Dextromethorphan (DXM) & Mephedrone
Dextromethorphan (DXM) is a synthetic substance primarily used as a cough suppressant in over-the-counter cold and flu medications. DXM is classified as a dissociative drug at higher doses due to its unique pharmacological profile.
At therapeutic doses, DXM works as a non-selective serotonin reuptake inhibitor, which contributes to its cough-suppressing effects. At these low doses, DXM has minimal psychoactive effects and is considered safe when used as directed.
At recreational or high doses, DXM produces a range of dissociative, hallucinogenic, and sedative effects due to its action on various receptor systems. The primary mechanism involves its role as a noncompetitive antagonist at N-methyl-D-aspartate (NMDA) receptors in the central nervous system. By blocking NMDA receptors, DXM disrupts normal glutamate signaling, leading to altered sensory perception, dissociation, and a feeling of detachment from the body and environment. This NMDA antagonism is responsible for the dissociative and psychedelic effects of DXM at high doses.
DXM is also metabolized in the liver by the enzyme CYP2D6 into dextrorphan (DXO), its primary active metabolite. DXO has a stronger affinity for NMDA receptors than DXM itself and is largely responsible for the dissociative effects. Individuals with genetic variations in CYP2D6 activity may metabolize DXM at different rates, leading to variability in effects and potential for toxicity.
In addition to NMDA receptor antagonism, DXM has effects on other neurotransmitter systems. It acts as a sigma-1 receptor agonist, which is thought to contribute to its antidepressant-like effects and some of the subjective experiences at high doses. It also interacts with the serotonin system, particularly by inhibiting serotonin reuptake, which can increase serotonin levels.
At higher doses, DXM can also influence dopamine and norepinephrine pathways, contributing to euphoria, stimulation, or agitation. These effects, combined with its dissociative properties, create the distinct stages or "plateaus" of DXM intoxication. Users often describe four plateaus, each with increasing intensity of dissociation, hallucinations, and physical impairment. The first and second plateaus typically involve mild euphoria and perceptual changes, while the third and fourth plateaus produce profound dissociation, intense hallucinations, and a loss of connection to reality.
Physiologically, DXM can increase heart rate and blood pressure, impair motor coordination, and induce nausea or vomiting. At very high doses, it may lead to dangerous side effects such as respiratory depression, seizures, and toxic psychosis.
Mephedrone, also known as 4-methylmethcathinone or "meow meow," is a synthetic stimulant and entactogen belonging to the cathinone class, which is chemically related to amphetamines and MDMA.
Mephedrone acts primarily as a substrate for monoamine transporters, particularly the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET). It is taken up into presynaptic neurons through these transporters and causes the release of neurotransmitters from vesicles into the synaptic cleft. This results in increased extracellular concentrations of dopamine, serotonin, and norepinephrine, amplifying their signaling and producing its characteristic effects.
The stimulation of dopamine release contributes to mephedrone's euphoric, rewarding, and reinforcing effects. This mechanism is similar to that of amphetamines, making it highly stimulating and potentially addictive. Increased dopamine activity in the mesolimbic pathway is associated with feelings of pleasure and motivation, which often leads to compulsive redosing behavior.
Serotonin release, facilitated by mephedrone’s action at SERT, contributes to its empathogenic effects, such as increased sociability, emotional openness, and feelings of connection with others. These effects are comparable to those of MDMA, although they are generally shorter in duration and less pronounced. Serotonin release also influences mood elevation and sensory enhancement, including intensified perceptions of music and lights.
Norepinephrine release, mediated by mephedrone's action at NET, is responsible for its stimulating properties, such as increased energy, alertness, and heart rate. This component also contributes to physical side effects, including increased blood pressure and vasoconstriction.
Mephedrone also has significant physiological effects due to its sympathomimetic activity. These include increased heart rate, elevated blood pressure, hyperthermia, sweating, pupil dilation, and reduced appetite. At high doses or with repeated use, it can cause serious side effects such as arrhythmias, seizures, and dehydration.
Combining DXM and mephedrone could lead to a highly unpredictable and potentially dangerous interaction due to the distinct pharmacological profiles of each substance.
One significant risk of this combination is the increased likelihood of serotonin syndrome. Both DXM and mephedrone elevate serotonin levels, with DXM acting as a serotonin reuptake inhibitor and mephedrone releasing serotonin from presynaptic neurons. Excessive serotonin activity can lead to symptoms such as agitation, confusion, rapid heart rate, high blood pressure, muscle rigidity, hyperthermia, and in severe cases, seizures or death.
Physiologically, the combination could strain the cardiovascular system. Mephedrone increases heart rate and blood pressure due to its sympathomimetic properties, while DXM can also elevate heart rate at high doses. Together, these effects may lead to significant cardiovascular stress, particularly in individuals with pre-existing conditions or those taking high doses. The potential for hyperthermia is also elevated due to the combined stimulant and dissociative effects, which can impair the body’s ability to regulate temperature.
Another concern is the potential for neurotoxicity. Mephedrone is associated with oxidative stress and damage to serotonin and dopamine neurons, particularly with repeated use. DXM, at high doses, has been implicated in neurotoxicity in animal studies through mechanisms such as excitotoxicity. Combining the two could exacerbate these effects, increasing the risk of long-term cognitive deficits, memory impairment, and mood disorders.
The subjective effects of this combination would likely be unpredictable and highly dose-dependent. Lower doses might produce an unusual mix of stimulation, euphoria, dissociation, and mild hallucinations, while higher doses could result in overwhelming sensory input, confusion, and a loss of control. The contrasting effects of stimulation and dissociation may also create a chaotic mental state, making it difficult for users to interpret their surroundings or manage the experience.
Currently, there is a lack of specific research on the combined use of DXM and mephedrone.
All things considered, we recommend avoiding this combination.
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