Treatment with FCE was conducted by one of the authors (PMSS) in the clinical setting. Either during or after the end of each patient’s treatment, patients (and, when needed patient’s parents) were invited to take part in this study by answering an online cross-sectional, patient-reported outcome survey.

Invitations were sent to 178 patients (53 males and 125 females), yielding responses from 48 individuals. To minimize formulation variability, we focused on patients using formulations from the same two Patient Societies, resulting in a sample of 30 patients, 29 females and one male. Initially, we analysed data for all 30 patients; however, after further consideration, we decided to focus solely on female participants. To maintain consistency with our original ID system, we retained the numerical identifiers followed by the letter “f” to indicate female patients, ensuring accuracy when correlating data with our raw dataset. Specifically, the male participant was identified as “24 m,” while the female participants included in this report were labelled sequentially as ”1f,” “2f,” and so on, up to “23f,” then continuing from “25f” to “30f”. No action was taken to influence the sample composition in terms of CPS etiology. The 29 remaining participants, diagnosed with various ICD-11 designations for CPS, willingly enrolled in this report. Participation involved granting access to their clinical records (Supplementary Material S1) and responding to the patient-reported outcome survey (Supplementary Material S2).

Our cohort encompassed patients with diverse chronic pain etiologies and varied access to FCE formulations (whole Cannabis sativa L. inflorescence extract), leading to the individualized tailoring of the treatment protocol concerning FCE formulations and dosages. Initial formulation selection was guided by the patient’s main symptoms, comorbidities, and prior treatment history: CBD-dominant extracts were generally chosen for inflammatory or nociplastic pain, anxiety, seizure history, or metabolic concerns, whereas THC-dominant extracts were indicated when insomnia, nausea, muscle spasms, or insufficient analgesia under CBD-dominant regimens were prominent.

Treatment began with minimal dosages—typically 1 to 3 drops/day (corresponding to approximately 2–7 mg/day CBD or 0.5–2 mg/day THC, depending on extract concentration)—and was titrated upward every few days according to patient-reported symptom relief and side-effect profile. Dosages were fine-tuned over two to 4 weeks, with adjustments aiming to maximize benefit while avoiding undesirable side effects. Stabilization was achieved through consensus between physician and patient. In most cases, this resulted in maintenance doses of 15–30 drops/day (roughly 22–37 mg/day CBD and 8–11 mg/day THC), administered orally in three daily doses.

Dosage increments typically continued until either: 1) target symptom control was achieved, or 2) side effects emerged, prompting dose stabilization or reduction. When a single extract did not provide adequate improvement based on these criteria, a second extract with complementary cannabinoid dominance was introduced at a low dose, and the CBD: THC ratio was progressively adjusted until an optimal balance between efficacy and tolerability was reached. The decision to combine extracts was based on persistent symptoms (e.g., poor sleep, anxiety, residual pain) known, from pharmacological rationale and prior clinical experience, to respond to the other cannabinoid profile (e.g., adding THC-dominant extract for refractory insomnia or adding CBD-dominant extract to mitigate THC-related anxiety).

Monthly evaluations were conducted for a trimester, followed by six-monthly assessments once symptoms were stabilized; in exceptional cases, weekly reassessments and adjustments were necessary. The average CBD concentration at the treatment’s outset was 22.52 mg/day, increasing to 47.14 mg/day at the end, while the average THC concentration started at 8.23 mg/day and reached 11.32 mg/day at the conclusion. The average CBD: THC proportion for all patients was roughly 3.3:1. Ultimately, each patient arrived at an individualized dosage regimen (Table 1), as comprehensively described in Supplementary Material S1. In cases where treatment involved more than one oil type at the same time, final dosage of each cannabinoid was calculated adding their respective content per ml of each extract. All adjustments, including reasons for switching or combining extracts, are detailed in Supplementary Material S1, which shows for each patient the initial choice, criteria for change, and final stabilized regimen.

Most patients reported choosing to acquire their FCEs from non-industrialized civil patients’ societies for economic reasons. To minimize sample heterogeneity, we included only patients who used FCEs from two specific patients’ societies. Thus, the cannabis extracts used by patients in this study were either produced and sold by the Brazilian Society of Medicinal Cannabis Patients (AMAME) or by the Cannabic Society in Defense of Life (Maria Flor/MALELI). Depending on the society to which the patient was affiliated, the CBD-dominant FCEs had a CBD ratio of either 4:1 or 21:1, while THC-dominant FCEs had a ratio of either 1:38 or 1:22. Information on particular oils used and their cannabinoid proportions per patient can be found on Supplementary Material S1. The quality and cannabinoid concentrations of the FCEs were verified by independent laboratory analysis using high-performance liquid chromatography (HPLC). Thus, composition information was provided by the associations, along with documentation from these certified independent laboratories containing quality and composition analyses of samples from the different formulations used (Supplementary Materials S4, S5). Full CBD and THC concentrations from those certificates were used as values for calculation of each patient’s extract regimen.

We employed a structured, patient-reported, cross-sectional retrospective outcome survey sent by e-mail to the patients or their families (Supplementary Material S2). The survey structure was adapted from the epidemiological methodology previously used by Fleury and colleagues (Fleury-Teixeira et al., 2019). The survey consisted of multiple-choice questions about the perceived effects of FCE treatment in several symptoms and burden-related categories, in which we have employed a Likert-like scale (Joshi et al., 2015). Each question presented six possible answers: “Does Not Apply”, “Considerable worsening”, “Moderate worsening”, “No change”, “Moderate improvement”, and “Considerable improvement”. Apart from the “Do not apply” answer, numeric labels (-2, −1, 0, 1 and 2) were assigned to each answer.

It has been shown, by qualitative content analysis, that not all aspects considered important by chronic pain patients to their function and wellbeing are properly evaluated by standard questionnaires commonly used to assess the impact of chronic pain in their lives (Calmon Almeida et al., 2020). Calmon Almeida et al. (2020) results indicated that the patient’s perception of their physical capacity and ability to perform daily activities, as well as emotional and contextual factors, should be included in clinical assessments to fully understand chronic pain patient´s needs. Therefore, we have included in our Patients’ Self-Reported Outcome Survey questions concerning a wide range of core and comorbidities symptoms of CPS, as well as practical aspects to evaluate the effects of FCE treatment on both clinical and personal life burdens. We also included two multiple choice and two open-ended questions concerning the overall quality of life of the patients and their families, respectively. These later questions were analysed by Qualitative Content Analysis (see in the next section).

The survey inquired about the perceived FCE treatment outcome on 9 symptom categories and 6 additional aspects, as follows:

Pain episodes (PE);

These questions refer specifically to the effects observed after FCE inclusion in the patient’s treatment scheme. Most, but not all, patients were already using other medications to treat chronic pain before the inclusion of FCE. Data concerning side effects and use of other medications (categories 14 and 15) were obtained by a different type of multiple-choice questionnaire (see Supplementary Material S2) and complemented by information from the patients’ clinical files.

Invitations were sent to 178 (53 males and 125 females) potential participants and 48 of them agreed to take part in the research by answering our survey and giving their written consent for their chart’s information. Following the exclusion criteria described in Methods, the final cohort included a total of 29 CPS patients aged 27 to 84 (only females).

The participants were randomly assigned numeric labels followed by a letter, “f” for female (see methods for further explanation regarding the ID system). Details on all participants can be found in Table 1. ICD descriptors included under “Chronic Pain Syndromes” were M16, M25.5, M53.3, M54, M54.2, M54.4, M54.5, M79.1, M79.6, M79.7, M79.9, M89, G43 and G54, being defined as such by the physician according to clinical criteria. Six people interrupted treatment with FCE of their own accord: three of them had financial restrictions (6f, 15f and 28f), two of them felt pain had decreased enough to suspend FCE use (26f and 29f), and one stopped after medical recommendation due to concomitant treatment for bipolar disorder (20f). Thus, treatment duration ranged from 1 to 44 months (13 months, on average). The average weight of the cohort slightly decreased as cannabinoid concentrations used for treatment increased in comparison to initial proportions (Table 1). In only one case, 1f, the survey was answered by a third person. In Table 2 we provide the raw data from the survey answers of all participants about their perceived effects of FCE treatment. Responses were marked as a hashtag in cases when a given symptom/aspect did not apply to that patient. We have separated the 13 main categories addressed by multiple-choice questions in two subgroups: “Perceived symptomatic effects” and “Perceived personal life effects” (Table 2). Data about side effects and use of other medication are shown in Tables 7, 8.

Patients reported expressive improvement across all evaluated categories after FCE was included in their treatment scheme as an adjuvant or the only pharmaceutical treatment. We highlight that all patients reported alleviation on the intensity of “Pain episodes” (Figure 2), and most of them also reported subsequent/concomitant improvements on comorbid symptoms, as well as on personal life-related aspects (Table 2; Figure 2). Some level of improvement was reputed present whenever “Moderate improvement” (Mi) and/or “Considerable improvement” (Ci) was different from zero (Figure 2). “Moderate improvement” was the most frequent perceived outcome for most symptomatic categories: “Decreased libido or other sexual disfunctions” (Mi: 33%, Ci: 13%); “Memory and cognitive problems” (Mi: 42%, Ci: 21%); “Motor impairment” (Mi: 32%, Ci: 43%); “Distress and irritability” (Mi: 52%, Ci: 33%); “Anxiety crisis and/or panic attacks” (Mi: 48%, Ci: 30%); “Sadness, melancholy, and prostration” (Mi: 72%, Ci: 14%); “Persistent feeling of fatigue” (Mi: 70%, Ci: 15%); “Sleep issues” (Mi: 48%, Ci: 41%); and “Pain episodes” (Mi: 41%, Ci: 59%). Thus, in 8 out of 10 symptomatic categories 70%–90% of the patients perceived some level of improvement after FCE treatment. Only two categories, “Reduction of libido” and “Memory and cognitive deficits”, showed less frequent improvements, so that some improvement was perceived by 46% and 63% of the patients, respectively. The category “Memory and cognitive deficits” corresponded to most cases of worsening symptoms (8%). In two categories, “Pain episodes” and “Motor impairments”, the most frequent outcome was “Considerable improvement”. In only one category, “Decreased libido”, “No change” was the most frequent perceived outcome.

The subgroup of personal life-related categories presented a large percentage of some improvement and no cases of worsening (Figure 2): “Negative impacts over social and family relations” (Mi: 54%, Ci: 38%), “Inability to perform a professional occupation” (Mi: 44%, Ci: 52%); Overall quality of life of the patient (Mi: 21%, Ci: 72%); Overall quality of life of the family (Mi: 31%, Ci: 69%).

The responses to the two open-ended questions exploring the impact of FCE treatment on quality of life, initially provided in Brazilian Portuguese, underwent meticulous translation into English. The comprehensive translations are presented in their entirety in Supplementary Material S3.

We employed qualitative content analysis to delve into these open-ended responses, aiming to uncover the subjective and practical implications of CPS and assess the impact of cannabis-based treatment on both patients and their families’ quality of life. While the Patient-reported Outcome Survey comprises structured, multiple-choice inquiries covering predetermined clinical, functional, and personal dimensions, our focus here is on the unscripted insights spontaneously shared by patients. The qualitative content analysis allows us to gain a comprehensive understanding, directly from the patients’ perspectives, regarding the effects of both CPS and cannabis-based treatment on their own quality of life and that of their families. The data collected is devoid of predefined parameters, offering a holistic view that encapsulates the nuanced experiences and challenges faced by patients undergoing CPS and FCE treatment.

Although patients in our survey reported experiencing a range of side effects (see Table 7), these were consistently categorized as mild to moderate. Importantly, none of the patients discontinued FCE treatment due to side effects throughout the duration covered by this report. Typically, side effects were transient and predominantly manifested at the onset of treatment (see Table 8). Notably, seven patients reported no side effects during the reporting period. No distinct correlation was observed between the use of other medications and the severity of side effects reported by patients when responding to the Patient-Reported Outcome Survey. However, it is noteworthy that even the mild or moderate effects outlined in Tables 7, 8 could potentially be attributed to drug interactions. Most patients (93%) underwent treatment for 3 months or longer, suggesting stability in these results. However, it is important to acknowledge that beyond our data collection period, other potential side effects may emerge due to slower interactions with other medications. We will further address this matter in the discussion section.

Most patients (83%, n = 24 out of 29) were already taking traditional analgesics prior to starting FCE treatment (refer to Table 8). After starting FCE treatment, a considerable number of these patients (66%, n = 16 out of 24) reduced or discontinued their analgesic use, while a few patients (8%, n = 2 out of 24) switched to either duloxetine or a combination of lysine clonixinate and cyclobenzaprine, and some patients (21%, n = 5 out of 24) continued with the same analgesic dose. Only one patient (19f) increased the analgesic dose. Among the patients who were not taking analgesics before FCE treatment (n = 5), none of them added any medication during the treatment period. Additionally, 20 (69%) of all patients were taking medication for anxiety and/or mood disorders (see Table 8), and out of those, 10 (50%) patients reduced or completely stopped taking their medication after FCE treatment. One patient (2f) discontinued quetiapine, reduced pregabalin, and added duloxetine, while only one patient (19f) increased Pregabalin dosage. The remaining eight patients continued with the same dosage of their medication for anxiety and/or mood disorders.

The individually tailored FCE dosage scheme reported here presented tangible and significant benefits across all the CPS symptomatic categories in the presented cohort (14 different ICD descriptors). Our data were drawn from medical records and a comprehensive patient survey combining multiple-choice and open-ended questions. The open-ended responses were analysed using QCA, a method widely applied to clinical data—such as narratives, medical records, and interviews—to explore patient experiences and assess treatment impacts (Bardin, 2004; Fontanella et al., 2006; Lim et al., 2017; Urech et al., 2019; Greenfield et al., 2020; Faria-Schutzer et al., 2021; McKeon et al., 2021; Mattila-Rautiainen et al., 2023). QCA has been especially useful in chronic illness research (Dehghani et al., 2019; Calmon Almeida et al., 2020; Abaah et al., 2023; Lundin et al., 2023) by offering deeper insight into patients’ subjective perceptions and attitudes toward care (Pope and Mays, 1995; Fontanella et al., 2006; Campos and Turato, 2009; Schwieger-Briel et al., 2015; Lim et al., 2017; Calmon Almeida et al., 2020; Faria-Schutzer et al., 2021). In our study, QCA revealed that FCE treatment positively impacted patients’ practical and emotional lives, with benefits often extending to family members—even among those already using conventional medications.

Our exploratory, real-life approach provided a broader understanding of the potential benefits of FCEs across diverse CPS conditions (see Supplementary Material S1). Although mild to moderate side effects were reported, none were mentioned in the open-ended responses.

Chronic pain, the core CPS symptom, was alleviated to some extent in all 29 patients: 60% reported considerable relief, and 40% moderate relief (Figure 2). While placebo effects cannot be ruled out in this open-label study, several factors support a pharmacologically mediated therapeutic benefit. At the time of the survey, most patients (69%) had used FCEs for 6 months or longer (Table 1), and 83% had been on analgesics prior to FCE treatment (Table 8). Among these, 16 (66%) discontinued or reduced use and only one increased dosage. None of the five patients who were not previously on analgesics started new medications during treatment. These findings suggest the reported pain relief is unlikely to be solely due to placebo.

Psychological distress was the second most frequent symptom group. After FCE treatment, most patients reported improvements in categories such as cognitive problems (64%), distress/irritability (78%), anxiety (79%), melancholy (83%), fatigue (85%), and sleep disturbances (89%) (Figure 2). At baseline, 70% were already on mood or anxiety medications; half of them reduced or discontinued use post-FCE (Table 8). Only one patient increased medication dosage. Together, these results reinforce that the benefits perceived were probably not merely placebo-driven, but accompanied by tangible reductions in pharmacological burden and improvements in wellbeing. See Section 4.3 (Limitations) for a deeper discussion about placebo effect and other potential sources of response bias.

Our findings are in line with the scientific literature, both basic and clinical, that demonstrate an interconnected combination of positive effects of cannabinoids on both the pain itself and the comorbid psychological aspects typically observed in CPS. For instance, cannabis is known to have significant effects on the affective and higher-order perceptual aspects of pain (La Porta et al., 2015; Racz et al., 2015; Bajic et al., 2018; Mecca et al., 2021; van den Hoogen et al., 2021) due to the distribution of cannabinoid receptors in frontal-limbic areas such as the amygdala, raphe, and anterior cingulate cortex, all of which are involved in pain perception (Lee et al., 2013; Weizman et al., 2018). Alterations in the medial prefrontal cortex endocannabinoid signalling have been shown to be an important contributing factor to depression following persistent neuropathic pain in rats (Mecca et al., 2021). Constant, unrelenting pain can lead to anxious and/or depressive states (Kao et al., 2021; Meda et al., 2022; Nowinka et al., 2022; Rogers et al., 2022) and can prevent CPS patients from engaging in everyday activities, including socialization (Di Tella et al., 2015; Grabli et al., 2021). Chronic pain can also impact cognitive processes such as memory and attention (Moriarty et al., 2011; Phelps et al., 2021), leading to increases in polypharmacy to manage not only pain but also secondary problems arising from the main disorder. Indeed, a significant portion of medication expenses are allocated to addressing these issues (Kronborg et al., 2009; Phillips, 2009), which could be reduced with the introduction of FCEs as a treatment option (Bellnier et al., 2018; Erku et al., 2021).

It is important to notice, however, that cannabinoids exert a significant inhibitory effect on hepatic metabolic enzymes responsible for metabolizing various pharmaceutical drugs (Bornheim et al., 1993; Yamaori et al., 2011; Jiang et al., 2013; Yamaori et al., 2014; Engeleit et al., 2021; Vaughn et al., 2021), including certain antidepressants, potentially intensifying their effects (Anderson et al., 2021). This can occasionally lead to adverse effects (Nanan et al., 2022). Cannabidiol, specifically, has demonstrated less pronounced effects on the metabolism of sertraline, fluoxetine, and mirtazapine in vitro, but it significantly affects the metabolism of citalopram in humans, resulting in increased plasma concentrations (Anderson et al., 2021). While we have not observed any adverse effects clearly linked to this interaction, we cannot rule out the possibility that some side effects and/or the observed psychological improvements may be partially attributable to the influence of cannabinoids on antidepressant metabolism.

Cannabinoid signalling through either CB1 or CB2 receptors is central to the analgesic effect of cannabinoids on inflammatory pain (Zhang et al., 2003; Valenzano et al., 2005; Pernia-Andrade et al., 2009; Berger et al., 2014; Krustev et al., 2014; Zhang et al., 2014; Xu et al., 2016; Thompson et al., 2020; Park and Watkins, 2021; Bogdan et al., 2022). Accordingly, both THC and CBD has been shown to be effective in reducing persistent inflammatory or neuropathic pain in rodents (Britch et al., 2020; Mitchell et al., 2021). In further agreement with our results, studies have demonstrated that a combination of CBD and THC in FCE may be more effective for treating chronic pain (Longo et al., 2021), and a growing number of evidences support the use of cannabis-based medicines to treat psychological, social and functional aspects of pain and CPS-associated comorbidities (Jones et al., 1981; Pertwee, 1999; Aggarwal et al., 2009; Avello et al., 2017; Kosiba et al., 2019; Lake et al., 2020; Li et al., 2020; Stith et al., 2020; Feinstein et al., 2021; Gruber et al., 2021; Khurshid et al., 2021; Aebischer et al., 2022; Berger et al., 2022; Kuhathasan et al., 2022; Leung et al., 2022; Sachedina et al., 2022).

It is also important to underscore the significance of the individualized approach employed here in defining the FCE dosage scheme in each patient. Contemporary medicine is exploring the benefits of a more personalized approach that considers various aspects of a patient’s medical history, such as genetic profiles and comorbidities (Cortese, 2007; Cilli et al., 2022). This is particularly important in chronic conditions, where idiosyncrasies necessitate regular dose adjustments to optimize treatment progression and adherence (Cilli et al., 2022). Because the endocannabinoid system regulates both central and peripheral pain-related circuits, and cannabinoids can block spinal, peripheral and gastrointestinal mechanisms underlying pain, it has been proposed, with growing data support, that some pain-inducing conditions may be related to congenital or acquired reduction of endocannabinoid signalling tone (Russo, 2004; Smith and Wagner, 2014; Russo, 2016), which would concur to individual variability in the tonic state of cannabinoid receptors and endocannabinoid-metabolizing enzymes. Furthermore, since it has been shown that there is important genetic variability in the metabolization of phytocannabinoids (Hryhorowicz et al., 2018), and in the individual susceptibility to the effects of phytocannabinoids over drug-metabolizing enzymes (Bardhi et al., 2022), both pharmacokinetics and drug-drug interactions of phytocannabinoids are likely to vary significantly among individuals. All these considerations are of particular importance when considering cannabis use for treating various CPS conditions in female patients, since cannabinoid pharmacology related to pain exhibits sex-specific differences (Fattore and Fratta, 2010; Blanton et al., 2021; Santoro et al., 2021). Notably, pain perception, coping mechanisms, and general pharmacological sensitivity vary between male and female patients (Fillingim, 2002; Frot et al., 2004; Garofalo et al., 2006; Gallagher, 2010; Gazerani et al., 2021; Failla et al., 2023). Additionally, risk factors for certain CPS conditions—such as pregnancy, motherhood, and hormonal fluctuations across a woman’s lifespan—are specific to females (Wijnhoven et al., 2006; Fattore and Fratta, 2010).

Here, each patient ultimately reached a personalized dosage regimen tailored to their overall needs (Table 1). To facilitate comparisons between individual symptomatic outcomes and CPS subtypes (see Supplementary Material S1), we developed the General Outcome Score (GOS, see Table 2) as a composite measure reflecting both benefits and potential trade-offs. It may also be useful for analyzing side effects and changes in previously used medications (see Table 8). The lowest possible GOS is −2.0, and the maximum is 2.0. All patients showed a positive GOS, ranging from 0.4 to 2.0, with a mean of 1.08 ± 0.43, indicating that every participant reported greater satisfaction with their treatment following the inclusion of FCE. While the small sample size limits definitive conclusions, no clear relationship emerged between dosage levels, CBD/THC ratios, or treatment outcomes across different CPS subtypes (see Supplementary Material S1). Therefore, although our data do not support specific recommendations regarding optimal extract composition or dosage for each CPS condition, the findings suggest that treating chronic pain with an individualized dosage scheme and as a syndromic entity—rather than as isolated subtypes—can be effective. The flexible, individualized titration protocol evaluated here, therefore, successfully addressed a broad spectrum of symptoms, including pain, regardless of the CPS subtype.

While randomized clinical trials (RCTs) remain the gold standard in clinical research, they pose challenges for cannabinoid therapies due to the vast variability in cannabis formulations and the genetically influenced differences in individual responses. These complexities make standardization of dosages and compositions difficult and highlight the value of real-world evidence (RWE) during this still exploratory stage of cannabinoid research. RWE studies offer broader inclusion criteria, flexible dosing, and the ability to address syndromic conditions and comorbidities beyond narrowly defined core symptoms (Baumfeld Andre et al., 2020; Banerjee et al., 2022). They also enhance ecological validity and may detect long-term or rare side effects, which are often missed in controlled trials.

In our study, the real-life approach—employing personalized FCE dosages across diverse CPS conditions, with long-term use and psychosocial evaluation—was essential to capture therapeutic outcomes realistically. However, inherent limitations must be acknowledged (Crisafulli et al., 2023). Patients who experienced positive outcomes may have been more likely to complete the retrospective, cross-sectional online survey, introducing possible selection bias. Additionally, the absence of direct researcher-participant interaction during the survey process, while minimizing interviewer influence, meant that the survey data were based solely on self-reported subjective patient perception (except for side effects and other medications, which were complemented with information from clinical records).

Ultimately, pain, lack of libido, fatigue, and mood disorders, for instance, are internal, inherently subjective experiences, making them largely inaccessible to direct quantitative measurement—especially in their chronic forms. Therefore, self-reported outcome instruments are essential tools for assessing the efficacy of treatments for CPS and related mood or functional disorders, as they provide unique access to the patient’s pain experience and overall wellbeing (Mosko et al., 1989; Schierhout and Myers, 1996; Bovier et al., 2004; Cuijpers et al., 2010; Morso et al., 2011; Karibe et al., 2014; Altenstein-Yamanaka et al., 2017; Ohno et al., 2017; Murphy et al., 2018; Ben Tekaya et al., 2019; Vincent et al., 2019; Riddle and Reza Jafarzadeh, 2022; Turnbull et al., 2022; Eiger et al., 2024; Gupta et al., 2024; Huang et al., 2025). In fact, self-report measures are often regarded as the “gold standard” for evaluating pain-related outcomes, particularly when supplemented with objective indicators such as changes in the use of rescue treatments (i.e., additional medications or interventions) (Dworkin et al., 2005), as was done in this report.

Despite their strengths, self-reported outcome instruments pose notable methodological challenges. On the positive side, they are easy to administer, cost-effective, and capable of capturing nuanced, individual variations in symptoms that may escape clinical observation—provided they are carefully designed and clearly communicated to ensure patient comprehension (Turk et al., 2003; Turk et al., 2008; Patrick et al., 2011b; a). In the context of chronic pain research, such tools offer direct insights into pain intensity, affective distress, and the psychosocial and functional impacts on daily life—dimensions that are not adequately captured by physiological markers alone (Dworkin et al., 2005; Turk et al., 2016). Likewise, mood disorders such as depression and anxiety often manifest internally, making self-assessment scales crucial for diagnosis and monitoring (Kroenke et al., 2001).

In this study, we adapted elements from multiple instruments to develop a customized, multifactorial, yet simplified, Patient-Reported Outcome Survey. This tool was designed to allow patients to easily and simultaneously evaluate multiple aspects of their CPS using a unified, non-numerical scale (later translated into numeric scores for analysis). However, like all self-report tools—particularly those used in open-label or non-blinded designs, which is the case here—our instrument is susceptible to several sources of response bias. These include social desirability, recall inaccuracies, participant expectations, placebo effects, and behavioral changes stemming from participants’ awareness of being observed, i.e., the Hawthorne effect (Enck et al., 2013; Hrobjartsson et al., 2014; Shiozawa et al., 2014; Chiarotto et al., 2019; Wang et al., 2023). In our study, we relied on three key aspects to help mitigate these potential sources of bias: 1) the duration of treatment, which exceeded 6 months for most participants, likely reducing the influence of short-term placebo responses and patient expectations, as well as the impact of possible Hawthorne effect; 2) the observation of reduction in the use of other medications—both for pain and mood disorders—which offer supportive and objective evidence of treatment impact, and 3) the use of an online survey format, completed without any direct contact with physicians or researchers, which may have helped reduce social desirability bias as well as the Hawthorne effect.

The original treatment protocol was not designed as a research intervention, but rather as compassionate clinical care conducted by the physician. Lacking a standardized baseline, we developed a custom cross-sectional outcome survey to assess psychological, functional, and symptomatic aspects of CPS using a single response scale. Although this limits direct numerical comparisons with other studies, the use of a narrow scale enhanced comparability across patients and better captured the complexity of chronic pain syndromes as experienced individually. It also helped mitigate the limitations inherent in assigning numerical values to subjective perceptions—an issue particularly problematic given the significant influence of emotional states and hormonal levels on pain perception (Wijnhoven et al., 2006; Reicherts et al., 2013; Lumley et al., 2021). Thus, the focus of this study was not statistical generalization, but rather an in-depth understanding of patient-reported outcomes across multiple CPS presentations.

We also developed our own questionnaire to assess adverse effects associated with cannabis extract use because conventional instruments—such as the Common Terminology Criteria for Adverse Events (CTCAE), the UKU Side Effect Rating Scale, and the Systematic Assessment for Treatment Emergent Events (SAFTEE)—do not specifically address some acute or subjective effects commonly associated with cannabis, including red eyes, and the sensation of feeling high (Levine and Schooler, 1986; Lingjaerde et al., 1987; Trotti et al., 2003). Although often mild, these effects are clinically relevant when evaluating the tolerability of cannabinoid-based therapies. By including cannabis-specific symptoms, we aimed to enhance the ecological validity of our study and provide a more comprehensive picture of real-world patient experiences.

Furthermore, our questionnaire captured not only the presence of adverse effects but also their intensity (mild, moderate, or severe) and temporality (transient vs. persistent). This level of detail is typically absent from standard instruments, which tend to focus on general or class-specific events and rarely incorporate patient-centered measures of symptom duration or subjective severity. We believe our approach yields a more nuanced and clinically meaningful profile of tolerability, supporting better-informed therapeutic decisions in real-life settings.

Finally, our Patient-Reported Outcome Survey has not yet undergone formal psychometric validation for use as a generalizable statistical instrument to support comparisons across different studies. This represents an important next step in our research agenda, but it falls beyond the scope of the present article.