Promethazine and Dextromethorphan: A Critical Review of Pharmacology, Risks, and Emerging Concerns

Abstract

Promethazine, a first-generation antihistamine with potent sedative and antiemetic properties, is frequently encountered in clinical practice and, increasingly, in recreational drug use. Its co-administration with dextromethorphan (DXM), a widely available cough suppressant, presents a complex pharmacological interaction with potentially severe consequences. While the combination may be prescribed for specific indications, its misuse and availability on the illicit market have raised significant concerns. This review delves into the multifaceted aspects of promethazine, encompassing its mechanism of action, therapeutic applications, adverse effects, and the synergistic dangers when combined with DXM. Furthermore, we explore the pharmacological rationale behind these dangers, examine emerging trends in recreational use, and discuss strategies for mitigation and prevention. This analysis aims to provide a comprehensive understanding of the risks associated with promethazine, particularly in the context of DXM co-ingestion, and to inform safer prescribing practices, public health interventions, and harm reduction strategies.

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

1. Introduction

Promethazine hydrochloride is a phenothiazine derivative exhibiting antihistaminic, sedative, antiemetic, and anticholinergic properties. It is clinically indicated for a range of conditions, including allergic reactions, motion sickness, nausea and vomiting, and as a sedative or pre-operative adjunct (Simons et al., 2004). Dextromethorphan (DXM), a morphinan derivative, is a widely available over-the-counter (OTC) cough suppressant acting primarily as an NMDA receptor antagonist and a sigma-1 receptor agonist (Miller, 2005). The combination of promethazine and DXM, often found in prescription cough syrups, is intended to address both cough suppression and associated symptoms like nausea or sleep disturbances. However, the synergistic effects of these two drugs, particularly when taken in supratherapeutic doses or combined with other central nervous system (CNS) depressants, can lead to significant morbidity and mortality.

The rise in recreational use of promethazine-containing cough syrups, often mixed with soda and referred to as “purple drank” or “lean,” has amplified the risk profile. This practice is driven by the sedative and euphoric effects perceived by users, often without a full appreciation of the potential dangers. The combination of promethazine’s CNS depressant effects with DXM’s dissociative properties can result in respiratory depression, seizures, coma, and death (Anderson et al., 2012). Furthermore, the lack of standardized dosing and the variability in promethazine and DXM concentrations in illicitly obtained products contribute to unpredictable and potentially lethal outcomes.

This review aims to provide a comprehensive overview of promethazine’s pharmacology, therapeutic uses, and adverse effects, with a specific focus on the risks associated with its co-administration with DXM. We will explore the underlying mechanisms of toxicity, examine the prevalence of recreational use, and discuss strategies for preventing and mitigating the harmful consequences of this dangerous drug combination.

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

2. Promethazine: Pharmacology and Mechanisms of Action

Promethazine is a first-generation H1-receptor antagonist belonging to the phenothiazine class of drugs. Its pharmacological profile is characterized by a complex interplay of actions at multiple receptor sites, contributing to its diverse therapeutic and adverse effects.

2.1. Histamine H1-Receptor Antagonism

The primary mechanism of action of promethazine is the competitive antagonism of histamine H1 receptors. Histamine, a biogenic amine, plays a crucial role in allergic reactions, inflammation, and neurotransmission. By blocking H1 receptors, promethazine effectively reduces histamine-mediated effects such as vasodilation, increased vascular permeability, bronchoconstriction, and pruritus (Simons et al., 2004). This antihistaminic activity is the basis for promethazine’s use in treating allergic rhinitis, urticaria, and other allergic conditions.

2.2. Muscarinic Receptor Antagonism (Anticholinergic Effects)

Promethazine exhibits significant anticholinergic activity, blocking muscarinic acetylcholine receptors. This antagonism results in a variety of effects, including dry mouth, blurred vision, constipation, urinary retention, and tachycardia. The anticholinergic properties also contribute to promethazine’s antiemetic effects, as acetylcholine plays a role in the emetic reflex pathway. However, these anticholinergic effects can also be problematic, particularly in elderly patients who are more susceptible to their adverse consequences, such as cognitive impairment and increased risk of falls (Tune & Egeli, 1968).

2.3. Dopamine Receptor Antagonism

As a phenothiazine derivative, promethazine possesses dopamine receptor antagonistic properties, although to a lesser extent than some other antipsychotic agents. This dopamine receptor blockade contributes to promethazine’s antiemetic effects by inhibiting dopamine-mediated neurotransmission in the chemoreceptor trigger zone (CTZ) of the medulla oblongata (Anderson et al., 2012). However, dopamine receptor antagonism can also lead to extrapyramidal side effects (EPS), such as dystonia, akathisia, and parkinsonism, although these are less common with promethazine than with high-potency antipsychotics.

2.4. Alpha-Adrenergic Receptor Antagonism

Promethazine also exhibits alpha-adrenergic receptor antagonistic activity, which can result in vasodilation and orthostatic hypotension. This effect is particularly pronounced in patients who are volume-depleted or taking other medications that lower blood pressure. The alpha-adrenergic blockade can also contribute to dizziness and lightheadedness.

2.5. Central Nervous System Depression

Promethazine is a potent CNS depressant, causing sedation, drowsiness, and impaired cognitive function. This effect is mediated by a combination of its antihistaminic, anticholinergic, and alpha-adrenergic antagonistic properties. The CNS depressant effects of promethazine are additive with other CNS depressants, such as alcohol, benzodiazepines, and opioids, increasing the risk of respiratory depression and coma.

2.6. Metabolism and Pharmacokinetics

Promethazine is metabolized primarily by the liver via CYP2D6 and to a lesser extent by CYP2C19. Genetic polymorphisms in these enzymes can affect promethazine metabolism, leading to interindividual variability in drug exposure and response (von Moltke et al., 2001). The elimination half-life of promethazine is approximately 9-16 hours, and its effects can persist for several hours after administration. This relatively long half-life contributes to its prolonged sedative effects and increases the risk of drug accumulation with repeated dosing.

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

3. Dextromethorphan: Pharmacology and Mechanisms of Action

Dextromethorphan (DXM) is a synthetic morphinan derivative that is widely used as an over-the-counter cough suppressant. Unlike opioid cough suppressants such as codeine, DXM has minimal affinity for opioid receptors and does not typically produce significant analgesic or euphoric effects at therapeutic doses. However, at higher doses, DXM exhibits a complex pharmacological profile, acting as an NMDA receptor antagonist, a sigma-1 receptor agonist, and a serotonin reuptake inhibitor (SRI) (Miller, 2005).

3.1. NMDA Receptor Antagonism

The primary mechanism of action responsible for DXM’s cough-suppressant effects is its antagonism of the NMDA receptor. NMDA receptors are glutamate receptors that play a critical role in neuronal excitability, synaptic plasticity, and pain transmission. By blocking NMDA receptors in the cough center of the brainstem, DXM reduces the sensitivity of the cough reflex and suppresses coughing. At supratherapeutic doses, NMDA receptor antagonism contributes to DXM’s dissociative and hallucinogenic effects, similar to those produced by ketamine and phencyclidine (PCP).

3.2. Sigma-1 Receptor Agonism

DXM also acts as an agonist at the sigma-1 receptor, a transmembrane protein that is widely distributed throughout the brain and body. The precise role of the sigma-1 receptor is not fully understood, but it is thought to be involved in modulating neuronal excitability, synaptic plasticity, and stress responses. Sigma-1 receptor agonism may contribute to DXM’s antidepressant and anxiolytic effects, as well as its potential for abuse (Maurice & Goguadze, 2006). High doses can cause psychosis via sigma-1 agonism.

3.3. Serotonin Reuptake Inhibition (SRI)

DXM and its primary metabolite, dextrorphan (DXO), inhibit the reuptake of serotonin, increasing serotonin levels in the synaptic cleft. This SRI activity can contribute to DXM’s antidepressant and anxiolytic effects, but it also increases the risk of serotonin syndrome, particularly when DXM is combined with other serotonergic drugs, such as selective serotonin reuptake inhibitors (SSRIs) or monoamine oxidase inhibitors (MAOIs). Furthermore, DXM can act as a prodrug for DXO, the metabolite also possesses stronger activity in each of the aforementioned areas.

3.4. Metabolism and Pharmacokinetics

DXM is rapidly absorbed from the gastrointestinal tract and metabolized primarily by CYP2D6 to dextrorphan (DXO), which is also active. Genetic polymorphisms in CYP2D6 can significantly affect DXM metabolism, with some individuals being poor metabolizers and others being ultrarapid metabolizers. Poor metabolizers experience higher plasma concentrations of DXM and may be more susceptible to its adverse effects, while ultrarapid metabolizers experience lower plasma concentrations of DXM and may be less responsive to its therapeutic effects (Schmid et al., 2007). The effects of DXM can last between 3-6 hours depending on dose and metabolism.

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

4. Promethazine and Dextromethorphan Interaction: Synergistic Risks

The co-administration of promethazine and dextromethorphan (DXM) presents a complex pharmacological interaction with potentially dangerous consequences. The synergistic effects of these two drugs, particularly when taken in supratherapeutic doses or combined with other CNS depressants, can lead to significant morbidity and mortality. The combined CNS depressant effects are the main contributor to risk.

4.1. Additive CNS Depression

Both promethazine and DXM possess CNS depressant properties, and their combined use results in an additive effect. Promethazine’s antihistaminic, anticholinergic, and alpha-adrenergic antagonistic actions contribute to sedation, drowsiness, and impaired cognitive function, while DXM’s NMDA receptor antagonism and sigma-1 receptor agonism also contribute to CNS depression. When taken together, these drugs can synergistically depress the CNS, leading to respiratory depression, coma, and death. This risk is further amplified when promethazine and DXM are combined with other CNS depressants, such as alcohol, benzodiazepines, or opioids.

4.2. Increased Risk of Respiratory Depression

Respiratory depression is a major concern with promethazine and DXM co-ingestion. Promethazine can directly depress the respiratory center in the brainstem, while DXM can indirectly contribute to respiratory depression by causing muscle relaxation and decreasing the sensitivity of the respiratory center to carbon dioxide. The combined effects of these two drugs can lead to hypoventilation, hypoxia, and respiratory arrest. Individuals with pre-existing respiratory conditions, such as asthma or chronic obstructive pulmonary disease (COPD), are at increased risk of respiratory complications.

4.3. Potentiation of Anticholinergic Effects

Promethazine exhibits significant anticholinergic activity, and its co-administration with DXM can potentiate these effects. While DXM does not possess intrinsic anticholinergic properties, its NMDA receptor antagonism can indirectly enhance cholinergic neurotransmission in some brain regions. The combined anticholinergic effects of promethazine and DXM can lead to dry mouth, blurred vision, constipation, urinary retention, tachycardia, and cognitive impairment. These effects can be particularly problematic in elderly patients, who are more susceptible to anticholinergic toxicity.

4.4. Serotonin Syndrome Risk

Although DXM’s serotonin reuptake inhibition (SRI) is relatively weak at therapeutic doses, it can still contribute to serotonin syndrome, particularly when combined with other serotonergic drugs. Promethazine, in addition to other mechanisms, can indirectly lead to increased serotonin levels. Serotonin syndrome is a potentially life-threatening condition characterized by a triad of symptoms: mental status changes (e.g., confusion, agitation), autonomic instability (e.g., tachycardia, hyperthermia, diaphoresis), and neuromuscular abnormalities (e.g., tremor, hyperreflexia, clonus). The risk of serotonin syndrome is increased when promethazine and DXM are combined with SSRIs, MAOIs, or other serotonergic agents.

4.5. QTc Prolongation

Both promethazine and DXM have been associated with QTc prolongation, a risk factor for potentially fatal cardiac arrhythmias. QTc prolongation refers to an increase in the corrected QT interval on an electrocardiogram (ECG), which reflects the time it takes for the ventricles of the heart to repolarize after each heartbeat. Prolongation of the QTc interval increases the risk of developing torsades de pointes, a type of ventricular tachycardia that can lead to sudden cardiac death. The combined use of promethazine and DXM may further increase the risk of QTc prolongation, particularly in individuals with pre-existing cardiac conditions or those taking other medications that prolong the QTc interval.

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

5. Recreational Use of Promethazine and Dextromethorphan: The “Purple Drank” Phenomenon

The recreational use of promethazine-containing cough syrups, often mixed with soda and referred to as “purple drank,” “lean,” or “sizzurp,” has emerged as a significant public health concern. This practice is driven by the perceived sedative and euphoric effects of the combination, often without a full appreciation of the potential dangers. The “purple drank” phenomenon has gained popularity among adolescents and young adults, fueled by its portrayal in popular music and social media.

5.1. Motivations for Recreational Use

Individuals who engage in the recreational use of promethazine and DXM often report seeking a combination of effects, including:

• Sedation and relaxation: Promethazine’s antihistaminic and anticholinergic properties produce a calming and relaxing effect, which users often find appealing.
• Euphoria and disinhibition: DXM’s NMDA receptor antagonism can induce feelings of euphoria, disinhibition, and altered perception.
• Social influence and peer pressure: The use of “purple drank” is often associated with a particular subculture and may be driven by social influence and peer pressure.
• Novel experiences: Many users take high doses of DXM and promethazine to create hallucinogenic and altered states of consciousness.

5.2. Prevalence and Demographics

The prevalence of recreational promethazine and DXM use is difficult to quantify, as it is often underreported and not specifically tracked in national surveys. However, anecdotal evidence suggests that the practice is widespread, particularly among adolescents and young adults in urban areas. Studies have shown that certain demographic groups, such as African Americans and individuals with a history of substance abuse, may be at higher risk.

5.3. Risks and Consequences

The recreational use of promethazine and DXM carries significant risks and consequences, including:

• Overdose and death: The combination of promethazine and DXM can lead to respiratory depression, coma, and death, particularly when taken in supratherapeutic doses or combined with other CNS depressants.
• Seizures: DXM, particularly at high doses, can lower the seizure threshold and increase the risk of seizures.
• Cardiovascular complications: Promethazine and DXM can both prolong the QTc interval and increase the risk of cardiac arrhythmias.
• Cognitive impairment: Chronic use of promethazine and DXM can lead to cognitive impairment, including memory problems and difficulty concentrating.
• Psychiatric complications: DXM can trigger or exacerbate psychiatric symptoms, such as anxiety, depression, and psychosis.
• Dependence and addiction: While not typically considered highly addictive, chronic use of promethazine and DXM can lead to psychological dependence and withdrawal symptoms upon cessation.

5.4. Challenges in Detection and Treatment

The detection and treatment of recreational promethazine and DXM use pose several challenges:

• Lack of awareness: Many healthcare professionals are not fully aware of the risks associated with recreational promethazine and DXM use.
• Difficulty in diagnosis: The symptoms of promethazine and DXM overdose can be nonspecific and may mimic other medical conditions.
• Limited treatment options: There are no specific antidotes for promethazine or DXM overdose, and treatment is primarily supportive.
• Stigma and secrecy: Individuals who engage in recreational promethazine and DXM use may be reluctant to seek medical help due to stigma and fear of legal consequences.

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

6. Mitigation and Prevention Strategies

Addressing the risks associated with promethazine and DXM, both in therapeutic and recreational contexts, requires a multi-faceted approach encompassing safer prescribing practices, public health education, and harm reduction strategies.

6.1. Safer Prescribing Practices

• Judicious use of promethazine: Prescribers should carefully consider the risks and benefits of promethazine before prescribing it, particularly in patients with pre-existing respiratory conditions, cardiovascular disease, or a history of substance abuse. Consider alternative therapies when possible.
• Avoidance of co-prescription with other CNS depressants: Promethazine should not be co-prescribed with other CNS depressants, such as alcohol, benzodiazepines, or opioids, unless absolutely necessary. If co-prescription is unavoidable, patients should be closely monitored for signs of respiratory depression and other adverse effects.
• Patient education: Patients should be educated about the risks associated with promethazine and DXM, including the potential for respiratory depression, seizures, and QTc prolongation. They should be advised to avoid combining these drugs with alcohol or other CNS depressants and to seek medical attention if they experience any concerning symptoms.

6.2. Public Health Education

• Targeted awareness campaigns: Public health campaigns should be targeted at adolescents and young adults to raise awareness of the risks associated with recreational promethazine and DXM use. These campaigns should emphasize the potential for overdose, seizures, cardiovascular complications, and cognitive impairment.
• Social media interventions: Social media platforms can be used to disseminate accurate information about the risks of promethazine and DXM and to counter misinformation and glamorization of “purple drank.”
• Community outreach programs: Community outreach programs can provide education and support to individuals at risk of recreational promethazine and DXM use. These programs should focus on harm reduction strategies, such as safe dosing practices and recognizing the signs of overdose.
• School-based prevention programs: School-based prevention programs can educate students about the risks of drug use and promote healthy decision-making skills. These programs should be evidence-based and tailored to the specific needs of the community.

6.3. Harm Reduction Strategies

• Naloxone distribution: Naloxone, an opioid antagonist, can reverse the effects of opioid overdose and prevent death. Naloxone distribution programs should be expanded to include individuals at risk of promethazine and DXM overdose, as opioids are frequently used in combination with these drugs.
• Overdose prevention education: Overdose prevention education should be provided to individuals at risk of promethazine and DXM overdose, as well as their friends and family members. This education should include information about recognizing the signs of overdose, administering naloxone, and calling emergency services.
• Safe injection sites: Safe injection sites, also known as supervised consumption sites, provide a safe and hygienic environment for individuals to use drugs under medical supervision. These sites can reduce the risk of overdose, infection, and other harms associated with drug use.
• Drug checking services: Drug checking services allow individuals to have their drugs tested for purity and adulterants. This information can help individuals make informed decisions about their drug use and reduce the risk of overdose.

6.4. Legislative and Regulatory Measures

• Increased regulation of promethazine: Promethazine is currently available over-the-counter in some jurisdictions. Increased regulation of promethazine, such as requiring a prescription for its purchase, may help to reduce its availability for recreational use.
• Restrictions on marketing and advertising: Marketing and advertising of promethazine-containing cough syrups should be restricted to prevent the glamorization of recreational use.
• Enhanced law enforcement efforts: Law enforcement efforts should be focused on disrupting the illicit supply of promethazine and DXM and prosecuting individuals involved in the manufacture and distribution of counterfeit products.

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

7. Future Directions

Further research is needed to fully understand the risks associated with promethazine and DXM, particularly in the context of recreational use. Future research should focus on:

• Epidemiological studies: Epidemiological studies are needed to better understand the prevalence and trends of recreational promethazine and DXM use.
• Pharmacological studies: Pharmacological studies are needed to further investigate the mechanisms of toxicity associated with promethazine and DXM co-ingestion.
• Clinical trials: Clinical trials are needed to evaluate the effectiveness of different treatment strategies for promethazine and DXM overdose.
• Qualitative research: Qualitative research is needed to understand the motivations and experiences of individuals who engage in recreational promethazine and DXM use.
• Development of new antidotes: Research should be conducted to develop new antidotes for promethazine and DXM overdose.

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

8. Conclusion

Promethazine, while a useful medication for various conditions, carries significant risks, particularly when combined with dextromethorphan (DXM). The synergistic CNS depressant effects, increased risk of respiratory depression, potentiation of anticholinergic effects, potential for serotonin syndrome, and QTc prolongation necessitate careful consideration and prudent prescribing practices. The rise of recreational “purple drank” use further exacerbates these risks, demanding targeted public health interventions, harm reduction strategies, and enhanced awareness among healthcare professionals and the public. By implementing these measures, we can mitigate the dangerous consequences of promethazine and DXM co-ingestion and protect vulnerable populations from harm.

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

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