily in adults indicating no such concerns [37, 83]. Moreover, elevated liver enzymes are not present in patients receiving nabiximols [91, 92].

Cannabis registries provide a wealth of safety data in real-world long-term use, although due to the wide array of products used within registries, determining specific association with Δ9-THC or CBD elements can be challenging. One broad pattern is that most AEs are of mild or moderate severity, often transient, rarely cause treatment discontinuation, and that preparations are generally well tolerated [57, 58, 60, 116, 121, 125]. Those using primarily Δ9-THC-rich preparations, e.g., as in Israel, report a broad range of side effects: most frequently dizziness (8.2%), dry mouth (6.7%), increased appetite (4.7%), sleepiness (4.4%). Cognitive effects included euphoria (4.3%), confusion (1.7%), hallucinations (1.2%), and restlessness in 1.4%, although anxiety was uncommon (0.3%) [58]. Cardiac palpitations were infrequent (0.8%) [58]. A similar profile has recently been reported from a smaller Australian cohort receiving a Δ9-THC-rich product, with dizziness, fatigue, and increased appetite each reported by 10%, although with dry mouth reported by 24% [127]. This cohort, which also evaluated AEs observed with balanced and CBD-dominant products, allows a useful comparison. While dizziness, fatigue, and increased appetite observed with balanced Δ9-THC and CBD products were each reported at a relatively similar frequency as seen for Δ9-THC-dominant products, 10% also reported nausea and diarrhea, while 24% reported a sedative effect, with broadly similar patterns seen with patients receiving a CBD-dominant product [127].

From the data we describe above, it would appear that CBMPs have a favorable safety profile, although some differences exist depending on the cannabinoid involved. ∆9-THC is associated with a greater number and broader range of side effects than CBD, and it is likely that it is the ∆9-THC component of medical cannabis that carries the greater risk of AEs, in particular psychoactive effects including euphoria. Incorporation of CBD into ∆9-THC-rich regimens may attenuate any acute intoxicating effects of ∆9-THC and reduce any treatment-associated anxiety [167]. Most studies evaluating this interaction are heterogeneous regarding dosing routes and study populations (chiefly involving recreational cannabis users rather than for medical use) [89, 168]. Some supportive data exist, however, for use of CBD at high doses, leading to reduced euphoria in individuals using recreational cannabis, although conversely concomitant use of lower CBD doses may enhance intoxicating effects [71, 72]. However, some small RCTs have shown no evidence for CBD in modulation of acute ∆9-THC effects of ∆9-THC in recreational cannabis users [73–75]. While it seems possible, even likely, that there may be some genuine effect of adding CBD to ameliorate such effects, at present, however, the benefits remain uncertain [65, 169]. This said, such an approach remains part of some treatment recommendation strategies [95]. Finally, oral CBMPs have an inherently safer profile than inhaled formulations, where, drawing from studies of recreational cannabis use, it is likely that inhaled CBMPs may confer a greater risk of respiratory disease compared to other routes [164, 170, 171].

Discussion

In this narrative review, we evaluated the evidence for some therapeutic benefits and the safety profile of medical cannabis and CBMPs. These agents span an enormous range of product and formulations, dosage, and administration, and there remain substantial knowledge gaps with regards to optimal formulations, dosage, and administration routes for specific clinical indications. Furthermore, as we have outlined, often at great length, in real-world use, individual patients often (indeed usually) receive both ∆9-THC and CBD components within their treatment regimens, though the relative predominance, concentrations, and dosing of each may change (as may the administration route). These factors hinder evaluating and quantifying the benefits and safety specifically associated with these individual ∆9-THC and CBD components. While this hampers making recommendations for specific CBMP regimens, some broad conclusions can be proposed. While CBMPs as a group show some efficacy in reducing chronic pain, there are more supportive data for ∆9-THC-predominant products and for balanced ∆9-THC/CBD preparations, although some data indicate that CBD-rich products also may provide pain reduction. Balanced products are also most effective in reducing spasticity in MS, and while most formulations show benefit in providing symptomatic benefits in reducing anxiety, nausea, and in improving sleep, the place of specific ∆9-THC or CBD-dominant and balanced products is more subtle and choice guided by specific circumstances.

Safety and tolerability would appear to be quite acceptable, a valid observation both for agents such as nabiximols [91, 92], and for the range of CBMP products in real-world use in cannabis registries [57, 58, 60, 116, 121, 125]. Although psychoactive and cognitive effects may be problematic in a small number of patients receiving ∆9-THC, this may be attenuated by concomitant CBD use [89, 167] and by gradual up-titration as described above [173, 181, 182]. Furthermore, in contrast to recreational cannabis use, where dependence is well documented [65, 183, 184], there seems little if any evidence from the larger cannabis registries in Israel and Australia involving more than 14,000 patients to indicate any such concerns with prescribed CBMPs [57, 58, 116].

One important finding in many real-world studies is that benefits were accompanied by reductions in symptomatic medication use and an increase of overall well-being. This was particularly observed for chronic pain populations where pain reduction was accompanied by substantial reduction in opioid use [57, 58, 117, 126, 131, 133]. However, data for the benefits of CBMPs in reducing opioid needs remain inconsistent. Some evidence commentaries [195], and a number of systematic reviews and meta-analysis have concluded that there is no evidence from randomized studies [111, 196]. However, one recent meta-analysis, which also evaluated observational study data, reported substantial impact on opioid use; the pooled prevalence for opioid reduction in observational studies being 85% (95% CI, 64–92.8%) while opioid cessation was found in 39% of patients (95% CI, 15–64%) [104]. In addition, a prospective study reporting the use of different ∆9-THC and CBD regimens over 6 months, in which with significant improvements in pain scores and QoL outcomes were observed, reported substantial reductions in opioid use, both in the number of patients using opioids and in dosage used [197]. However, one must be cautious when considering this issue. While some reduction in opioid use is observed in some patient populations (e.g., patients with chronic pain) when given medical cannabis/CBMPs, the supportive evidence for any such benefit is highly heterogeneous. Further research is necessary to inform clinicians on this matter. Furthermore, we do not suggest that medical cannabis or CBMPs be used specifically to reduce concomitant opioid use (although that may be a benefit for some patients).

All these patterns are important when considering the overall risk–benefit analysis accommodating symptomatic relief (and reduced symptomatic medication use), and broader benefits in improved well-being and QoL, with safety and tolerability aspects. Safety and potential for harmful effects remain a primary consideration when recommending and monitoring use of any medical cannabis product [61, 173]. One recent report from clinicians experienced in both pain management and/or CBMP use considered these elements within a multicriteria decision analysis model to evaluate comparative risks and benefits of a wide range of analgesics, including opioids of different potency, and of oral CBMPs in the management of chronic neuropathic pain [198]. It was observed that the most favorable benefit–safety balance was seen for CBMPs rather than conventional analgesics, with balanced products favored marginally over CBD-dominant or ∆9-THC-dominant products [198]. Nevertheless, there remains a need for further clinical studies, ideally RCTs, to better define the risk–benefit profiles of the many various CBMPs preparations in specific patient populations.

Conclusions

Through the present narrative review, it can be stated that findings from clinical studies and real-world data provide some evidence for the use of medical cannabis and CBMPs as an adjunctive therapy in some patients in a range of chronic conditions including neuropathic pain, multiple sclerosis, oncologic supportive care, and palliative care. Medical cannabis and CBMPs are generally well tolerated and with an acceptable safety profile. As use of these agents are likely to increase, the observations reported here can help inform physicians and other professionals on use in their daily practice.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Both Gérard Mick and Pascal Douek contributed to the conceptualization, review, and writing of the manuscript, take responsibility for the integrity of the work as a whole, and have approved the final manuscript for submission.

Funding

Laboratoires Boiron (Messimy, France) funded this review and all costs related to the development and publication of this manuscript, including the journal’s Rapid Service fee.

Data Availability

All data discussed and analyzed in this study are from publicly available peer-reviewed articles. Data were drawn from included articles in their original form and not modified. The original studies and investigators are duly cited in the reference list.

Declarations