Dextromethorphan (DXM) & LSD
Dextromethorphan (DXM) is a synthetic morphinan compound that primarily acts as a cough suppressant but has additional pharmacological effects depending on the dose. It functions as an NMDA receptor antagonist, a sigma-1 receptor agonist, and an inhibitor of serotonin and norepinephrine reuptake.
When taken in higher doses, DXM produces dissociative and hallucinogenic effects due to its antagonism of NMDA receptors, which are glutamate-gated ion channels critical for synaptic plasticity and neuronal communication. Blocking these receptors disrupts normal excitatory neurotransmission, leading to alterations in perception, thought processes, and sensory integration. The sigma-1 receptor activation may contribute to neuroprotection and modulation of neurotransmitter systems, possibly influencing mood and cognition.
DXM is metabolized primarily in the liver by cytochrome P450 2D6 into dextrorphan (DXO), its active metabolite. DXO has a higher affinity for NMDA receptors and is responsible for much of the dissociative effects associated with high-dose DXM use. The metabolic rate varies between individuals, with some being poor metabolizers due to genetic variations in CYP2D6 activity, leading to prolonged effects and increased susceptibility to adverse reactions.
In addition DXM inhibits the reuptake of serotonin and norepinephrine, potentially leading to serotonergic effects that can range from mild mood elevation to serious complications like serotonin syndrome if combined with other serotonergic drugs. It also interacts with opioid receptors, though it lacks significant analgesic properties.
Lysergic acid diethylamide (LSD) is a potent serotonergic hallucinogen that primarily exerts its effects by interacting with serotonin (5-hydroxytryptamine, 5-HT) receptors in the brain. The primary target of LSD is the 5-HT2A receptor, a G-protein-coupled receptor that plays a critical role in sensory perception, cognition, and mood regulation. When LSD binds to 5-HT2A receptors, it induces a conformational change that leads to altered signaling through intracellular pathways, including the activation of phospholipase C and increased calcium ion release. This results in changes in neuronal excitability, synaptic plasticity, and functional connectivity between different brain regions.
LSD also interacts with other serotonin receptors, including 5-HT1A, 5-HT2B, and 5-HT2C, contributing to its complex effects on mood, cognition, and perception. Additionally, LSD has some affinity for dopamine D2 receptors, which may contribute to its stimulating and psychotomimetic properties. By modulating dopamine activity, LSD can enhance motivation, reward sensitivity, and spontaneous thought generation. LSD also affects the locus coeruleus, a brainstem nucleus responsible for processing sensory information and regulating arousal. By altering the way sensory stimuli are filtered and interpreted, LSD leads to an enhanced perception of external and internal experiences, often resulting in synesthesia, visual distortions, and profound changes in thought patterns.
Neuroimaging studies have shown that LSD disrupts the default mode network (DMN), a collection of interconnected brain regions involved in self-referential thinking, ego integrity, and the distinction between self and environment. The disruption of the DMN is associated with the characteristic ego dissolution and altered self-perception experienced during LSD intoxication. By increasing global brain connectivity and reducing hierarchical processing, LSD promotes a state of cognitive flexibility, allowing for novel associations, increased introspection, and a breakdown of rigid thought patterns.
At high doses, LSD can produce intense hallucinations, altered sense of time, and profound mystical or existential experiences. Physiologically, LSD causes mild sympathomimetic effects such as increased heart rate, elevated blood pressure, and pupil dilation due to its interactions with the autonomic nervous system.
The combination of DXM and LSD would likely produce a complex and unpredictable interaction due to their overlapping and distinct mechanisms of action. At the serotonergic level, combining compounds could lead to excessive 5-HT2A activation, potentially amplifying perceptual distortions, synesthesia, and ego dissolution. This may result in intensified psychedelic effects, with heightened visual hallucinations, altered thought patterns, and an increased likelihood of dissociation. The serotonergic overlap also raises the risk of serotonin syndrome, a potentially dangerous condition characterized by hyperthermia, autonomic instability, neuromuscular abnormalities, and altered mental status. The severity of this risk depends on the doses involved and individual metabolic factors, particularly cytochrome P450 2D6 activity, which affects DXM metabolism.
The combination might blur the boundary between psychedelic and dissociative experiences, inducing dream-like distortions and impairing the ability to integrate sensory input and thoughts coherently. Users might experience a profound disconnect from their surroundings, difficulty communicating, and a distorted sense of self and time.
This combination could lead to excessive dopaminergic stimulation, increasing the risk of paranoia, delusional thinking, and manic-like states, particularly at high doses. The unpredictability of dopamine’s role in psychedelic and dissociative experiences may contribute to erratic mood shifts and emotional instability.
Physiologically, both substances can increase heart rate and blood pressure due to their sympathomimetic properties, leading to potential cardiovascular strain. DXM, particularly at higher doses, can cause significant ataxia, dizziness, and nausea, which might make the LSD experience less controllable and more physically uncomfortable. The combination could also prolong the overall experience, as DXM’s long-lasting effects may extend the dissociative state beyond LSD’s typical duration.
Cognitively, this combination might lead to profound but chaotic introspection. While LSD generally enhances cognitive flexibility and promotes insight, DXM’s dissociative properties could fragment thoughts, making it difficult to maintain coherence or derive meaningful interpretations from the experience. This could either result in an overwhelming sense of confusion or, in some cases, facilitate deep dissociative introspection that might feel meaningful but be difficult to recall or integrate after the experience ends.
Psychological risks are significant, as the combination could increase the likelihood of anxiety, panic, or psychotic-like states, particularly in individuals prone to mental health disorders. The loss of cognitive grounding might increase the risk of reckless behavior, self-harm, or dissociation severe enough to impair memory formation.
Users have described profound experiences characterized by both heightened sensory perception and dissociative states. For instance, one individual recounted alternating between feelings of "complete oneness" and "complete dissociation," leading to a sensation of being "fully alive and fully dead at the same time."
Another account detailed an overwhelming experience where the individual felt deeply depersonalized, experiencing intense visual hallucinations and a sense of sinking within oneself. This person emphasized that while the combination led to a profound trip, it was so powerful and terrifying that they were hesitant to repeat it.
Discussions among users suggest that combining DXM and LSD can significantly potentiate the effects of both substances. Some recommend starting with lower doses than usual due to this amplification. For example, one user advised taking a low dose of DXM first to manage its side effects before introducing LSD, noting that this approach allowed for better control over the trip.
However, it's important to note that these reports are subjective and based on individual experiences. The combination of DXM and LSD can lead to unpredictable and potentially dangerous outcomes. Users have reported severe nausea, intense dissociation, and overwhelming psychological effects.
Given the lack of controlled studies on this combination, individuals are advised to approach it with caution and be aware of the potential risks involved. This combination requires a lot of experience with substances separately, compliance with minimum dosages, rare repetition and a meaningful approach.
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