Declinul cognitiv determinat de abuzul de dextrometorfan – scurt review

Introduction

Dextromethorphan (DXM) has been available over the counter in the USA since its FDA approval in 1958 as an antitussive. It is now contained in more than 140 over-the-counter (OTC) cough and cold medicines sold across the 50 states of the United States of America^(1,2). At the recommended therapeutic dose of 10-30 mg every 4-8 hours in adults, DXM has been shown to suppress the cough reflex through the cough center in the medulla oblongata, with a favorable safety and tolerability profile⁽³⁾. Nevertheless, the substance has been abused since at least the 1960s, when its predecessor was withdrawn from the US market due to widespread recreational abuse. However, since the end of the 1990s, the recreational abuse of DXM has again become a public health problem due to the widespread availability, low cost and the fact that the substance is legal, along with the false belief that OTC drugs are always safe regardless of dosage. According to epidemiological data from the National Poison Data System (NPDS), the number of cases of DXM abuse reported to California Poison Control Centers increased tenfold between 1999 and 2004, with the 15-16-year-old age group being the most commonly affected^(4,5).

At supratherapeutic dosages, DXM exerts dose-dependent dissociative and hallucinogenic effects through its principal mechanism of action as a noncompetitive antagonist of the NMDA receptor, placing it pharmacologically in the same class as phencyclidine (PCP) and ketamine. The neuropsychiatric effects of supratherapeutic DXM dosing have been defined as consisting of four dose-dependent “plateaus” of effect, from mild perceptual distortions and alcohol-like sedative effects at lower dosages to extreme dissociative, hallucinatory and out-of-body experiences at the highest dosages of DXM⁽⁶⁾. The pharmacological profile of DXM is unique in its danger as an abused substance because of its dose-dependent effects and its capacity to elicit extreme effects across the range of supratherapeutic dosages of 1.5 mg/kg and beyond. Despite the now more widespread recognition of DXM’s abuse liability and acute neurobehavioral toxicity, the cognitive effects of DXM abuse – particularly when long-term in nature – have not yet been sufficiently characterized in the scientific and clinical literature. The first formal case report of cognitive deterioration as a sequela of long-term DXM abuse was published in 1994 by Hinsberger, Sharma and Mazmanian, who established that severe, progressive and persistent cognitive deterioration is a real-world consequence of long-term DXM abuse⁽⁷⁾.

Pharmacology and mechanisms

NMDA receptor antagonism

The most important mechanism of cognitive toxicity of DXM and its main active metabolite, dextrorphan, at supratherapeutic concentrations is the noncompetitive antagonism of the NMDA receptors, which are the main ionotropic glutamate receptors and play a key role in synaptic plasticity, long-term potentiation, learning and memory⁽³⁾. Dextrorphan, formed by O-demethylation of DXM via CYP2D6, is a potent antagonist of the NMDA glutamate receptor, binding to the PCP/MK-801 site on the ion channel pore, thereby preventing calcium entry into the cell in response to glutamate⁽⁸⁾.

NMDA receptors are highly expressed in brain regions important for cognition, such as the hippocampus, entorhinal cortex and prefrontal cortex. Their antagonism by DXM and dextrorphan interferes with glutamate transmission, which is important for working memory, episodic memory, attention and executive function. Studies in animals have shown that DXM impairs spatial learning and memory through an NMDA-dependent mechanism, disrupting hippocampal-prefrontal circuitry⁽⁹⁾. Unlike MK-801, a potent NMDA receptor antagonist, DXM, which is administered orally, does not induce Olney’s lesions, that are associated with MK-801. Histological examination of rat brains after single or repeated dosing with DXM failed to demonstrate any neuronal vacuolization or degeneration in the re­tro­­splenial cortex or posterior cingulate cortex, in contrast to MK-801⁽¹⁰⁾. This suggests that the cognitive toxicity of DXM is functional rather than structural, although the long-term effects of chronic exposure to DXM on synaptic plasticity are unknown^(11,12).

Serotonergic and sigma-1 receptor activity

Besides its action as an antagonist at the NMDA receptor, DXM has been shown to act through several receptor systems that are involved in its acute and toxic effects⁽¹¹⁾. DXM also inhibits norepinephrine reuptake, qualifying it as a nonselective serotonin-norepine­phrine reuptake inhibitor (SNRI). This is clinically relevant because, at high doses, this drug has the potential to cause serotonin syndrome⁽¹³⁾. DXM also acts as an agonist at the sigma-1 receptor, which is involved in the regulation of neurotransmission, neuroplasticity, oxidative stress and calcium signaling^(14,15). The serotonergic effects of DXM are particularly relevant in the context of its potential toxicity in overdose and abuse. DXM-induced serotonin syndrome is a dose-related toxic effect of the drug, which is defined by abnormalities in mental status, autonomic hyperactivity and neuromuscular abnormalities. This has the potential to cause serious complications, including hyperthermia, rigidity, rhabdomyolysis and death. It is noteworthy that supratherapeutic doses of DXM and standard doses of SSRIs have the potential to cause clinically relevant cases of serotonin syndrome^(16,17). Besides its serotonergic effects, which contribute to its toxicity, DXM is shown to increase serotonin release⁽¹³⁾. Besides its action at the NMDA receptor, blockade of this receptor can affect the dopaminergic system in the mesolimbic system. This occurs through reduced inhibition of the midbrain dopamine system, which increases dopamine release in the ventral striatum, leading to euphoria, reinforcement and psychotomimetic effects. This interaction between the glutamatergic and dopaminergic systems underlies the drug’s acute effects and the potential for long-term adaptations in the reward system⁽¹⁹⁾.

The CYP2D6 pharmacogenomic factor

The metabolism of DXM into its active and cognitive toxic metabolite, dextrorphan, is mainly catalyzed by cytochrome P450 2D6 in the liver. This enzyme is highly polymorphic with significant clinical consequences for toxicity risk⁽⁸⁾. About 5-10% of Caucasians are poor metabolizers (PMs), with reduced ability to form dextrorphan due to loss-of-function alleles. As a consequence, they accumulate DXM, which produces unique, more intense central nervous system (CNS) effects than extensive metabolizers. Extensive metabolizers (EMs) tole­rated doses of 3-6 mg/kg in a study, whereas PMs poorly tolerated even at 3 mg/kg⁽²²⁾.

Pharmacokinetically, DXM is rapidly metabolized to dextrorphan in extensive metabolizers after an oral dose of 30 mg, with plasma DXM levels almost undetectable. However, in PMs, DXM is retained at much higher levels with a half-life of 29.5 hours, thereby increasing the risk of toxicity even at recommended doses⁽⁸⁾. EMs that abuse high doses of DXM, on the other hand, produce high levels of its more active form, dextrorphan, which is an NMDA antagonist, thereby causing the desired cognitive effects⁽²⁰⁾. Of particular concern is that CYP2D6 inhibitors, which include SSRIs, tricyclic antidepressants and antipsychotics, have been known to convert EMs into PMs, thereby significantly increasing the levels of DXM, with cognitive toxicity, serotonin toxicity, etc.⁽²²⁾

Acute cognitive effects of high-dose dextromethorphan

The extent of cognitive impairment induced by acute high-dose DXM use in humans has been well delineated by controlled human studies. In a double-blind, placebo-controlled dose-escalation study, single oral doses of 100-800 mg/70 kg induced dose-dependent cognitive impairment across multiple cognitive domains over six hours⁽²³⁾.

Sustained and focused attention

High-dose DXM impairs sustained and focused attention in a dose-dependent manner. Performance on attentional tasks is significantly impaired at doses of 200 mg/70 kg or higher, which is associated with sedation and dysfunction in NMDA-dependent prefrontal-parietal networks⁽²³⁾. These effects persist even after adjusting for psychomotor slowing, indicating that the direct effects on attentional functions, coordination and balance disturbances occur at 400 mg/70 kg or higher, which can increase the risk of injury^(24,25).

Working memory

Working memory is significantly impaired in DXM users. Impairment in working memory is significant at 200 mg/70 kg or higher, which is comparable to that induced by the benzodiazepine triazolam⁽²³⁾. DXM-induced impairment in working memory is significantly greater than that induced by psilocybin, indicating specific effects on NMDA-dependent memory functions⁽²⁴⁾.

Episodic memory

High-dose DXM impairs episodic memory, an effect associated with dysfunction in hippocampal NMDA-dependent consolidation. These effects are significant at 300 mg/70 kg or higher, indicating specific effects on memory functions. Impairment in episodic memory is associated with reduced correlation between confidence and accuracy, suggesting that DXM users may be unaware of their cognitive impairment and are at an in­creased risk of injury⁽²³⁾.

Executive function/response inhibition

Executive functions, including inhibition, planning and cognitive control, are significantly impaired in DXM users. These effects are significantly higher among DXM users than among psilocybin users⁽⁴⁾. The dissociative effects of DXM on the central nervous system cause impairment in executive functions, which is comparable to the effects of ketamine or phencyclidine (PCP)⁽⁶⁾. Additional cognitive impairment in psychomotor slowing, coordination and balance disturbances occurs at 400 mg/70 kg or higher, which can increase the risk of injury⁽²⁵⁾.

Chronic cognitive decline from sustained DXM abuse

Although the acute cognitive effects of DXM abuse are well understood, the chronic neurocognitive effects of DXM abuse are clinically significant and not as well understood. The information available is largely derived from case reports which indicate that chronic cognitive deterioration is associated with chronic DXM abuse⁽⁷⁾.

Landmark evidence of cognitive deterioration

One landmark case report published in 1994 described severe cognitive deterioration associated with chronic DXM abuse. The case described significant cognitive impairment in memory, attention and other cognitive abilities, well below normal levels. The landmark case excluded other potential contributing factors, making it likely that DXM abuse was responsible for the cognitive impairment⁽⁷⁾. Other case reports describe psychological dependencies, mood disorders that include euphoria and rebound-related depressions, mania and cognitive impairment that persists despite attempts of detoxification⁽⁵⁾. This indicates that chronic DXM abuse leads to neuroadaptive changes in glutamatergic, serotonergic and dopaminergic systems⁽¹¹⁾.

Neurochemical mechanisms

Chronic exposure to DXM is likely to result in upregulation of NMDA receptors as a compensatory response. This overactivity is likely to lead to excitotoxicity and neuronal damage in areas such as the hippocampus and prefrontal cortex⁽¹¹⁾.

Additionally, repeated activation of sigma-1 receptors may affect neuroplasticity pathways, including brain-derived neurotrophic factor and protein synthesis, as well as long-term cognitive function⁽¹⁵⁾. In a practical setting, this may be compounded by the use of polydrug combinations, including alcohol, cannabis and benzodiazepines, resulting in additive or synergistic neurotoxicity⁽⁵⁾.

DXM-induced psychosis

DXM-induced psychosis, defined as hallucinations, delusions and disorganized thought, is a well-recognized effect of high-dose DXM, and may result in long-term cognitive dysfunction⁽⁶⁾. Recurring psychotic episodes, clearly linked to DXM use, have been documented, often requiring pharmacotherapy and showing gradual improvement after drug withdrawal.

NMDA receptor hypofunction results in hyperactivation of the mesolimbic dopamine system, a neurochemical profile that parallels schizophrenia^(18,19,26). Repeated episodes of psychosis may render the individual more susceptible to long-term psychotic disorders, but this theory has yet to be tested. DXM-induced psychosis-related cognitive dysfunction – including impaired attention, executive dysfunction and disorganized thinking – may persist after the acute episode, suggesting that neurochemical imbalances outlast the acute pharmacological effect of the drug^(6,27).

Vulnerable population

Adolescents and the developing brain

Adolescents are the most vulnerable demographic to DXM-induced cognitive toxicity, given their large proportion of DXM use and the fact that the brain regions targe­ted by DXM, such as the prefrontal cortex, hippocampus and mesocortical dopamine system, continue to develop into the mid-20s^(4,28). The NMDA receptor blockade during this developmental period may impair synaptic pruning and maturation, leading to long-term cognitive, emotio­nal and decision-making consequen­ces⁽¹¹⁾. Moreover, peak DXM abuse is typically in the 15 to 16-years-old age range, which is also the most sensitive developmental period of prefrontal cortex maturation⁽⁴⁾.

Polydrug users

DXM is commonly used in combination with other drugs by the majority of DXM abusers, who are typically polydrug users. DXM is commonly co-administered with other drugs such as alcohol, cannabis, benzodiazepines, opioids and stimulants, which increases the risk of adverse medical outcomes⁽⁵⁾. The coadministration of DXM and selective serotonin reuptake inhibitors is particularly hazardous, being likely to cause serotonin syndrome, especially in adolescents undergoing psychiatric treatment⁽¹⁶⁾. Moreover, experimental data show that DXM can potentiate the cognitive toxicity of other drugs, such as morphine, which impairs memory through synergistic effects in the hippocampus and prefrontal cortex, indicating that DXM-induced cognitive toxicity is more than additive in polydrug regimens⁽⁹⁾.

Clinical presentation and diagnosis

The clinical presentation of DXM-induced cognitive toxicity can vary from dissociative intoxication to chronic neuropsychiatric dysfunction. The symptoms of acute exposure to DXM include confusion, disorientation, memory impairment, agitation, nystagmus and ataxia. The dose-dependent effects of DXM can be best described by the “plateau” model, which includes the following levels of exposure to DXM⁽⁶⁾:

• first plateau (1.5-2.5 mg/kg) – mild stimulation, perceptual changes;
• second plateau (2.5-7.5 mg/kg) – cognitive, motor impairment;
• third plateau (7.5-15 mg/kg) – extreme hallucinations, dissociation;
• fourth plateau (>15 mg/kg) – complete dissociation from reality.

The clinical presentation of DXM-induced cognitive toxicity poses a significant challenge in the form of undetectability in standard urine drug screens, which leads to unexplained altered mental states or psychosis, making it difficult to diagnose the condition⁽⁶⁾. It is, therefore, essential to include questions about over-the-counter medications, such as cough syrups/cold medications, in the history, especially in young people⁽²⁹⁾. The key to diagnosing DXM-induced cognitive toxicity is the temporal association of exposure with the onset of symptoms, which resolve with discontinuation, although some cases may experience incomplete recovery. The management of DXM-induced psychosis includes supportive care, with abstinence from the drug and monitoring of the symptoms. Antipsychotics such as olanzapine, risperidone and quetiapine can be used to control the symptoms of psychosis⁽¹⁹⁾. Naloxone, which is used in some cases of altered levels of consciousness, is of uncertain value in DXM-induced psychosis due to the non-opioid action of DXM^(1,2).

Conclusions

Dextromethorphan abuse poses an underappreciated yet considerable risk of cognitive impairment, which can range from acute dose-proportional deficits in attention, working memory, episodic memory, executive function and metacognition to chronic neuropsychiatric degeneration, which may persist despite abstinence⁽⁷⁾. The adolescent brain is particularly susceptible to these effects, with brain regions such as the hippocampus and amygdala which are impacted by NMDA receptor antagonism, in active developmental stages during adolescence⁽⁴⁾. In addition, serotonin syndrome is another potentially life-threatening complication of DXM abuse, especially in polydrug users, with possible long-term neurological consequences^(30,31). A high index of suspicion for DXM abuse is warranted in cases of unexplained cognitive or psychiatric symptoms, especially since it is not routinely tested for in toxicology screens and can masquerade as other psychiatric illnesses⁽⁶⁾. Future research should include neurocognitive testing, neuroimaging and pharmacogenomics to elucidate further the nature of cognitive impairment due to DXM abuse and possible treatments. Currently, evidence supports considering chronic high-dose DXM abuse, especially among adolescents and young adults, as a neurotoxic hazard with possible long-term cognitive consequences⁽³²⁾.

Autor corespondent:  Ina PogoneaE-mail: ina.pogonea@usmf.md

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.