Providing straightforward information pertaining to drugs, drug use & drug policy. The Grey Pages promotes drug-related literacy and advocates a system of viable and tolerant drug policies. This is my personal collection of commentaries, essays, tid-bits, and other such writings on everything ranging from drug use, drug policy and drug-myths, to drug-science, addiction, human behavior, and the workings of the human brain. I started this blog with a particular focus on opioids, and over the past year have found my interest gravitate toward the intriguing, ever-changing world of designer intoxicants (i.e. "research chemicals" or "designer drugs").

Friday, April 27, 2012

The 4 Plateaus: Pharmacology of the DXM Experience

The pharmacological actions of DXM are dose dependent. The subjective and behavioral effects are uniquely defined by various stages of receptor action and receptor saturation.

Low Doses (1st Plateau) - PCP2 mediated increase in dopaminergic tone, PCP1 mediated NMDA Blockade

Dopaminergic effects of DXM are most prominent in the lower range of recreational doses. DXM blocks the reuptake of dopamine by its action at the PCP2 receptor site, located on the surface of the dopamine reuptake complex. Increased synaptic dopamine in the VTA and nucleus accumbens is associated with a state of well being and elevated mood; it is also believed to play a role in the reward, reinforcement, and potential for addiction often attributed to DXM use. Dextromethorphan in this dose range, also known as the first plateau, may produce an invigorating state of pleasure similar to stimulants such as cocaine. Common are feelings of megalomania, delusions of grandeur, self affirmations, increased self confidence, and changes in ego. Auditory stimulation such as music is extremely pleasant, while motor stimulation such as movement (walking, dancing, etc) is desireable as well. As PCP2 sites become saturated with higher doses, PCP2 related dopaminergic effects reach a plateau, becoming less pronounced as sigma1 receptor activity (which runs counter to the aforementioned dopaminergic action) begins to define the experience.

Moderate Doses (2nd and 3rd Plateau) - Sigma agonism, PCP1 mediated NMDA blockade

Dose dependent action of DXM
Source: braintechllc.com
Sigma activity characterizes what is known as the "second plateau". In the moderate dose range, sigma activity becomes more pronounced. Activation of the sigma-1 receptor counteracts the dopaminergic activity observed in the lower dose range. There is increasing alteration of sensory perception and memory. Brain-motor coordination begins to be affected, leading to a robotic-like movement of arms and legs which is especially apparent when walking. the sensation may be described as attempting to walk in zero gravity, and struggling for one's feet to touch the ground. Psychotomimetic (psychotic-like) effects may be present at this dose. 

Cognition is increasingly affected at this level. Blockade at NMDA receptors impairs the mediating of memory and the brain's ability to coordinate communication between conscious mind and data storage sites in the brain - one may lose his/her sense of time, and is often able to perform repetitive or mundane tasks without becoming bored; this may include staring at a wall, or masturbation (joking. jacking off while tripping might be dangerous) - This inability to become bored with repetition has been linked to an inhibition of short term memory. Abstract or bizzarre patterns of thought may become apparent to others, while the user might not perceive their thinking this way. 

As what is termed as the "third plateau" is reached, inhibition of sensory input begins to manifest. Sensory communication from the body and senses to the brain becomes "choppy" - The manifestation of this is bizarre. Events may not be perceived in the mind for seconds or even minutes after their occurence, or might not be experienced at all. One may experience tunnel vision, and lose the sense of self identity, while struggling to understand the current environment. Simply put, one may experience a loss of awareness as to the nature of one's environment, or they may lose their sense of "existence" in general.

High Doses (4th Plateau) - PCP1 mediaterd NMDA blockade 

As sigma receptors become saturated with much higher doses, the sigma action of the 2nd and 3rd plateaus begins to level off, while the action of NMDA blockade continues to progress. The effects of the "4th Plateau" are predominantly associated with NMDA blockade - characterized by a progressive disconnect between sensory input/consciousness, and between areas throughout the brain. The potent NMDA blockade observed at these dose levels has been associated with greater concentrations of the major metabolite, dextrorphan (DXO) - which is much more potent than DXM as an NMDA antagonist.

DXO and the parent drug bind to the PCP1 site located on the interior surface of the NMDA ion channel complex (this is the source of its NMDA antagonistic action). Perhaps the most bizzare effect at this dose level are the increasing gaps in sensory input; this means literally what it sounds like - all physical and environmental perception experiences cut-offs; the best way to describe this experience is simply; an irregular and bizzare state of consciousness where rather than awareness of one's body or environment, there is awareness of nothing; this may be experienced as a complete 'white out' phase, or the complete loss of self awareness. This may be accompanied by strange, disconnected behavior, or a complete incapacity for motor movement and speech.

Sources and Further Off-Site Reading:

Psychopharmacology of Dextromethorphan 
In Depth Neuropharmacology of Dextromethorphan (Erowid) 
Neuropharmacology of PCP 
Sigma, NMDA, and PCP Receptors 

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