Despite the use of standard anesthetic techniques, this case demonstrates an atypical outcome not readily explained by established causes of local anesthetic failure, known drug interactions, or underlying medical conditions. However, this presentation is consistent with emerging reports in an individual with chronic cannabis use, suggesting altered pain thresholds and anesthetic responses to local anesthetic. The growing number of these emerging cases remains largely unexplored, and the phenomenon remains poorly characterized, particularly within the field of dentistry. As cannabis use becomes more prevalent, understanding its potential impact on perioperative pain management is increasingly important for dental and surgical providers [1], [2], [5].

This case adds to the increasing body of evidence suggesting that cannabis use may alter pain pathways. Similar to hyperalgesia observed with long-term opioid use, cannabis may contribute to heightened pain sensitivity. While cannabis has historically been perceived to have analgesic properties, an individual of long term cannabis use grows, emerging research suggests that long-term or heavy use may paradoxically result in increased pain perception [1], [6]. Chronic exposure to cannabinoids, particularly THC, has been associated with adaptive changes in the endocannabinoid system, including receptor desensitization and downregulation, which may diminish endogenous pain modulation over time.

Central sensitization has been proposed as a mechanism underlying pain hypersensitivity in a variety of chronic pain conditions and is characterized by amplification of neural signaling within central nociceptive pathways, resulting in exaggerated responses to painful stimuli. Such alterations in pain processing may provide a useful framework for understanding the atypical presentation observed in this case [10].

Cannabis exerts its effects through exogenous cannabinoids, primarily THC and CBD, which interact with CB1, CB2, and transient receptor potential (TRP) channels involved in nociception. Activation of CB1 receptors influences neurotransmitter release that alter pain perception, CB2 receptors are more closely associated with inflammatory responses, and TRPV1 receptors are involved in the detection of noxious stimuli and thermal pain. 2 The clinical implications of these pathways as they relate to anesthetic efficacy, and the interactions between these systems not well understood, particularly in the context of cannabinoid exposure. Chronic exposure to THC has been preliminarily associated with downregulation and desensitization of CB1 receptors, which may contribute to altered central pain processing and paradoxical hyperalgesia [7].

Concurrently, cannabinoids have been shown to modulate TRPV1 receptor activity, a central mediator of nociceptive signaling and peripheral pain sensitivity [8]. This interaction may result in altered pain thresholds and exaggerated responses to noxious stimuli, including to local anesthetic injection as was seen in this case. Importantly, central sensitization has been shown to manifest clinically as hyperalgesia and exaggerated responses to noxious stimuli. These responses may occur despite relatively limited peripheral pathology and may result in pain presentations that appear disproportionate to the provoking stimulus [10]. While these mechanisms remain incompletely understood, they provide a biologically plausible explanation for the atypical pain response observed.

Compoundingly, acute exposure or withdrawal from substances has been associated with increased sensitivity to pain and stress, a concept that could potentially apply to cannabis [3], [7]. In this case, the patient’s uncertain timing of last use followed by later admission of recent intake raises the possibility that either acute intoxication or early withdrawal could have been contributors to the exaggerated response.

An interesting consideration in this case is the presence of irreversible pulpitis, a persistent inflammatory disease of the dental pulp characterized by irreversible structural and functional damage. Resultantly, those patients frequently require supplemental anesthetic techniques and repeat administration. Furthermore, inflammatory sensitization associated with irreversible pulpitis is known to produce clinical presentations that mimic other pain disorders through generating diffuse and referred pain responses, including TMJ, TMD, and neuropathic pain disorders. Therefore, the patient's underlying pulpal pathology likely contributed to the pain experienced and the anesthetic challenges encountered during treatment. However, while irreversible pulpitis represents an important competing explanation, the abrupt onset, severity, and behavioral nature of the patient's response appeared atypical when compared with clinical courses commonly observed. Most notably, contradictory to typical anesthetic failures of inflamed pulp in which gradual development of inadequate anesthesia is typically observed, this patient experienced immediate hyperalgesic response to the injection. Thus, further pointing towards central sensitization factors. As such, it is possible that cannabis-associated alterations in pain processing acted synergistically with the existing inflammatory condition, amplifying an already sensitized pain state and resulting in the exaggerated presentation observed in this case [10], [11].

From a pharmacokinetic perspective, interactions between local anesthetics and cannabinoid remain poorly studied [3]. Cannabinoids are known to influence cytochrome P450 enzyme activity, potentially altering drug metabolism. Both THC and CBD have been shown to inhibit multiple CYP450 isoenzymes, including CYP3A4, CYP2C9, and CYP2C19, with CBD demonstrating more potent inhibitory effects. These interactions may alter the metabolism of concurrently administered medications, potentially leading to changes in drug plasma levels and duration of action. While local anesthetics such as lidocaine are partially metabolized by CYP450 enzymes, the clinical significance of cannabinoid-mediated CYP inhibition on local anesthetic metabolism remains unclear. Altered enzymatic activity may contribute to variability in anesthetic onset, efficacy, and duration. Additionally, chronic cannabis use may induce adaptive changes in hepatic enzyme activity, further complicating the predictability of drug metabolism in these patients. Although direct evidence linking CYP450 modulation by cannabinoids to local anesthetic failure is limited, this mechanism represents a plausible contributing factor to the atypical anesthetic response observed in this case [9].

Furthermore, well established cannabis-induced vasodilation and reflex tachycardia may result in increased systemic absorption of local anesthetics, thereby reducing efficacy at the target site. THC has been shown to induce peripheral vasodilation through CB1 receptor–mediated effects on vascular smooth muscle, as well as through modulation of autonomic tone. This vasodilatory response is often accompanied by reflex tachycardia, likely secondary to decreased systemic vascular resistance, as well as compensatory sympathetic activation [1], [5]. Thus, potentially explaining the need for repeated anesthetic administration observed in this case.

We hypothesize that this patient’s cannabis use contributed to both hyperalgesia and difficulty achieving adequate anesthesia. This case underscores the need for increased clinician awareness of potential anesthetic challenges in patients who use cannabis, particularly with chronic use [1], [2], [5]. Thorough preoperative screening, including specific inquiry into the timing, frequency, and method of cannabis use, is essential. Providers should be prepared to modify anesthetic strategies, including the use of alternative agents or buffering techniques, while remaining mindful of maximum safe dosing to avoid toxicity.