NegEnt Micellar CBD for Canine Anxiety and Stress-Related Disorders: Scientific Rationale and Clinical Case Report

1. Introduction

Anxiety and stress-related behavioral disorders in dogs represent a major challenge in veterinary behavioral medicine. Conventional pharmacological options—primarily benzodiazepines and neuroleptics—show significant limitations in chronic emotional disorders. Benzodiazepines may induce paradoxical excitement, disinhibited aggression, and impaired learning (Overall, 2013; Crowell-Davis & Murray, 2006). Neuroleptics suppress behavioral output without modulating underlying emotional dysregulation and may cause dysphoria, motor rigidity, and cognitive dulling (Landsberg et al., 2012).

Cannabidiol (CBD) has emerged as a promising option for emotional disorders in dogs. Pharmacokinetic studies indicate that CBD is well tolerated (Deabold et al., 2019), and clinical observations in epileptic dogs show reductions in hyperarousal and stress-related behaviors (McGrath et al., 2019). A large survey of U.S. veterinarians reported that CBD is perceived as helpful for anxiety and emotional dysregulation (Kogan & Hellyer, 2020).

NegEnt contains Terpenolol, a patented CBD-derived, micellar molecule; the proposed mechanisms of action, although supported by the CBD literature, must be specifically confirmed for Terpenolol, and further research to that end is currently underway, even though some preliminary data exist (Scrimali, 2026).

NegEnt was previously notified to the Italian Ministry of Health as a Class I Medical Device, based on a physical and reversible mechanism of action, consistent with the European regulatory definition of medical devices, which requires non-pharmacological, non-immunological, and non-metabolic activity (Directive 93/42/EEC; Regulation (EU) 2017/745).

The theoretical rationale of NegEnt relies on a quantum-physical reversible mechanism, in which micellized terpenolol modulates CB1 receptor conformational states through shifts in electronic energy, molecular resonance, and supramolecular dynamics. This approach aligns with the scientific framework describing medical devices acting through physical mechanisms, where therapeutic activity emerges from physical interactions (adsorption, modulation of molecular energy states, supramolecular structuring) rather than classical pharmacological receptor binding (Martini & Ravasio, 2020).

2. Case Description

Leo, a 4-year-old Italian Volpino, was adopted at two years of age and immediately displayed separation anxiety, object possessiveness, and heightened reactivity. At age three, his symptoms escalated into episodes of affective aggression triggered by accidental painful stimuli (e.g., stepping on a paw). His triggers included strangers approaching, loud noises, sudden movements, and proximity to his toys.

Daily signs of distress included growling, rigid posture, ears pulled back, fixed gaze, repeated yawning, and continuous lip-licking. Lip-licking is recognized as a parasympathetic self-soothing behavior elicited by negative emotional stimuli (Albuquerque et al., 2018). Leo’s hypervigilance prevented normal sleep; he woke at minimal noises and vocalized repeatedly, generating significant emotional and logistical strain for caregivers.

In severe anxiety, neurobiological stimulation surpasses the system’s plasticity threshold, leading to reactive allostasis, where environmental stimuli are no longer processed by cortical computational systems. This state prevents the formation of new positive associations, making behavioral rehabilitation ineffective without pharmacological modulation.

3. Methods

Leo received five drops of NegEnt Micellar CBD three times daily (total: 15 drops/day). Each drop contains 10 mg of micellized terpenolol, resulting in a daily dose of 150 mg, equivalent to 15 mg/kg/day for a 10-kg dog. The approximate volume per drop is 0.05 mL, for a total daily volume of 0.75 mL.

To evaluate potential withdrawal effects or rebound phenomena, a planned 2-day treatment discontinuation was implemented after the first week of administration. Following this brief experimental pause, the treatment was promptly resumed and maintained for a total duration of two months, and it is currently ongoing.

Composition of NegEnt Drops:

• Micellized terpenolol (CBD micellar form): 10 mg per drop
• Hydrophilic micelles (non-ionic pharmaceutical-grade surfactants)
• Terpenic carrier matrix
• Purified water
• CE-approved preservative for medical devices
• THC: not present

No other pharmacological agents were used during the observation period. Behavioral changes were monitored daily by caregivers.

4. Results

4.1. Sleep Restoration

Within days, Leo began sleeping for extended periods in relaxed postures, with near-complete disappearance of nocturnal vocalizations.

4.2. Morning Arousal Regulation

Stress-related yawning and agitation upon waking were replaced by calm behavior and a relaxed facial expression.

4.3. Reduction of Stress-Related Reactivity

During the initial week of treatment, no episodes of intra-domestic aggression or biting occurred. Possessiveness and hyperactivity decreased markedly.

4.4. Improved Social Behavior

During walks, anxious barking toward conspecifics was replaced by curious and positive interest.

4.5. Impulse Control, Absence of Rebound, and Long-Term Follow-Up

The day after the planned 2-day treatment discontinuation, Leo encountered his primary trigger (accidental paw pressure). He growled as a warning but did not escalate to biting, suggesting an increased latency between stimulus and reaction, as well as a retention of the therapeutic benefit. No signs of withdrawal, distress, or rebound anxiety were observed during the 48-hour suspension.

Following the resumption of the protocol, the treatment was extended for two months and is still active at the time of writing. Over this extended period, Leo showed stable behavioral consolidation, sustained improvement in sleep quality, and a persistent reduction in hyperarousal, with no documentation of adverse side effects or diminished efficacy (tolerance).

4.6. Cognitive and Motor Integrity

No sedation, confusion, or motor impairment was observed. Leo remained alert, coordinated, and capable of emotional modulation.

Table 1. A synopsis of the clinical behavioural parameters before and after micellar CBD (NegEnt) administration.

Behavioral Domain	Baseline (Before Treatment)	First Week Evaluation	Long-Term Follow-Up (2 Months)
Sleep Qualilty	Hypervigilance, frequent waking at minimal noises, nocturnal vocalizations.	Extended sleep periods, relaxed postures, near-complete disappearance of vocalizations	Stable sleep consolidation, persistent absence of nocturnal distress.
Morning Arousal	Stress-related yawning and acute agitation upon waking	Calm behavior and relaxed facial expression upon waking.	Sustained morning emotional regulation.
Intradomestic Reactivity	High reactivity, object possessiveness, episodes of affective aggression (biting triggers).	Marked decrease in possessiveness and hyperactivity; zero aggression/biting episodes.	Continuous behavioral stability; zero recurrence of biting episodes.
Social Behavior (Walks)	Anxious barking toward conspecifics	Anxious barking replaced by curious and positive interest.	Consolidated positive social interaction with other dogs.
Impulse Control	Low latency between trigger (e.g., accidental pain) and aggressive reaction	Increased latency (warning growl without escalating to biting).	Maintained impulse control; no rebound effects observed.
Cognitive & Motor Status	Chronic emotional dysregulation, high distress.	Alert, coordinated, capable of emotional modulation (no sedation)	Persistent cognitive and motor integrity; excellent tolerability.

Table 1. A synopsis of the clinical behavioural parameters before and after micellar CBD (NegEnt) administration.

Behavioral Domain	Baseline (Before Treatment)	First Week Evaluation	Long-Term Follow-Up (2 Months)
Sleep Qualilty	Hypervigilance, frequent waking at minimal noises, nocturnal vocalizations.	Extended sleep periods, relaxed postures, near-complete disappearance of vocalizations	Stable sleep consolidation, persistent absence of nocturnal distress.
Morning Arousal	Stress-related yawning and acute agitation upon waking	Calm behavior and relaxed facial expression upon waking.	Sustained morning emotional regulation.
Intradomestic Reactivity	High reactivity, object possessiveness, episodes of affective aggression (biting triggers).	Marked decrease in possessiveness and hyperactivity; zero aggression/biting episodes.	Continuous behavioral stability; zero recurrence of biting episodes.
Social Behavior (Walks)	Anxious barking toward conspecifics	Anxious barking replaced by curious and positive interest.	Consolidated positive social interaction with other dogs.
Impulse Control	Low latency between trigger (e.g., accidental pain) and aggressive reaction	Increased latency (warning growl without escalating to biting).	Maintained impulse control; no rebound effects observed.
Cognitive & Motor Status	Chronic emotional dysregulation, high distress.	Alert, coordinated, capable of emotional modulation (no sedation)	Persistent cognitive and motor integrity; excellent tolerability.

5. Discussion

The clinical improvements observed in this case are consistent with emerging evidence supporting CBD as a promising anxiolytic agent in dogs. Unlike benzodiazepines—which may produce paradoxical agitation, disinhibited aggression, and impaired learning—CBD exerts multimodal emotional regulation without compromising cognition or motor coordination (Overall, 2013; Crowell-Davis & Murray, 2006). Neuroleptics, while capable of suppressing overt behavioral responses, do not address underlying emotional dysregulation and may cause dysphoria or cognitive dulling (Landsberg et al., 2012).

Micellar terpenolol CBD offers additional advantages due to its supramolecular structure. Enhanced hydrosolubility and bypass of first-pass metabolism allow rapid absorption at low doses. More importantly, terpenolol appears to modulate CB1 receptors through quantistic allosteric mechanisms, altering receptor conformational energy states and electron-transfer coefficients. This reversible physical mechanism is coherent with the regulatory classification of NegEnt as a Class I Medical Device, where therapeutic action is attributed to physical interactions rather than pharmacological receptor occupation (Martini & Ravasio, 2020).

Notably, the 2-day experimental discontinuation highlighted the absence of rebound anxiety or withdrawal symptoms, which are common limitations of conventional psychotropic drugs. Furthermore, the excellent safety and tolerability profile observed over the subsequent two months of continuous administration underscores the potential of micellar terpenolol CBD as a viable, long- term therapeutic tool.

Although this is a single case report, the findings suggest that micellar terpenolol CBD may represent a valuable adjunct to behavioral therapy in dogs with severe anxiety and stress-related dysregulation. Controlled studies are needed to evaluate its efficacy, safety, and mechanistic profile.