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PLOS One logoLink to PLOS One
. 2024 Jan 31;19(1):e0296698. doi: 10.1371/journal.pone.0296698

Danish dog owners’ use and the perceived effect of unlicensed cannabis products in dogs

Pernille Holst 1,*, Annemarie Thuri Kristensen 1, Maja Louise Arendt 1,*
Editor: Lucy J Troup2
PMCID: PMC10830036  PMID: 38295012

Abstract

The interest in the use of medical cannabis has increased in recent years in both human and veterinary fields. In Denmark, there are no veterinary-licensed medical cannabis or cannabinoid supplements, and it is illegal to prescribe or sell cannabinoids intended for the treatment of veterinary patients. This study aimed to explore the unlicensed cannabinoid use in Danish dogs, by questioning dog owners about usage, indication for use, way of purchase, and their perceived effect of the cannabinoid treatment. An anonymous online survey was distributed via social media. The total number of respondents were 2,002, of which 38% indicated using or having administered cannabinoids to their dog. The majority of the respondents confirming the use of cannabinoids (93%) had used cannabidiol drops/oil and only few (4%) reported using Δ9-tetrahydrocannabinol-based products. Most owners (67%) purchased the products online. The three most common indications for use were pain alleviation, behavioural issues, and allergy. When asked about the respondent-perceived effect the majority reported a good or very good effect. The indication with the highest percentage of owner-perceived positive effect (77%) was pain alleviation. This study shows that, despite no licensed veterinary cannabinoid products being available in Denmark, dog owners do supplement their dogs with cannabinoids and the majority of these perceive that the treatment had a positive effect. This supports the need for more evidence-based knowledge in veterinary cannabinoid therapy.

Introduction

In recent years, the use of medical cannabis has received renewed interest in both human and veterinary medicine. After the discovery of the endocannabinoid system in the late 1980s [1], researchers have been exploring the system as a potential treatment target [2]. Cannabis is the popular name for the plant Cannabis sativa and products derived from the plant. Cannabis sativa contains over 100 cannabinoids with cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) being the two main cannabinoids [3]. In human medicine, a substantial amount of clinical research concerning medical cannabis has been conducted and is currently ongoing. A search in the WHO International Clinical Trials Registry Platform in September 2022, showed 265 active clinical trials registered [4]. Several pre-clinical and pharmacokinetic studies on veterinary cannabinoids have been conducted [518] but only a limited number of clinical trials in dogs have been published. The majority of studies have focused on investigating the effects of cannabinoids on osteoarthritis-related pain, but there have also been reports of studies on idiopathic epilepsy, behavioural modification, and canine atopic dermatitis [16, 1931].

There is an increasing availability of commercial cannabis-based extracts, nutraceuticals, supplements, feed additives, and treats aimed at companion animals. Unlike medical products, these types of cannabis-based products are not subject to regulation, including standardized evaluation of cannabinoid quality and quantity, screening for contaminants, and microbial testing. In a market review by Bonn-Miller et al. (2017), the content and labelling of 84 commercially available CBD extracts on the US market were analyzed. Of these, only 32% correctly labeled the actual CBD content, with 42% of products being under-labelled, and 26% being over-labelled. In addition, non-labelled cannabinoids, including THC, were found in up to 20% of the products [32]. Similar results have been reported in commercially available CBD extracts in the European Union, with some products containing potentially hazardous contaminants and most lacking information about THC content [33]. A study by Wakshlag et al. (2020) analyzed the content of THC, CBD, other selected cannabinoids, terpenes, and heavy metals in 29 full-spectrum commercially available veterinary products. They found that only 10 of the 29 products fell within 10% of the label claims regarding cannabinoid content, and 4 of the 29 products contained heavy metals [34]. When dog owners self-prescribe these unregulated CBD products, the lack of consistency in labelling content poses a significant challenge to accurately determining dosage and assessing effects. In the worst-case scenario, this inconsistency may pose a health risk to the dog, particularly concerning THC and heavy metal intoxication. In Denmark recreational cannabis is prohibited, and medical cannabis has been illegal up until 2018 when a national pilot programme was passed by the Danish government, allowing human physicians to prescribe medical cannabis for certain indications. The purpose of the programme was to enable the prescription of medical cannabis to patients experiencing a lack of effect from conventional therapy. Veterinary prescription is not included in the programme [35]. In Denmark, there are no approved veterinary medical cannabis products, and no veterinary cannabinoid supplements or feed additives are registered by the Danish Veterinary and Food Administration, Ministry of Food, Agriculture and Fisheries. As a result, it is illegal to sell or prescribe cannabinoids for the treatment of veterinary patients. There are many anecdotal reports on the use and effect of cannabinoid products for various health conditions in companion animals. Three surveys have investigated the use of veterinary cannabinoids among companion animal owners in the US and Canada. The results showed that the most frequent reasons for use were managing seizures and pain, and there was a generally positive perception of its effectiveness by the owners [3638].

This study aimed to investigate the use of unauthorized cannabinoids in Danish dogs, including indications for use as well as the owner-perceived effect. An underlying incentive was furthermore to provide information on indications with high owner-perceived effects, which future academic research could build upon. Given the lack of legal veterinary cannabinoid products, an anonymous survey was deemed the most appropriate method to obtain this information.

Material and methods

Survey

The questionnaire was developed, and the data was collected using the survey platform SurveyXact by Ramboll, (Rambøll, Denmark). A pilot questionnaire was designed and reviewed by the co-investigators and was tested by staff at the University of Copenhagen, Denmark. Feedback was provided in an iterative process and the questionnaire was refined to eliminate inappropriate branching, improve flow, and correct misleading response options. The study was approved by the Ethical and Administrative Committee, Department of Veterinary Clinical Sciences, University of Copenhagen (study identification number EAU:2020–20).

Participants were selected by convenience sampling. The open survey was advertised via the Facebook page of the University Hospital for Companion Animals, University of Copenhagen. In addition, various dog societies and breeder associations were contacted, and they shared the survey link via their social media platforms.

An introduction with the aim of the study, the number of questions, the expected time for completion, and a declaration of anonymity were provided at the beginning of the questionnaire. The survey consisted of a maximum of eight structured questions in a branching series with only relevant questions being displayed based on the respondent’s reply to previous questions. Upon completion of the questionnaire, the respondents agreed that the data could be used for research and publication. The full questionnaire can be viewed in S1 Appendix. All data were collected anonymously, and no personal data were collected or stored. The online questionnaire was available from July 2019 to November 2019.

Demographic variables

The first two questions included demographic variables including which area in Denmark the respondents were located (greater Copenhagen, northern Zealand, other Zealand, Funen, northern Jutland, central Jutland, southern Jutland, islands) and what their dog weighed in kilograms (small < 10 kg, medium 10–20 kg, large 20–30 kg, extra-large/giant >30 kg).

Cannabinoid use, product type, indication and way of purchase

The respondents were questioned about their use or past use of cannabinoid products for their dogs. Those who confirmed usage were directed to a subsequent section containing more detailed inquiries and were asked (a) what type of product/s they had used (CBD drops/oil, CBD capsules, CBD ointment/cream, CBD powder, CBD spray, products primarily containing THC, cannabis tea, other formulations of cannabis/hemp products). The last option had an open-ended text box where the respondents could add-in additional information on cannabinoid formulations/types not covered by the questionnaire. Respondents could select more than one indication; (b) for which indications they used cannabinoids (treatment of cancer, treatment of pain, treatment of poor appetite, treatment of gastrointestinal disease or clinical signs, disease prevention or well-being purposes, treatment of allergy, treatment of seizures). Additionally, there was an open-ended text box for alternative indications. Respondents could select more than one indication; (c) if they experienced an effect of the treatment (very convincing and good effect, convincing with some effect, possible but not convincing effect, no effect); (d) where they purchased the cannabinoid product (internet, pharmacy, herbalist, abroad, at a market). For alternative or elaborate answers an open-ended text box was available. All open-ended text boxes were checked for answers which should have been included in the predefined categories and the data was adjusted so they were included in the appropriate predefined categories.

Use of other herbal remedies

All respondents, regardless of their response to the use of cannabinoids, were asked if they had treated their dogs with other herbal remedies.

Statistical analyses

Descriptive and simple percentage data were collected via SurveyXact by Ramboll (Rambøll, Denmark) and figures were generated in GraphPad Prism version 8.00 for Windows (GraphPad Software, La Jolla, California, USA). The survey data were downloaded into IBM SPSS 26 (IBM, New York, USA) for statistical analysis. As not all respondents replied to all questions and some questions had the option of multiple answers, there is a difference in total sums between questions. The percentages were calculated based on the total number of responses to the individual questions. The association between the categorical variables “geographic location” and “the choice to treat with cannabinoids” was assessed using a chi-square test. Binomial logistic regression analysis was performed with 95% confidence intervals to determine the odds ratios for cannabinoid use in the geographic regions. The statistical analysis for indication and owner-perceived effect of treatment was performed using the non-parametric Kruskal-Wallis test followed by a post-hoc test using Dunn’s test applying Bonferroni correction for multiple testing. For all statistical analyses, a P value less than 0.05 was considered statistically significant. The inclusion criteria for participation were dog owners in Denmark, and all non-completed questionnaires were excluded from the analysis.

Results

Out of 2,091 respondents who initiated the survey, 2,002 respondents completed the survey for a completion rate of 95.7%. Only completed surveys were included in the analyses.

Demographics

The crude demographics showed respondents were concentrated around the two largest cities in Denmark (capital region, n = 1,044, 52% and central Jutland, n = 343, 17%). The weight of the respondents’ dogs was distributed as 24% (n = 486) being under 10 kg, 24% (n = 470) between 10 and 20 kg, 25% (n = 501) between 20 and 30 kg, and 27% (n = 545) over 30 kg (Table 1).

Table 1. Demographic characteristics of the respondents.

Demographic characteristics Respondents
n %
Completed questionaires 2,002 96
Partial completed questionaires 89 4
Location
 Greater Copenhagen (Capital region) 430 22
 Northern Zealand (Capital region) 209 10
 Other Zealand (Capital region) 405 20
 Funen 190 10
 Northern Jutland 186 9
 Central Jutland 343 17
 Southern Jutland 188 9
 Islands 51 3
Dog weight
 Small < 10 kg 486 24
 Medium 10–20 kg 470 24
 Large 20–30 kg 501 25
 Extra-large or giant >30 kg 545 27

Use of cannabinoid products for dogs

Of the 2,002 completed questionnaires, 752 (38%) respondents reported having used at least one cannabinoid product for their dog, while 1,250 (62%) had never used such products. A chi-square test was used to assess the association of living area, with the reporting of treatment with cannabinoids, and a significant association was found (X2 (7, N = 2,002) = 16.61, p = 0.020). Binominal logistic regression revealed that living in greater Copenhagen was negatively associated with cannabinoid use in dogs, with the respondents having an odds ratio of 0.69 related to using cannabinoids (P = 0.04, OR 0.69, 95% CI = 0.48–0.98).

Cannabinoid formulation and type

Out of the 752 respondents who reported having treated their dog with at least one cannabinoid product, the most commonly used product was CBD drops/oil, used by 697 (93%) respondents. CBD ointment/cream was the second most commonly used product, used by 67 (9%) respondents, while CBD capsules and spray were used by 29 (4%) and 27 (4%) respondents respectively. CBD powder was used by seven (1%) respondents. Thirty-six (5%) respondents indicated having used other cannabinoid or hemp formulations and 33 (4%) reported experience with the use of products primarily containing THC. Of all the respondents confirming the use of cannabinoids, 113 (15%) had used more than one cannabinoid formulation or type, with the majority having tried two different formulations or types. Three respondents indicated having tried four different cannabinoid formulations or types. The evaluation of 36 open-ended text box answers showed that 15 of the responses should have been included in the predefined categories. When adding these (six CBD oil, two CBD cream, and seven CBD capsules) to the appropriate categories, the overall frequencies were not affected. The open-ended text boxes also revealed additional cannabinoid formulations and types not included in the predefined categories. The most common were hemp oil (n = 12) and hemp seed oil (n = 4), followed by homemade mixtures (n = 2) and hemp tablets (n = 1). There were also two unusual responses, one related to ‘secondary marijuana smoke inhalation’ and another to ‘marijuana mixed with food’.

The indication for the use of cannabinoids

Pain management was the most common reason for using cannabinoids, with 36% (n = 376) of respondents reporting this as a reason. The second most common indication was allergy (11%, n = 122), followed by disease prevention/well-being (9%, n = 100) and seizure control (4%, n = 40). Of the inappropriate free text responses nine respondents recorded “epilepsy” in the free text and not in the predefined category “seizure control”. Similarly, eight respondents recorded “well-being” as free text, instead of indicating “disease prevention or well-being purposes” in the predefined category. Two additional major categories of indication were identified from the 28% (n = 299) of respondents who typed in other indications as free text. These were “behavioural issues” (n = 154), and “dermatological disease” (n = 34). Overall, the behavioural issue category was the second-largest indication group and included conditions such as anxiety, stress, fireworks-, and thunder phobia. The remaining indications were miscellaneous and included: neurological disease including dementia, intervertebral disc disease, and meningitis (n = 21); respiratory disease including pneumonia, cough, and excess sputum production (n = 12); cancer including treatment of splenic tumor, of an undiagnosed tumor, and cancer prevention (n = 3), palliative purposes (n = 5); reproductive issues including stimulation of neonatal weight gain, stabilizing hormonal status in a pregnant bitch, and mastitis (n = 2); immunological disease including autoimmune disease (n = 2); as an anti-inflammatory agent (n = 2); renal disease (n = 2); pancreatitis (n = 1); heart disease (n = 1); prostatic disease (n = 1); as bacteriostatic agent (n = 1); immune-stimulation (n = 1), and prevention of medical side effects from other treatments (n = 1). The corrected distribution of indications for cannabinoid use is reflected in Table 2, which considers the adjustments made to the categorical sums.

Table 2. The distribution of the indications for which owners administered cannabinoids to their dogs.

Indicationsb Responses
n %
Pain 403 39
Behavioural issue 154 15
Allergy 122 12
Disease prevention or well-being 108 10
Cancer 71 7
Seizure 49 5
Gastrointestinal disease 35 3
Dermatological disease 34 3
Poor appetite 19 2
Other 42 4
Total 1,037a 100

a The respondents (n = 752) could choose more than one indication for cannabinoid use, explaining the total number of indications being 1,037.

b Corrected and adjusted for inappropriate free-text registrations.

Owner-perceived efficacy of cannabinoid treatment

Out of the 752 respondents who had used cannabinoids for their dogs, 48% (n = 363) reported a “very convincing and good effect”, 29% (n = 217) indicated “convincing with some effect”, whilst 18% (n = 137) were uncertain of the effect (“possible, but not convincing effect”), and only 5% (n = 35) reported observing “no effect”.

Difference in owner-perceived efficacy between indication groups

When analyzing the indication-specific owner-perceived effect of the cannabinoid treatment, only respondents reporting one treatment indication were included, as it was not possible to distinguish the effect between various indications. Of the 752 respondents confirming use of cannabinoids, 69% (n = 516) used cannabinoids for only one indication and the majority reported some degree of effect. For the three largest indication groups, pain management (n = 249), behavioural issue (n = 103), and allergy (n = 47), the perceived overall effect was high (Table 3).

Table 3. The owner-perceived effect of cannabinoid treatment in different indication groups.
Owner-perceived effect Pain Behavioural issue Allergy Cancer Seizure Well-being Gastro-intestinal disease Dermato-logical disease Other Appetite Total
Very convincing and good effect n 113 39 14 19 16 10 8 4 4 1 228
% 45 38 30 54 47 40 80 67 67 100 44
Convincing with some effect n 80 30 13 6 4 5 1 2 2 0 143
% 32 29 28 17 12 20 10 33 33 0 28
Possible, but no convincing effect n 43 25 16 8 10 10 1 0 0 0 113
% 17 24 34 23 29 40 10 0 0 0 22
No effect n 13 9 4 2 4 0 0 0 0 0 32
% 5 9 9 6 12 0 0 0 0 0 6
Total n 249 103 47 35 34 25 10 6 6 1 516

The respondent group using cannabinoids for pain management reported the highest percentage of perceived effect. Seventy-seven percent (n = 193) indicated either “very convincing and good effect” or “convincing with some effect”. Only five percent (n = 13) reported “no effect”, and 17% (n = 43) were unsure of the effect (“possible, but not convincing effect”). For behavioural issues, the majority (67%, n = 69) observed an effect. Nine percent (n = 9) reported “no effect”, and 24% (n = 25) reported a “possible, but not convincing effect”. When used for treatment of allergy, 57% (n = 27) reported a positive effect with an equal distribution of “very convincing and good effect” (30%, n = 14) and “convincing with some effect” (28%, n = 13). When the categories for effect in the allergy group were analyzed individually, the largest number of respondents were in the category “possible, but not convincing effect” with 34% (n = 16) indicating a lack of obvious effect. Nine percent (n = 4) reported “no effect”. The remaining indication groups had low total respondent numbers (n = 1–25). The indication that had the highest percentage of owners not perceiving any effect (12%, n = 4) was when used for seizure control (n = 34). As differences in the owner-perceived effect between the indication groups could reflect a true difference in response to treatment of different disease states a Kruskal-Wallis test was performed and provided weak evidence of a difference χ 2(9, N = 516) = 19.808, p < 0.019, E2 = 0.40. A multiple comparison post hoc test with a Dunn’s test did however not show any significant differences in perceived effect between the indication groups (p >0.05, adjusted using the Bonferroni correction).

Purchase

The majority of respondents (67%, n = 507) purchased the cannabinoid product online, 6% (n = 42) purchased the product abroad, 3% (n = 22) from a herbalist, 2% (n = 14) from a market, and no respondents used a human licensed medical product purchased from a pharmacy. Twenty-two percent (n = 165) of the respondents additionally indicated a free-text option and indicated purchase through private traders (n = 45), retailers (n = 40), veterinarians (n = 20), alternative therapists (n = 20), and other (n = 39). Of the 20 respondents purchasing cannabinoid products through veterinarians, indications for use were: pain management (n = 12), behavioural issue (n = 6), cancer (n = 4), appetite stimulation (n = 1), kidney disease (n = 1), and allergy (n = 1).

Use of other types of herbal remedies

In total, 30% (n = 609) of all respondents had used other herbal remedies. Of these, 44% (n = 265) had also used cannabinoids. The herbal remedies most often reported were aloe vera, Bach® Original Flower Remedies, Kalm (ScanVet Animal Health A/S) (l-tryptophan, milk protein, vitamin B and l-theanine), fish oil, homoeopathy, green-lipped mussels, chondroitin, hyaluronic acid, glucosamine, pro- and prebiotics, psyllium, valerian root, and yeast extracts. A complete overview of used herbal remedies is listed in S2 Appendix.

Discussion

The study explored the use and perceived efficacy of cannabinoid treatment in dogs in Denmark. The results indicate that cannabinoids are used for a variety of reasons, and most are purchased online. The majority of respondents perceived that the treatment improved their dogs’ medical condition or well-being. Despite the lack of licensed cannabinoid-containing products for pets, and even though it is illegal to sell or prescribe cannabinoids for animals in Denmark, this survey of over 2,000 dog owners found that 38% of the respondents had used a cannabinoid product. Three prior surveys in the US and Canada have explored the use and owner-perceived efficacy of cannabinoids among dog owners with sample sizes of 106, 632, and 1,068 [3638]. The proportion of dog owners using cannabinoids was higher in the previous US and Canadian studies (79.8% and 78.3%) compared to the current Danish study [36, 38]. The difference may be due to study selection bias or the difference in the availability of cannabinoid products in North America and Denmark. In Denmark, the recreational use of cannabis is illegal, and human medical cannabis prescription is in its infancy, which may affect owner’s awareness and willingness to use cannabinoids in their dogs. This assumption is supported by a Slovenian study which found a slight association between owners’ personal experience with cannabinoid and their use in pets [39].

The most often stated indications for cannabinoid treatment were pain management, behavioural issues, and allergy. Similar results were reported in the North American surveys, where pain management, anxiety, and inflammatory disease were the most common indications [36, 38]. Besides these indications, the respondents reported a very large range of indications for which they used cannabinoids.

The majority of dog owners perceived a positive effect of the cannabinoid treatment for various indications. This could be due to a placebo effect or selection bias, or it could reflect a real therapeutic effect or improved quality of life for the treated dogs. However, there are no veterinary clinical trials to support or refute these findings for indications other than osteoarthritis-related pain, noise-induced anxiety, aggression, voluntary activity, canine atopic dermatitis, and seizures [16, 1924, 2628, 30, 31]. The indication with the highest owner-perceived efficacy was pain management where 77% experienced a positive effect with the majority reporting an obvious and good effect. The most common cannabinoid used in this group was CBD. Support for beneficial effects of CBD in the management of osteoarthritis-related pain in dogs has been reported in three double-blinded, randomized clinical trials [16, 20, 24]. Gamble et al. (2018) performed a randomized, placebo-controlled, cross-over, and double-blinded study with administration of 2 mg/kg CBD every 12 hours in 16 dogs. At two and four weeks into treatment, the Canine Brief Pain Inventory (CBPI) and a Hudson activity score showed a decrease in pain and an increase in activity compared to baseline (p < 0.01). The subjective veterinary clinical assessment in the study also showed a decrease in pain scores from baseline (p < 0.02) [16]. Similar findings were reported by Verrico et al. (2020) who investigated the effect of two CBD doses and liposomal CBD in 20 dogs with osteoarthritis-related pain. They found a decrease in pain estimated by the Helsinki Chronic Pain Index (HCPI) (p <0.01) in dogs treated with either 1.2 mg/kg/day CBD or 20 mg/day liposomal CBD [20]. Only one double-blinded, cross-over, and placebo-controlled study has used objective evaluation methods in addition to the subjective Clinical Metrology Instruments (CMI) in the investigation of the effect of 2.5 mg/kg CBD every 12 hours in osteoarthritis-related pain. Even though they found similar results in the subjective measurements (Liverpool Osteoarthritis in dogs and CBPI) as in the two previous studies, the objective measurements from accelerometry and objective gait analysis with pressure-sensitive walkway did not identify a significant difference between CBD and placebo groups after 6 weeks of treatment [24]. The disparity between the results from owner-driven subjective assessment tools (CMIs) and the objective assessment methods could indicate that the observations are reflections of CBD’s effect on other factors influencing the quality of life (better quality of sleep, reduced anxiety, better ability to cope with pain) than a true analgesic effect. Recent systematic reviews and meta-analyses’ have been conducted in the human field investigating the efficacy of cannabinoid treatment in different pain phenotypes. When evaluating the cannabinoid efficacy in chronic non-cancer pain patients, moderate quality of evidence for a small beneficial effect was reported [40], whilst when used in adult cancer-related pain patients the conclusion was that the effect of cannabinoids in addition to opioid treatment did not reduce pain in these patient phenotypes [41]. In our study, it was not possible to recognize which pain phenotypes (inflammatory pain, neuropathic pain, cancer-induced pain, chronic pain, acute pain) the owners were treating, but if dogs experience the same pain phenotypes as is described in humans, there might be certain subgroups of dogs in which cannabinoids are more effective than others. In contrast to the veterinary studies the human studies are based on cannabinoid products containing both CBD and THC, which could affect the outcome and efficacy of pain management. The second largest indication category was behavioural issues which included but was not restricted to treatment of anxiety, stress, firework- and thunder phobia. The owner-perceived effect of CBD treatment was high (67%). These findings are not supported by current studies investigating behavioural modification in dogs after CBD treatment. One study investigated the effect of 1.25 mg/kg CBD daily on aggression and stereotypic behaviour and did not recognize a difference between the treatment group and placebo group (p = 0.078) [23]. A second study aimed to investigate the effect of 0.7 mg/kg CBD every 12 hours on firework phobia and did not register any anxiolytic effect (plasma cortisol levels, pulse, anxiety-related behaviour) after the CBD treatment [22]. Interestingly the category with the highest percentage of owners not observing an effect was in the seizure group where 12% reported no effect. McGrath et al. (2019) published the first clinical trial using 2.5 mg/kg CBD every 12 hours as adjunctive therapy in epileptic dogs and reported a reduction in seizure frequency in the treatment group compared to the placebo group (p <0.01). Supporting these findings is a study by Garcia et al. (2022) who reported a 50% reduction in epileptic activity in six out of 14 dogs when treated with 2 mg/kg CBD compared to no reduction in epileptic activity in the placebo group (p = 0.02) [31]. The relatively high percentage of perceived lack of effect compared to other indications in our study could reflect several causes. The seizure group had few individuals compared to the pain management and behavioural issue group as well as seizure activity can be a very obvious clinical sign that is difficult to neglect or overlook by the owner. Clinical signs in the other categories can be relatively difficult to assess for owners and may even be overlooked and could thereby have been perceived as treatment effects by the owner.

One surprising finding was that 20 respondents indicated that they had purchased cannabinoid products through their veterinarian. The veterinary market in Denmark is highly regulated and it is illegal for a veterinarian to prescribe cannabinoids. The indications for use of the veterinarian-prescribed cannabinoids were pain management, behavioural issues, cancer, appetite stimulation, kidney disease and allergy. Even though many in vitro and in vivo studies have shown promising tendencies for treatment of all of the above-mentioned indications [42, 43], it is only the use in osteoarthritis-related pain management, canine atopic dermatitis and behavioural issue that is evidence-based and supported by canine clinical trials [16, 20, 22, 23, 28, 30].

Our study suggests that CBD drops/oil are the most popular type and formulation of cannabinoids and was used by 93% of the respondents confirming use of cannabinoids. It is not possible from the survey to identify the precise cannabinoid content or concentration in the used products. None of the respondents indicated using registered human medical cannabinoid products, which are the only products with controlled and documented cannabinoid content legally available in Denmark. A concern with the use of unauthorized cannabinoid products is the lack of content specification and batch analysis. The reported products in this study have the potential of not containing any cannabinoids. It has been documented that a discouraging number of veterinary products labelled as containing specific types and amounts of cannabinoids, had divergent content [34]. Furthermore, some respondents indicated using pure hemp seed oil which does not contain cannabinoids except if contaminated [44]. The uncertainty of content in the cannabinoid products is challenging for both dosing recommendations and effect evaluation, especially because the appropriate therapeutic dose could vary for different medical conditions. For seizure control in dogs, there is an indication that plasma concentration levels correlate with the effect [21], just as it has been shown that low-dose CBD (0.5 mg/kg/day) did not have the same positive effect on pain scores as higher CBD (1.2 mg/kg/day) concentrations [20]. Besides the challenges in dose recommendations and effect evaluation when using products with either unknown or varying cannabinoid content, it is especially critical regarding the THC concentration. Dogs are more sensitive to the psychoactive properties of THC compared to humans, possibly due to larger quantities of CB1 receptors in the brain, which can lead to high morbidity rates when exposed to THC [45]. In our study, very few reported intentionally using products primarily containing THC (4%).

Our study found that respondents living in Greater Copenhagen (Capital area) were less likely to supplement their dogs with cannabinoids. The reason for this is not clear, but it could be speculated to be linked to the higher educational level of the general population in this area, making these owners more adherent to evidence-based therapies, and less motivated for “alternative treatments”. This statement is however contradicted in the Slovenian study which did not find owner educational status as a predictor of treating pet animals with cannabinoids [39].

The authors would like to address some of the limitations of this study. First, it should be emphasized that this survey of owner-perceived effects should not be seen as a validation of the efficacy of any of the mentioned cannabinoid formulations or types. The study was designed as a short simple questionnaire for distribution via social media to secure as many respondents as possible. The potential bias with this type of self-selected convenience sampling is that dog owners with very strong opinions for or against cannabinoid use could be more motivated to participate (selection bias) and caution should be taken in concluding that this is a true representation of the general population. Secondly, the recognition of treatment effect is based on owner observations with a lack of standardized efficacy evaluation tools and without placebo or control groups (detection bias), resulting in a risk of reporting high numbers of both placebo and nocebo effects. Furthermore, the survey does not consider the owner’s capability to evaluate medical conditions and responses. Lastly, the treatments reported are not standardized or even documented regarding cannabinoid profile, content, or dosage.

Conclusion and perspectives

Danish dog owners administer cannabinoids for a broad range of different medical and behavioural conditions, despite no legal products being available on the Danish market. The majority of the owners perceive a very good or good effect of the cannabinoid treatment, especially when used for pain management. Most owners purchase the cannabinoid product online and most often use CBD drops/oil.

While caution must be exercised in interpreting the results, this study supports the need for more evidence-based knowledge within the companion animal field of cannabinoids, as some dog owners self-prescribe cannabinoids for a wide variety of medical conditions in their dogs. Pet owners do request information on cannabinoid products and currently, it is challenging for veterinarians to provide evidence-based information and dosing recommendations. Pet owners are to a high degree left to seek information and recommendations from commercial websites, family, friends, or anecdotal sources, which may not be factual or impartial.

As the majority of studies have focused on osteoarthritis-related pain, it is possible that cannabinoids may have a therapeutic rationale for additional veterinary indications or health-related conditions, not yet explored. Based on the findings of this study the authors suggest conductance of larger double-blinded, randomized and controlled clinical and dose-escalating trials, especially in areas of different pain phenotypes, behavioural modulation, and allergy. Future studies should be conducted using quality-controlled products with defined and documented cannabinoid content, profile, and concentrations and importantly should include objective assessment methods.

Supporting information

S1 Appendix. Survey questionnaire.

The questionnaire has for this publication been translated from the original survey language (Danish).

(PDF)

S2 Appendix. Overview of reported use of herbal remedies by respondents.

The list has for this publication been translated from the original survey language (Danish).

(PDF)

S1 File. Dataset.

(XLSX)

Acknowledgments

The authors would like to acknowledge and express their sincere thanks to Assistant Professor Anna Mueller, DVM, Ph.D. for input and management of the recruitment advert on the University Hospital for Companion Animals’ Facebook page enabling the high respondent numbers, to the Danish Kennel Klub and their magazine “Hunden”, as well as our veterinary colleagues who distributed the online survey and not least to all the Danish dog owners who showed interest and contributed to the study. We would also like to thank the Section of Biostatistics, Statistical Advisory Service, University of Copenhagen for their assistance with the statistical analysis.

Data Availability

All relevant data are within the manuscript and its Supporting information files.

Funding Statement

The author(s) received no specific funding for this work.

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Decision Letter 0

Lucy J Troup

20 Oct 2023

PONE-D-23-05678Danish dog owners’ use and the perceived effect of unlicensed cannabis products in dogsPLOS ONE

Dear Dr. Holst,

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Reviewers' comments:

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Comments to the Author

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: First it should be noted I am not well versed in qualitative studies.

Research regarding the relationship between dogs and cannabinoids is in its infancy. Studies which aim to understand this relationship are extremely important. This study does a good job at beginning to highlight how and why cannabinoids are used on dogs in Denmark, and acts as an introduction to guide further research. Authors did an excellent job detailing the limitations of this study. Their inferences were conservative, but present very useful information for researchers to use moving forward. The previous reviewers have done a good job ruling out the majority of issues this manuscript had, and my comments are quite minor. The following are suggestions I have to finalize the manuscript before publishing.

Main comments

Throughout the manuscript there are issues with grammar. Although this has been addressed by the other reviewers, the remaining mistakes still take away from the message the authors want to send. It's a good idea to put the manuscript through "Grammarly", as it will likely catch the remaining grammatical errors this manuscript has (https://www.grammarly.com/). Be consistent with spacing between paragraphs and indentations at the beginning of paragraphs.

The authors state that one of their objectives it to highlight where future research could be focused. This is study is offers a unique perspective on future studies that hasn't been seen in equivalent studies performed elsewhere. As qualitative studies are important for hypothesis generation, it would be nice if the authors expanded on this (in either the discussion or conclusion) to specifically highlight what studies they would recommend.

Minor comments

Line 45-Space after registered.

Paragraph of line 55- Id recommend concluding this paragraph with the point of stating cannabis products are mislabeled or contaminated. I don't follow the relevance. Or maybe change it to highlight the dangers of self-prescribing.

Line 69- Replace "on till" with "until".

Line 82- Remove comma after "research"

Line 227-Table 3 isn't completely visible.

Line 239-Make it clear exactly what and why these tests are being performed, i.e., your goal.

Line 293-Be consistent with spacing between values and unites of measurement. This occurs throughout the manuscript.

Reviewer #2: With much interest I have read and reviewed the manuscript titled: ‘Danish dog owners’ use and the perceived effect of unlicensed cannabis products in dogs’. The researchers studied unlicensed cannabinoid use in Danish dogs, by questioning dog owners on usage, including reasons and perceived effectiveness.

I would recommend the study to be accepted for submission by PloSOne and feel the study is relevant as interest among dog owners seems increasing, regarding cannabis products as possibly relevant for instance as pain treatment and to modulate behaviour; yet presently studies on the topic are few. This study indicates how without a veterinary licence, cannabinoid products are opted for by Danish dog owners, how the products are bought, for which purposes and how owners perceive their effectiveness.

The study method is based on surveying a convenience sample, recruited via social media, with 38% of 2,002 respondents indicating use of cannabis products for the dog.

Minor revisions

- May I suggest to write 2,002 (and 2,091, 1,044, etc.) as to assist the reader in recognising it as a number?

- Line 50, ‘On the other hand’ -> perhaps another start of the sentence positions it more optimally? I was also wondering if the three surveys that are mentioned after this sentence, are not better addressed elsewhere? (Or alternatively the whole text from line 50 – 55 may be better positioned elsewhere? Note that line 77 mentions ‘anecdotal’ also. Perhaps the text may fit here, leading up to the study aim?)

- Line 70/71, although ‘physicians’ will be sufficient indication for native speakers, perhaps adding ‘human’ somewhere may aid non-native speakers in understanding rapidly that this text is about indications for human conditions/human patients?

- ‘Feedstuff’ (line 56/74, I am unsure here, but is this terminology not normally used for livestock more so than dogs (or other companion animals)? It may be that you intend to indicate livestock feedstuff?

- Would it be of relevance to (eg. near line 58) briefly explain that many cannabinoids from Cannabis sativa exist and that often cannabidiol (CBD) and 19-tetrahydrocannabinol (THC) are present in products in larger amounts ant that the latter is deemed toxic to dogs?

- Line 83: is ‘legality’ the optimal word choice?

- With regard to Methods, would you not want to indicate earlier on (than line 13) that the questionnaire is available as an Appendix?

- Line 114: ‘this section’ -> perhaps describe ‘this’, so which section, e.g. the section on cannabinoid product use?

- Line 119: ‘for which’ i.s.o. ‘which’?

- Line 158, did the questionnaires report?

- Line 160, is it ‘decision to treat’ or e.g. ‘reporting of treating the dog with…’?

- Line 162 ‘pet dogs’, but before this ‘dogs’. (Also in line 163.)

- Line 164: note that there is a discrepancy in # of decimal places between OR and CI.

- Line 173: is ‘positive respondents’ the optimal word choice? (Also in line 350).

- Line 175-177: ‘The evaluation of 36 open-ended text boxes provided by the respondents showed that some responses should have been included in the predefined categories.’ -> you may want to address in the Methods section how you evaluated the open-ended text data. This may also allow you to write more ‘result style’ in this section after line 175.

- When reading ‘Seizure control’ – line 188, I wondered how this related to ‘neurological disease including epilepsy’ – line 193. The explanation is found in line 201 onwards. You may want to (after providing detail in the Methods section, see previous comment) simply provide the results here after correctly categorizing data from open-ended text data. You can list how you categorized items in an Appendix. The benefit may be that results become graspable more easily for your readers. Table 2 is already valuable to do so, but you may reconsider positioning and writing as to also end this paragraph a little more strongly?

- Table 3 was not completely in view in the pdf.

- Line 229-230 ‘reported the highest degree of perceived effect’ -> you may want to check if this sentence reflects correctly what you aim to state here; is it the highest degree or e.g. the highest percentage of….

- Line 229-241 is interesting to read, but as a thought: The table presents the percentage and numbers per scale item, would it create a more graspable text if you’d mention here the binary effect versus no effect for each use purpose (indication) in this text part? This would perhaps facilitate a comparison between use purposes?

- Line 250: ‘Twenty-two percentage’ -> ‘percent’ or ‘a percentage of …’, I think?

- Line 258/259: are Kalm® and Bach® brand names? Then you may need to indicate that somehow?

- Line 266/297: ‘Despite the lack of licensed cannabinoid-containing products for pets, and ==despite the fact== that it is illegal to sell or prescribe (…).

- Line 275: ‘This == e.g. assumption/suggestion== is’.

- Line 278: ‘The most often stated indications for the cannabinoid treatment was pain management, (…)’ -> ‘were’ i.s.o. ‘was’?

- Line 317/318: ‘but it is likely that dogs also experience certain pain entities where cannabinoids are potentially more effective’ -> note the difference from pain type (terminology in previous sentences) and ‘pain entities’ and is it ‘likely’ (and if so, can you refence that?) or would you want to word the sentence a little more carefully?

- Line 326/327: font difference and ‘they’ may not be the optimal way to reflect back on ‘second study’.

- Line 337-340: Text ‘Furthermore (…) overlooked’: While understanding what you intend to indicate here, you may want to rewrite this text a little (and add some references?) as it may not be clear why to your reader why more obvious signs are more or less related to placebo effect? Not also that the final sentence part seem to miss a word or two (eg. ==may==even== be== overlooked).

- Line 343: indications? (plural).

- Well done for mentioning the study limitations clearly at the end of the discussion section. I was wondering about a possible influence of some other aspects, particularly if the (clearly described) choice of testing for associations only with the ‘1 treatment indication’ could have led to additional bias. (As for instance a very ‘contented’ person providing of cannabinoid products to a dog, may use more broadly than a less ‘contented’ person? However, this does not seem to regard a very large part of your dataset.

- Line 389: ‘medical’, does this include ‘behavioural’?

- Line 390: ‘are’=> ‘being’?

**********

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Reviewer #1: No

Reviewer #2: No

**********

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PLoS One. 2024 Jan 31;19(1):e0296698. doi: 10.1371/journal.pone.0296698.r003

Author response to Decision Letter 0


4 Dec 2023

Dear Editors,

The authors would like to thank the reviewers and section editor for their careful reading and thoughtful comments that helped improve the quality and clarity of the manuscript. We especially want to thank the reviewers for the time and effort taken to review our study, and for their insightful and encouraging comments.

We have addressed all the comments in the revised manuscript and have hopefully satisfied the raised concerns. The detail of the changes made is given below.

Response to Editor

Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.

## Thank you for bringing this to our attention. The style requirements have been reassessed and corrected.

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

## One reference has been added to the revised manuscript: Weiblen GD, Wenger JP, Craft KJ, ElSohly MA, Mehmedic Z, Treiber EL, et al. Gene duplication and divergence affecting drug content in Cannabis sativa. New Phytologist. 2015;208(4):1241–50.

Response to Reviewer #1

First it should be noted I am not well versed in qualitative studies.

Research regarding the relationship between dogs and cannabinoids is in its infancy. Studies which aim to understand this relationship are extremely important. This study does a good job at beginning to highlight how and why cannabinoids are used on dogs in Denmark, and acts as an introduction to guide further research. Authors did an excellent job detailing the limitations of this study. Their inferences were conservative, but present very useful information for researchers to use moving forward. The previous reviewers have done a good job ruling out the majority of issues this manuscript had, and my comments are quite minor. The following are suggestions I have to finalize the manuscript before publishing.

## Thank you for your very generous and encouraging comments. We are very appreciative of your valuable input. To the best of our ability, we have revised the manuscript. The detail of the changes made is given below.

Throughout the manuscript there are issues with grammar. Although this has been addressed by the other reviewers, the remaining mistakes still take away from the message the authors want to send. It's a good idea to put the manuscript through "Grammarly", as it will likely catch the remaining grammatical errors this manuscript has (https://www.grammarly.com/). Be consistent with spacing between paragraphs and indentations at the beginning of paragraphs.

## Thank you very much for the grammatical, spelling, and structural edits throughout the manuscript and the recommendation of "Grammarly". The manuscript has been revised to the best of our ability.

The authors state that one of their objectives it to highlight where future research could be focused. This is study is offers a unique perspective on future studies that hasn't been seen in equivalent studies performed elsewhere. As qualitative studies are important for hypothesis generation, it would be nice if the authors expanded on this (in either the discussion or conclusion) to specifically highlight what studies they would recommend.

## We appreciate the comment. The revised manuscript has in addition to comments already made in the original manuscript’s Conclusion and Perspectives, been added text on future perspectives where we specify study details, (last paragraph in Conclusion and Perspectives).

Line 45- Space after registered.

## Thank you, space inserted.

Paragraph of line 55- Id recommend concluding this paragraph with the point of stating cannabis products are mislabeled or contaminated. I don't follow the relevance. Or maybe change it to highlight the dangers of self-prescribing.

## Thank you for highlighting this obvious point. We have added a concluding paragraph stating the concerns and potential health risks there are when owners self-prescribe these unregulated products.

Line 69- Replace "on till" with "until".

## Thank you for the spelling correction. Corrected in text.

Line 82- Remove comma after "research"

## Thank you for the grammatical edit. Corrected in text.

Line 227-Table 3 isn't completely visible.

## We are very sorry for the misunderstanding and for your inconvenience. We have contacted the publishing editor and have added an additional file labelled “Other_Table 3” to our submission of the revised paper. Please find the correspondence below.

Dear Editor

Thank you very much for the uplifting and positive response to our manuscript. We very much appreciate the reviewer’s inputs and we are addressing them at the moment.

I am however in doubt of one of the reviewer comments and I think I probably have misunderstood the guideline. I hope you can guide me on how to correct the issue.

We have a large table that extends beyond the margins and as I understood the guideline I should not try and fit it into the margins. I have most likely misunderstood the guidelines, as both reviewers have commented on it. Could you clarify how I should correct it in order to meet the reviewer’s comments.

From guideline:

Size: Tables do not have strict width and height requirements. Do not split your table or otherwise try to make the table appear within the manuscript margins if it does not fit on one page. In Word, tables that run off of the manuscript page can be seen using Draft View. In the PDF version of the published article, very wide tables may be printed sideways, and long tables may span more than one page.

Thank you very much, Pernille

Dear Dr. Holst,

Thank you for reaching out with your query.

You're correct, we do ask that you don't alter your tables to fit. This is in case of acceptance, the production team will use the tables as they're shown in the manuscript to put together the publishable version. When viewing your manuscript in Word using the draft view, the full Table 3 is completely visible, However, in the PDF file which is provided the the reviewers, the table is cut off.

I'd recommend when submitting your revised paper to keep the table in the manuscript as it is, but to also upload the table as a separate "Other" file. You can reference the separate file in your Response to Reviewers so the reviewers know this is the same Table 3 that's included in the manuscript and are able to examine the full table.

My apologies for the misunderstanding. Please let me know if you have any further questions or if you have concerns about this suggested solution.

Kind regards, Teresa Diviacchi, Publishing Editor

Line 239- Make it clear exactly what and why these tests are being performed, i.e., your goal.

## Thank you for the very relevant concern. We have rephrased the paragraph to state the intention of the performed tests more clearly. The paragraph reads; As differences in the owner perceived effect between the indication groups could be a reflection of a true difference in response to treatment of different disease states a Kruskal-Wallis test was performed and provided weak evidence of a difference χ 2(9, N = 516) = 19.808, p < 0.019, Ε2 = 0.40. A multiple comparison post hoc test with a Dunn's test did however not show any significant differences in perceived effect between the indication groups (p >0.05, adjusted using the Bonferroni correction).

Line 293- Be consistent with spacing between values and unites of measurement. This occurs throughout the manuscript.

## Thank you for the structural correction. The manuscript has been checked for spacing errors.

Response to Reviewer #2

With much interest I have read and reviewed the manuscript titled: ‘Danish dog owners’ use and the perceived effect of unlicensed cannabis products in dogs’. The researchers studied unlicensed cannabinoid use in Danish dogs, by questioning dog owners on usage, including reasons and perceived effectiveness.

I would recommend the study to be accepted for submission by PloSOne and feel the study is relevant as interest among dog owners seems increasing, regarding cannabis products as possibly relevant for instance as pain treatment and to modulate behaviour; yet presently studies on the topic are few. This study indicates how without a veterinary licence, cannabinoid products are opted for by Danish dog owners, how the products are bought, for which purposes and how owners perceive their effectiveness. The study method is based on surveying a convenience sample, recruited via social media, with 38% of 2,002 respondents indicating use of cannabis products for the dog.

## Thank you for your interest in our study and your valuable input. We are very appreciative and have to the best of our ability revised the manuscript. The detail of the changes made is given below.

- May I suggest to write 2,002 (and 2,091, 1,044, etc.) as to assist the reader in recognising it as a number?

## Thank you for this very valid point – text edited.

- Line 50, ‘On the other hand’ -> perhaps another start of the sentence positions it more optimally? I was also wondering if the three surveys that are mentioned after this sentence, are not better addressed elsewhere? (Or alternatively the whole text from line 50 – 55 may be better positioned elsewhere? Note that line 77 mentions ‘anecdotal’ also. Perhaps the text may fit here, leading up to the study aim?)

## Thank you for the suggestion. We have revised the text and have rearranged the paragraph.

- Line 70/71, although 'physicians' will be sufficient indication for native speakers, perhaps adding 'human' somewhere may aid non-native speakers in understanding rapidly that this text is about indications for human conditions/human patients?

## Thank you, we indeed agree with your reflection – text adjusted.

- 'Feedstuff' (line 56/74, I am unsure here, but is this terminology not normally used for livestock more so than dogs (or other companion animals)? It may be that you intend to indicate livestock feedstuff?

## Thank you for the insightful comment and we believe your understanding of the word feedstuff is correct. We apologize for the misuse of the word. In the Danish legislation all non-medical cannabinoid compounds that are produced by extraction are categorized as “feedstuff” (Danish: foderstof) disregarding what species they are intended. More appropriate would probably be the term “feed additive”, which also is the wording used in the EU legislation. Feedstuff has been substituted with feed additive in the text.

- Would it be of relevance to (eg. near line 58) briefly explain that many cannabinoids from Cannabis sativa exist and that often cannabidiol (CBD) and 19-tetrahydrocannabinol (THC) are present in products in larger amounts ant that the latter is deemed toxic to dogs?

## Thank you for this comment, we agree with this suggestion. We have now extended the Introduction and included a section clarifying cannabinoid content and potential risk of intoxication (Introduction, first and second paragraph).

- Line 83: is 'legality' the optimal word choice?

## Thank you for bringing this to our attention – the sentence is reformulated and reads: Given the lack of legal veterinary cannabinoid products, an anonymous survey was deemed the most appropriate method to obtain this information.

- With regard to Methods, would you not want to indicate earlier on (than line 13) that the questionnaire is available as an Appendix?

## We agree with the comment and have moved the Appendix reference to the third paragraph in the “Survey” section.

- Line 114: 'this section' -> perhaps describe 'this', so which section, e.g. the section on cannabinoid product use?

## Thank you for pointing this out. The text has been revised and read: The respondents were questioned about their use or past use of cannabinoid products for their dogs. Those who confirmed usage were directed to a subsequent section containing more detailed inquiries….

- Line 119: 'for which' i.s.o. ‘which’?

## Thank you – text corrected.

- Line 158, did the questionnaires report?

## Thank you for this obvious point – text revised and reads: Of the 2,002 completed questionnaires, 752 (38%) respondents reported having used at least one cannabinoid product for their dog, while 1,250 (62%) had never used such products.

- Line 160, is it 'decision to treat' or e.g. 'reporting of treating the dog with…'?

## We agree with the comment and have revised the text which reads: A chi-square test was used to assess the association of living area, with the reporting of treating with cannabinoids, and a significant association was found (X2 (7, N=2,002) = 16.61, p = 0.020).

- Line 162 'pet dogs', but before this 'dogs’. (Also in line 163.)

## Thank you for the comments, the text has been corrected for this inconsistency.

- Line 164: note that there is a discrepancy in # of decimal places between OR and CI.

## Thank you for bringing this to our attention. The decimals have been uniformed and read: Binominal logistic regression revealed that living in greater Copenhagen was negatively associated with cannabinoid use in dogs, with the respondents having an odds ratio of 0.69 related to using cannabinoids (P = 0.04, OR 0.69, 95% CI = 0.48-0.98).

- Line 173: is 'positive respondents' the optimal word choice? (Also in line 350).

## Thank you for the input. We agree and have changed the wording in the revised manuscript to:

Original line 173: Of all the respondents confirming the use of cannabinoids, 113 (15%) had used more than one cannabinoid formulation or type, with the majority having tried two different formulations or types. Original line 350: Our study suggests that CBD drops/oil are the most popular type and formulation of cannabinoids and were used by 93% of the respondents confirming the use of cannabinoids.

- Line 175-177: ‘The evaluation of 36 open-ended text boxes provided by the respondents showed that some responses should have been included in the predefined categories.’ -> you may want to address in the Methods section how you evaluated the open-ended text data. This may also allow you to write more ‘result style’ in this section after line 175.

## Thank you for the suggestion. The Material and Methods section has been revised and reads: The open-ended textboxes were checked for answers which should have been included in the predefined categories and the data was adjusted so they were included in the appropriate predefined categories. The Results section has been adjusted to: The evaluation of 36 open-ended text box answers showed that 15 of the responses should have been included in the predefined categories. When adding these (six CBD oil, two CBD cream, and seven CBD capsules) to the appropriate categories, the overall frequencies were not affected.

- When reading 'Seizure control' – line 188, I wondered how this related to 'neurological disease including epilepsy' – line 193. The explanation is found in line 201 onwards. You may want to (after providing detail in the Methods section, see previous comment) simply provide the results here after correctly categorizing data from open-ended text data. You can list how you categorized items in an Appendix. The benefit may be that results become graspable more easily for your readers. Table 2 is already valuable to do so, but you may reconsider positioning and writing as to also end this paragraph a little more strongly?

##Agreed, we have created confusion here by including “epilepsy” in the “neurological disease” free text category. The text has been revised.

- Table 3 was not completely in view in the pdf.

## We are very sorry for the misunderstanding and for your inconvenience. We have contacted the publishing editor and have added an additional file labelled “Other_Table 3” to our submission of the revised paper. Please find the correspondence below.

Dear Editor

Thank you very much for the uplifting and positive response to our manuscript. We very much appreciate the reviewers' input, and we are addressing them at the moment.

I am however in doubt of one of the reviewer comments and I think I probably have misunderstood the guideline. I hope you can guide me how to correct the issue.

We have a large table that extends beyond the margins and as I understood the guideline I should not try and fit it into the margins. I have most likely misunderstood the guidelines, as both reviewers have commented on it. Could you clarify how I should correct it in order to meet the reviewer’s comments.

From guideline:

Size: Tables do not have strict width and height requirements. Do not split your table or otherwise try to make the table appear within the manuscript margins if it does not fit on one page. In Word, tables that run off of the manuscript page can be seen using Draft View. In the PDF version of the published article, very wide tables may be printed sideways, and long tables may span more than one page.

Thank you very much, Pernille

Dear Dr. Holst,

Thank you for reaching out with your query.

You're correct, we do ask that you don't alter your tables to fit. This is in case of acceptance, the production team will use the tables as they're shown in the manuscript to put together the publishable version. When viewing your manuscript in Word using the draft view, the full Table 3 is completely visible, However, in the PDF file which is provided the the reviewers, the table is cut off.

I'd recommend when submitting your revised paper to keep the table in the manuscript as it is, but to also upload the table as a separate "Other" file. You can reference the separate file in your Response to Reviewers so the reviewers know this is the same Table 3 that's included in the manuscript and are able to examine the full table.

My apologies for the misunderstanding. Please let me know if you have any further questions or if you have concerns about this suggested solution.

Kind regards, Teresa Diviacchi, Publishing Editor

- Line 229-230 'reported the highest degree of perceived effect' -> you may want to check if this sentence reflects correctly what you aim to state here; is it the highest degree or e.g. the highest percentage of….

## Thank you for pointing this out to us. Degree has been changed to percentage.

- Line 229-241 is interesting to read, but as a thought: The table presents the percentage and numbers per scale item, would it create a more graspable text if you'd mention here the binary effect versus no effect for each use purpose (indication) in this text part? This would perhaps facilitate a comparison between use purposes?

##Thank you very much for this very relevant suggestion which we initially also considered by grouping the responses binary into "Effect" (including "Yes, very convincing and good effect" + "Yes, convincing with some effect" + "Possible, but not convincing effect") versus "No Effect" or alternatively “Effect” (including categories “Yes, very convincing and good effect” + “Yes, convincing with some effect”) versus “No Effect” (including “Possible, but not convincing effect” + “No Effect”).

In hindsight we have had doubts about how owners perceive the category “Possible, but not convincing effect” and we have had concerns about over-interpreting this category and have chosen not to include it in either effect or no effect. We have therefore chosen to keep the original text where only "Yes, very convincing and good effect" + "Yes, convincing with some effect" are considered an effect and summed in the text.

- Line 250: 'Twenty-two percentage' -> 'percent' or 'a percentage of …', I think?

## Thank you – spelling corrected.

- Line 258/259: are Kalm® and Bach® brand names? Then you may need to indicate that somehow?

## Thank you for this obvious point. The text has been revised and reads: The herbal remedies most often reported were aloe vera, Bach® Original Flower Remedies, Kalm (ScanVet Animal Health A/S) (l-tryptophan, milk protein, vitamin B and l-theanine), fish oil, homoeopathy, green-lipped mussels, chondroitin, hyaluronic acid, glucosamine, pro- and prebiotics, psyllium, valerian root, and yeast extracts.

- Line 266/297: 'Despite the lack of licensed cannabinoid-containing products for pets, and ==despite the fact== that it is illegal to sell or prescribe (…).

## Thank you for this comment, the text is revised.

- Line 275: 'This == e.g. assumption/suggestion== is’.

## Thank you for this comment, the text is revised and reads: This assumption is supported by a Slovenian study which found a slight association between owners’ personal experience with cannabinoid and their use in pets.

- Line 278: 'The most often stated indications for the cannabinoid treatment was pain management, (…)' -> 'were' i.s.o. ‘was’?

## Thank you – the text was corrected.

- Line 317/318: 'but it is likely that dogs also experience certain pain entities where cannabinoids are potentially more effective' -> note the difference from pain type (terminology in previous sentences) and 'pain entities' and is it 'likely' (and if so, can you refence that?) or would you want to word the sentence a little more carefully?

## Thank you for pointing this out and we do agree that the statement is too blunt. The text has been revised and reads: In our study, it was not possible to recognize which pain phenotypes (inflammatory pain, neuropathic pain, cancer-induced pain, chronic pain, acute pain) the owners were treating, but if dogs experience the same pain phenotypes as is described in humans, there might be certain subgroups of dogs in which cannabinoids are more effective than others.

- Line 326/327: font difference and 'they' may not be the optimal way to reflect back on ‘second study’.

## Thank you – the text was corrected.

- Line 337-340: Text 'Furthermore (…) overlooked': While understanding what you intend to indicate here, you may want to rewrite this text a little (and add some references?) as it may not be clear why to your reader why more obvious signs are more or less related to placebo effect? Not also that the final sentence part seem to miss a word or two (eg. ==may==even== be== overlooked).

## Thank you for pointing this out. We agree that the text in the manuscript is misleading in the sense that the placebo effect is directly linked to the owners' ability to assess treatment response. We have revised the text in the manuscript.

- Line 343: indications? (plural).

## Thank you – the text was corrected.

- Well done for mentioning the study limitations clearly at the end of the discussion section. I was wondering about a possible influence of some other aspects, particularly if the (clearly described) choice of testing for associations only with the '1 treatment indication' could have led to additional bias. (As for instance a very 'contented' person providing of cannabinoid products to a dog, may use more broadly than a less 'contented' person? However, this does not seem to regard a very large part of your dataset.

## Thank you for your comment and acknowledging the biased dataset and our efforts to not over-interpretate the data. We fully agree that there is additional bias, especially regarding our selection of included data.

- Line 389: 'medical', does this include 'behavioural'?

## Agreed, the term medical is probably not comprehensive enough. Although some of the behavioural issues probably will be medical conditions, there are very likely conditions that would not be classified as a medical conditions but rather behavioural issues. We have included "behavioural conditions" in the sentence.

- Line 390: 'are'=> 'being'?

## Thank you. Text corrected.

Thank you once again for the possibility to re-submit.

With kind regards

Pernille Holst

Attachment

Submitted filename: Response to Reviewers.pdf

Decision Letter 1

Lucy J Troup

18 Dec 2023

Danish dog owners’ use and the perceived effect of unlicensed cannabis products in dogs

PONE-D-23-05678R1

Dear Dr. Holst,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Lucy J Troup, Ph.D

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

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Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Thank you for addressing my comments.

There are still some grammatical errors. Put it through "Grammarly" again to catch them.

The use of spacing between paragraphs and indentations at the begining of paragraphs are still not consistent. Pick one style and stick with that style throughout the entire manuscript.

Quickly address those minor issues before publishing. I dont feel the manuscript needs to go through another round of revisions.

Good job and best of luck!

Reviewer #2: The authors have addressed all comments well and the improved manuscript will provide interesting information for its readers after publishing.

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Acceptance letter

Lucy J Troup

4 Jan 2024

PONE-D-23-05678R1

PLOS ONE

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Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Appendix. Survey questionnaire.

    The questionnaire has for this publication been translated from the original survey language (Danish).

    (PDF)

    S2 Appendix. Overview of reported use of herbal remedies by respondents.

    The list has for this publication been translated from the original survey language (Danish).

    (PDF)

    S1 File. Dataset.

    (XLSX)

    Attachment

    Submitted filename: Response to Reviewers.pdf

    Attachment

    Submitted filename: Response to Reviewers.pdf

    Data Availability Statement

    All relevant data are within the manuscript and its Supporting information files.


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