Dextromethorphan: A Comprehensive Review of Pharmacology, Neurobiological Effects, Abuse Liability, and Therapeutic Potential

Abstract

Dextromethorphan (DXM), a widely available over-the-counter (OTC) cough suppressant, has gained notoriety for its potential for abuse and psychoactive effects. This review provides a comprehensive overview of DXM, encompassing its pharmacology, mechanisms of action in the central nervous system, dose-dependent effects ranging from cough suppression to profound hallucinogenesis, long-term health consequences of chronic abuse, and clinically relevant drug interactions, particularly with promethazine and alcohol. Furthermore, this review examines current research efforts targeting potential treatments for DXM addiction and overdose, highlighting the complexity of managing DXM-related health issues. We delve into the enantiomer-specific effects of DXM and its metabolite dextrorphan (DXO), exploring their interactions with various receptors and transporters. This includes the sigma-1 receptor, which might modulate DXM’s behavioral effects, and the complex interplay between DXM and the glutamatergic system. We also discuss the emerging research on potential therapeutic applications of DXM beyond cough suppression, such as its use in treating neurological and psychiatric disorders. Finally, we assess the challenges in addressing DXM abuse, including the need for improved surveillance, prevention strategies, and effective treatment modalities.

Many thanks to our sponsor Maggie who helped us prepare this research report.

1. Introduction

Dextromethorphan (DXM) is a synthetic opioid derivative that acts primarily as a cough suppressant. First synthesized in the 1940s and approved for over-the-counter (OTC) use in the 1950s, it quickly became a common ingredient in numerous cough and cold remedies. Its widespread availability, ease of access, and relatively low cost have contributed to its increasing popularity as a recreational drug, particularly among adolescents and young adults. While intended for cough suppression at therapeutic doses, DXM exhibits a range of psychoactive effects at higher doses, including euphoria, altered perceptions, hallucinations, and dissociative experiences. These effects are mediated by its complex pharmacology, involving multiple neurotransmitter systems in the brain. The prevalence of DXM abuse has raised significant public health concerns, necessitating a thorough understanding of its pharmacology, neurobiological effects, potential health consequences, and effective treatment strategies.

The accessibility of DXM in OTC medications presents a unique challenge in managing its abuse. Unlike many other drugs of abuse that require illicit manufacturing or prescription acquisition, DXM is readily available in pharmacies and grocery stores. This ease of access, coupled with a lack of awareness among the general public regarding its potential for abuse, has contributed to its widespread misuse. Furthermore, the co-formulation of DXM with other active ingredients, such as acetaminophen, antihistamines (like promethazine), and decongestants, can exacerbate the potential for adverse health effects when taken in excessive doses. This review aims to provide a comprehensive examination of DXM, its effects, and the challenges associated with its abuse, offering insights for clinicians, researchers, and policymakers.

Many thanks to our sponsor Maggie who helped us prepare this research report.

2. Pharmacology of Dextromethorphan

2.1. Chemical Structure and Metabolism

DXM is chemically related to the opioid codeine, but it lacks significant opioid receptor agonist activity. Its chemical name is (+)-3-methoxy-N-methylmorphinan. Upon ingestion, DXM is rapidly absorbed from the gastrointestinal tract and undergoes extensive first-pass metabolism in the liver, primarily via the cytochrome P450 2D6 (CYP2D6) enzyme. This metabolic pathway converts DXM into its primary active metabolite, dextrorphan (DXO). DXO is considered to be more potent than DXM at several receptors, contributing significantly to the overall psychoactive effects. The CYP2D6 enzyme exhibits genetic polymorphism, leading to substantial inter-individual variability in DXM metabolism. Individuals can be classified as extensive metabolizers (EMs), intermediate metabolizers (IMs), poor metabolizers (PMs), or ultra-rapid metabolizers (UMs) based on their CYP2D6 activity. PMs exhibit reduced CYP2D6 activity, resulting in higher DXM concentrations and lower DXO concentrations. Conversely, UMs exhibit increased CYP2D6 activity, resulting in lower DXM concentrations and higher DXO concentrations. These differences in metabolic capacity can significantly influence the subjective effects and potential for toxicity of DXM. Another important metabolite is 3-methoxymorphinan, formed by CYP3A4. This metabolite is thought to contribute to some of the sedative effects associated with DXM use.

2.2. Receptor Binding and Neurotransmitter Interactions

DXM exerts its effects through a complex interplay of actions at various receptors and neurotransmitter systems in the brain. Its primary mechanism of action is believed to be as an antagonist of the N-methyl-D-aspartate (NMDA) receptor, a glutamate receptor involved in learning, memory, and synaptic plasticity. This NMDA receptor antagonism contributes to the dissociative and hallucinogenic effects observed at higher doses. DXM also acts as a sigma-1 receptor agonist. Sigma-1 receptors are involved in the regulation of intracellular calcium levels, neuronal excitability, and neuroplasticity. Activation of the sigma-1 receptor by DXM may contribute to its antidepressant and anxiolytic effects, as well as modulate the intensity of its psychoactive effects. Evidence suggests that the sigma-1 receptor might exert a neuroprotective role, mitigating some of the excitotoxic effects associated with NMDA receptor antagonism. DXM also acts as a serotonin reuptake inhibitor (SRI), which can increase serotonin levels in the synapse. This action can contribute to its mood-altering effects and potentially interact with other serotonergic drugs, leading to serotonin syndrome. In addition to these primary mechanisms, DXM also exhibits affinity for other receptors, including the muscarinic acetylcholine receptor, where it acts as an antagonist. It also shows some affinity for the nicotinic acetylcholine receptor. Its binding at these receptors contributes to the broader range of its effects, including cognitive impairment and anticholinergic side effects.

Many thanks to our sponsor Maggie who helped us prepare this research report.

3. Mechanisms of Action on the Brain

3.1. NMDA Receptor Antagonism and Glutamatergic System

DXM’s effects on the brain are primarily mediated through its antagonism of the NMDA receptor. NMDA receptors are crucial for synaptic plasticity and neuronal communication. By blocking these receptors, DXM disrupts normal glutamatergic neurotransmission, leading to dissociative and hallucinogenic effects. Glutamate is the brain’s primary excitatory neurotransmitter, and its dysregulation is implicated in a variety of neurological and psychiatric disorders. The NMDA receptor is a heterotetramer composed of several subunits, including GluN1, GluN2, and GluN3. DXM binds to the phencyclidine (PCP) binding site within the NMDA receptor channel, preventing the flow of ions through the channel. This blockade disrupts the normal flow of information between neurons, leading to altered perceptions of reality, feelings of detachment from one’s body, and cognitive impairment. The NMDA receptor antagonism of DXM can also lead to an increase in glutamate release in certain brain regions. This increase in glutamate release can, paradoxically, contribute to excitotoxicity, potentially leading to neuronal damage with chronic or high-dose use. The impact of DXM on the glutamatergic system is complex and varies depending on the dose, duration of exposure, and individual factors.

3.2. Sigma-1 Receptor Modulation

The sigma-1 receptor is a unique chaperone protein found in various regions of the brain, including the cerebral cortex, hippocampus, and cerebellum. DXM’s agonistic activity at the sigma-1 receptor is believed to modulate its overall behavioral effects. The sigma-1 receptor interacts with a variety of other proteins and receptors, influencing neuronal excitability, calcium signaling, and neuroplasticity. Activation of the sigma-1 receptor by DXM may enhance its antidepressant and anxiolytic effects. It also might modulate the intensity of its psychoactive effects, possibly by influencing the release of neurotransmitters such as dopamine and serotonin. Research suggests that sigma-1 receptor activation can promote neuroprotective effects, potentially mitigating some of the excitotoxic effects associated with NMDA receptor antagonism. However, the precise role of the sigma-1 receptor in mediating the effects of DXM remains an area of ongoing research.

3.3. Serotonin Reuptake Inhibition and Other Neurotransmitter Systems

DXM acts as an SRI, increasing serotonin levels in the synapse. Serotonin is a neurotransmitter involved in mood regulation, sleep, appetite, and other functions. By blocking the reuptake of serotonin, DXM increases its availability in the synapse, leading to mood-altering effects. However, this action also carries the risk of serotonin syndrome, particularly when DXM is combined with other serotonergic drugs. Serotonin syndrome is a potentially life-threatening condition characterized by agitation, confusion, rapid heart rate, high blood pressure, muscle rigidity, and seizures. The SRI activity of DXM is believed to contribute to its antidepressant effects. Beyond its NMDA receptor antagonism, sigma-1 receptor agonism, and serotonin reuptake inhibition, DXM also interacts with other neurotransmitter systems. Its affinity for muscarinic acetylcholine receptors contributes to anticholinergic side effects, such as dry mouth, blurred vision, and urinary retention. Its impact on other neurotransmitter systems contributes to the complex range of effects observed with DXM use.

Many thanks to our sponsor Maggie who helped us prepare this research report.

4. Dosage-Dependent Effects

The effects of DXM are highly dose-dependent, ranging from cough suppression at therapeutic doses to profound hallucinogenic experiences at higher doses. This dose-dependency is a crucial factor in understanding the potential for abuse and the associated health risks.

4.1. Therapeutic Doses (Cough Suppression)

At therapeutic doses (typically 10-30 mg every 4-8 hours), DXM primarily acts as a cough suppressant. It achieves this by reducing the sensitivity of the cough reflex in the brainstem. At these doses, DXM typically produces minimal psychoactive effects. However, some individuals may experience mild sedation or drowsiness. The cough-suppressant effects of DXM are generally well-tolerated at recommended doses. However, even at therapeutic doses, some individuals may experience side effects such as nausea, vomiting, dizziness, and constipation. These side effects are usually mild and transient.

4.2. Moderate Doses (Euphoria and Altered Perception)

At moderate doses (100-400 mg), DXM begins to produce more pronounced psychoactive effects. Users may experience euphoria, altered perception of time and space, increased sociability, and mild hallucinations. These effects are primarily attributed to NMDA receptor antagonism and serotonin reuptake inhibition. At these doses, the risk of adverse effects increases, including nausea, vomiting, dizziness, confusion, and impaired coordination. Some individuals may also experience anxiety or panic attacks. The effects at these doses can be unpredictable, varying depending on individual factors and the presence of other substances.

4.3. High Doses (Hallucinations and Dissociation)

At high doses (400 mg and above), DXM can produce profound hallucinogenic and dissociative effects. Users may experience vivid hallucinations, detachment from reality, out-of-body experiences, and a loss of sense of self. These effects are similar to those produced by other dissociative anesthetics, such as ketamine and PCP. At these doses, the risk of serious adverse effects is significantly increased. These effects can include seizures, respiratory depression, coma, and death. Users may also experience severe anxiety, paranoia, and psychosis. The effects at these doses can be highly unpredictable and potentially dangerous.

The concept of “plateaus” is often used to describe the subjective experience of DXM intoxication. While not formally recognized in pharmacological literature, it’s a common term used in online communities discussing DXM abuse, describing stages of intoxication associated with different dosage ranges and corresponding subjective effects. These plateaus are subjective estimations and their effects can vary widely among individuals.

• First Plateau (1.5-2.5 mg/kg): Mild euphoria, altered perception, and increased sociability.
• Second Plateau (2.5-7.5 mg/kg): More intense euphoria, vivid hallucinations, and impaired coordination.
• Third Plateau (7.5-15 mg/kg): Profound hallucinations, dissociation, and loss of sense of self.
• Fourth Plateau (15+ mg/kg): Complete dissociation, out-of-body experiences, and potential for serious adverse effects.

It is important to note that these plateaus are generalizations and that the actual effects experienced by an individual can vary depending on factors such as body weight, metabolism, and tolerance. The use of the plateau terminology should not be interpreted as an endorsement of DXM use, and it is essential to emphasize the potential dangers associated with high-dose DXM ingestion.

Many thanks to our sponsor Maggie who helped us prepare this research report.

5. Long-Term Health Consequences of Abuse

Chronic DXM abuse can lead to a range of long-term health consequences, affecting both physical and mental well-being. The severity of these consequences depends on the frequency and duration of abuse, as well as individual factors.

5.1. Neurocognitive Impairment

Chronic DXM abuse can lead to neurocognitive impairment, affecting memory, attention, executive function, and learning ability. The NMDA receptor antagonism associated with DXM may contribute to these cognitive deficits. Studies have shown that chronic DXM users exhibit reduced gray matter volume in several brain regions, including the hippocampus and prefrontal cortex, which are critical for cognitive function. These structural changes may underlie the observed cognitive deficits. The neurocognitive impairment associated with chronic DXM abuse can significantly impact an individual’s ability to function in daily life, affecting academic performance, work productivity, and social interactions. While some cognitive deficits may be reversible with abstinence, others may persist long-term.

5.2. Psychiatric Disorders

Chronic DXM abuse is associated with an increased risk of developing psychiatric disorders, including depression, anxiety, psychosis, and substance use disorders. The neurobiological changes induced by DXM can disrupt normal neurotransmitter function, predisposing individuals to these psychiatric conditions. DXM’s effects on the serotonergic system can contribute to the development of depression and anxiety. The NMDA receptor antagonism can trigger psychotic symptoms in vulnerable individuals. Chronic DXM abuse can also lead to dependence and addiction, characterized by compulsive drug-seeking behavior and withdrawal symptoms upon cessation of use. Individuals with pre-existing psychiatric disorders may be particularly vulnerable to the adverse effects of DXM abuse.

5.3. Physical Health Problems

Chronic DXM abuse can lead to a range of physical health problems, including liver damage, kidney damage, cardiovascular problems, and gastrointestinal issues. The metabolism of DXM in the liver can produce toxic metabolites that can damage liver cells. Chronic DXM abuse can also strain the kidneys, leading to kidney damage. The cardiovascular effects of DXM, such as increased heart rate and blood pressure, can increase the risk of heart attack and stroke. DXM abuse can also cause gastrointestinal problems, such as nausea, vomiting, diarrhea, and abdominal pain. The co-ingestion of DXM with other active ingredients, such as acetaminophen, can further exacerbate the risk of liver damage. The physical health problems associated with chronic DXM abuse can significantly impact an individual’s overall health and well-being.

5.4. The Problem of Additives

A significant concern in the context of DXM abuse is the presence of other active ingredients in OTC cough and cold medications. Many DXM-containing products also contain acetaminophen, antihistamines (like promethazine), and decongestants. These additives can pose significant health risks when taken in excessive doses. Acetaminophen can cause severe liver damage, even at relatively moderate doses. Antihistamines can cause drowsiness, confusion, and cardiovascular problems. Decongestants can cause increased heart rate, high blood pressure, and anxiety. The co-ingestion of DXM with these additives can exacerbate the potential for adverse health effects and increase the risk of overdose. It is crucial to carefully read the labels of DXM-containing products and to avoid taking excessive doses to minimize the risk of adverse effects.

Many thanks to our sponsor Maggie who helped us prepare this research report.

6. Interactions with Other Drugs

DXM can interact with a variety of other drugs, leading to potentially dangerous consequences. These interactions are primarily due to DXM’s effects on the CYP450 enzyme system and its actions on various neurotransmitter systems.

6.1. Promethazine

Promethazine is an antihistamine and antiemetic commonly found in cough and cold medications. When combined with DXM, promethazine can potentiate the sedative and anticholinergic effects of DXM, increasing the risk of drowsiness, confusion, and impaired coordination. Promethazine can also inhibit the CYP2D6 enzyme, which metabolizes DXM. This inhibition can lead to increased DXM concentrations and decreased DXO concentrations, potentially altering the subjective effects and increasing the risk of toxicity. The combination of DXM and promethazine should be avoided, as it can lead to unpredictable and potentially dangerous effects.

6.2. Alcohol

Alcohol is a central nervous system depressant that can potentiate the sedative and respiratory depressant effects of DXM. The combination of DXM and alcohol can lead to increased drowsiness, impaired coordination, respiratory depression, coma, and death. Alcohol can also inhibit the CYP2D6 enzyme, which metabolizes DXM. This inhibition can lead to increased DXM concentrations and decreased DXO concentrations, potentially altering the subjective effects and increasing the risk of toxicity. The combination of DXM and alcohol should be avoided, as it can lead to unpredictable and potentially fatal consequences.

6.3. Selective Serotonin Reuptake Inhibitors (SSRIs)

SSRIs are antidepressants that increase serotonin levels in the synapse. When combined with DXM, SSRIs can increase the risk of serotonin syndrome, a potentially life-threatening condition characterized by agitation, confusion, rapid heart rate, high blood pressure, muscle rigidity, and seizures. The combination of DXM and SSRIs should be avoided, as it can lead to serious and potentially fatal consequences.

6.4. Monoamine Oxidase Inhibitors (MAOIs)

MAOIs are antidepressants that inhibit the breakdown of monoamine neurotransmitters, such as serotonin, norepinephrine, and dopamine. When combined with DXM, MAOIs can lead to a hypertensive crisis, characterized by dangerously high blood pressure, headache, chest pain, and stroke. The combination of DXM and MAOIs is contraindicated, as it can lead to life-threatening complications.

6.5. Other CYP450 Inhibitors

Other drugs that inhibit the CYP2D6 enzyme, such as quinidine, fluoxetine, and paroxetine, can also increase DXM concentrations and decrease DXO concentrations, potentially altering the subjective effects and increasing the risk of toxicity. These drug interactions should be carefully considered when prescribing or using DXM.

Many thanks to our sponsor Maggie who helped us prepare this research report.

7. Current Research on Potential Treatments for DXM Addiction or Overdose

The treatment of DXM addiction and overdose is challenging due to the complex pharmacology of DXM and the potential for serious adverse effects. Current treatment strategies focus on supportive care and management of symptoms. However, research is ongoing to identify more effective treatments for DXM-related health issues.

7.1. Naloxone

Naloxone is an opioid receptor antagonist used to reverse opioid overdoses. While DXM is not a traditional opioid, it has been shown to have some affinity for opioid receptors. Naloxone may be effective in reversing some of the respiratory depressant effects of DXM overdose. However, naloxone is not a specific antidote for DXM overdose, and its effectiveness may be limited. Naloxone might be more effective when respiratory depression is caused by codeine or hydrocodone present in formulations with DXM.

7.2. NMDA Receptor Antagonists

Paradoxically, research is exploring the potential use of other NMDA receptor antagonists, such as ketamine, to treat DXM addiction. The rationale behind this approach is that low doses of ketamine might help to normalize glutamate neurotransmission and reduce craving and withdrawal symptoms. However, this approach is still in its early stages of development and requires further research.

7.3. Sigma-1 Receptor Antagonists

Given the role of the sigma-1 receptor in modulating the effects of DXM, research is exploring the potential use of sigma-1 receptor antagonists to treat DXM addiction. Sigma-1 receptor antagonists might help to reduce craving, withdrawal symptoms, and the reinforcing effects of DXM. However, this approach is also in its early stages of development and requires further research.

7.4. Cognitive Behavioral Therapy (CBT)

CBT is a type of psychotherapy that focuses on changing maladaptive thoughts and behaviors. CBT can be effective in treating substance use disorders, including DXM addiction. CBT can help individuals identify and manage triggers for DXM use, develop coping skills to resist cravings, and improve their overall psychological well-being. CBT is often used in combination with other treatment modalities, such as medication and support groups.

7.5. Future Directions

Future research should focus on developing more specific and effective treatments for DXM addiction and overdose. This research should include studies on the neurobiological mechanisms underlying DXM addiction, the development of novel medications that target these mechanisms, and the evaluation of different psychosocial interventions. It is also crucial to improve surveillance of DXM abuse and to develop effective prevention strategies to reduce the incidence of DXM-related health problems. A deeper understanding of individual variability in DXM metabolism and response is also crucial for personalized treatment approaches. This includes examining the role of genetic factors, age, sex, and co-existing medical conditions in influencing DXM’s effects.

Many thanks to our sponsor Maggie who helped us prepare this research report.

8. Conclusion

Dextromethorphan, while a widely available and generally safe cough suppressant at therapeutic doses, poses a significant risk for abuse and addiction due to its complex pharmacology and psychoactive effects. Its mechanisms of action, involving NMDA receptor antagonism, sigma-1 receptor agonism, and serotonin reuptake inhibition, contribute to a range of effects, from euphoria and altered perception to profound hallucinations and dissociation. Chronic DXM abuse can lead to serious long-term health consequences, including neurocognitive impairment, psychiatric disorders, and physical health problems. The interactions of DXM with other drugs, particularly promethazine, alcohol, and SSRIs, can further exacerbate the risk of adverse effects. Current treatment strategies for DXM addiction and overdose are limited, but research is ongoing to identify more effective treatments. Addressing the challenges posed by DXM abuse requires a multi-faceted approach, including improved surveillance, prevention strategies, and effective treatment modalities. Educational initiatives aimed at raising awareness about the risks of DXM abuse, particularly among adolescents and young adults, are crucial. Furthermore, regulatory measures to restrict access to high-dose DXM-containing products may be warranted. A comprehensive understanding of DXM’s pharmacology, neurobiological effects, and abuse liability is essential for clinicians, researchers, and policymakers to effectively address this growing public health concern.

Many thanks to our sponsor Maggie who helped us prepare this research report.

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