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Dextromethorphan as an Intoxicant: Behavioral and Neuropharmacological Effects

Copyright (C) 2002, Owen Emlen.  All Rights Reserved.

Western Washington University (WWU)

Dextromethorphan, or DXM, is a common drug used in cough syrup preparations.  DXM, along with Ketamine and Phencyclidine (PCP), belongs to a class of drugs called disassociative anesthetics.  These drugs are grouped together because they all antagonize NMDA receptors, eventually causing anesthetic disassociation from all sensory input.  At low doses, DXM suppresses the cough response.  At higher doses it causes dramatic shifts in sensory perception.  This paper reviews the neuropharmacological and behavioral properties of DXM when taken at several common recreational doses.  Behavioral effects are divided into three discrete dose-related levels based on receptor saturation and density.  After examining behavioral effects related to DXM’s pharmacodynamics, the paper covers DXM’s pharmacokinetics and the relationship to duration and intensity of effect.

Dextromethorphan, or DXM, is a common drug used in cough syrup preparations.  DXM replaced codeine in most over-the-counter preparations around 30 years ago in the USA, when it was shown to be a less addictive, equally effective alternative with fewer harmful side effects (Bem and Peck, 1992).  However, higher doses of DXM cause dramatic shifts in sensory perception, and therefore DXM is used as a recreational intoxicant as well.  This paper discusses the classification of DXM, its pharmacodynamics, and its behavioral effects at varying doses.  The last section covers DXM’s pharmacokinetics, including metabolism and the psychoactive properties of its metabolites.

DXM is a synthetic morphine analog.  However, DXM does not have any opiate-like effects, nor does it bind to opiate receptors.  Instead, DXM belongs to a class of drugs called the disassociative anesthetics.  This class of drug also includes Ketamine and Phencyclidine (PCP).  All disassociative anesthetics cause anesthesia and disassociation from sensory input at high doses by antagonizing NMDA receptors (McEnvoy, 1993).

Pharmacodynamics and Dose-related Behavioral Effects

Like many recreational drugs, DXM is not “clean”, in that it affects more than just NMDA receptors.  DXM’s behavioral and experiential changes are due to a unique combination of neuropharmacological effects, which include binding to Sigma₁, PCP₂, Sigma₂, and NMDA receptor sites (Zhou and Musacchio, 1991).  Sigma₁ and sigma₂ receptors are unique, non-opiod receptors (endogenous opioid peptides show little sigma activity, although many opiates also bind at these sites) (McCann et al., 1994).  PCP₂ receptors are located on dopamine reuptake complexes (Akunne et al., 1992).  NMDA receptors are involved in general glutamatergic excitatory action.  What makes DXM so interesting is that the behavioral changes caused by varying doses of the drug can be traced directly to proportional amounts of receptor occupation.  In this way, effects of DXM can be separated into three different behavioral and experiential “plateaus”.  These plateaus directly correlate with various dosages at which certain receptors become saturated.  In this way, DXM offers a unique glimpse at how neuropharmacological action is directly related to drug experience and behavioral changes (White, 2001, Section 9).  Throughout the following sections, please refer to figure 1 for a graph approximating the receptor binding (and saturation) as a function of DXM dose.

                                                                                   At a low dose (1.5 to 2.5 mg/kg), or “level 1”, the effects of DXM are mainly determined by its PCP₂ receptor binding profile (see figure 1).  When DXM binds to the PCP₂ binding site (which is located in the dopamine reuptake complex), dopamine reuptake is inhibited (Akunne et al., 1992).  This has the effect of raising synaptic dopamine levels, which has a similar end-effect (but of different magnitude) as the antidepressant Bupropion or the recreational drug cocaine (Witkin et al, 1993).  The PCP₂-related increase in dopamine levels may be related to the reports of euphoria at this first “dose level.”  These reports often link a feeling of euphoria to auditory stimulation (music) and motor stimulation (motion).  Prolonged use of DXM can lead to addiction in some individuals because of its dopaminergic activity (especially in the nucleus accumbens).  Although there are no dangerous physical withdrawal symptoms, psychological dependency (and withdrawal-related depression) can occur with regular use (McElwee, 1990).  Fortunately, it is reported (but has not yet been scientifically verified) that many users find significant negative effects also accompany the DXM experience.  These negative side effects may explain why so few people choose to use DXM regularly.  Acting counter to this dopamine increase, activation of sigma₁ receptors, located on dopaminergic nerve terminals, reduces normal NMDA-stimulated dopamine release (Gonzales et al., 1995).  At low doses, binding to sigma₁ is relatively low.  However, at higher doses, PCP₂ receptors become saturated and sigma₁ activity continues to increase.  For this reason, synaptic dopamine increase is most dramatic at this low dose level and diminishes at higher doses.  This dopamine regulation at higher doses may also help explain why DXM is not more commonly abused.

At a moderate dose (2.5 to 7.5 mg/kg), or “level 2”, PCP₂ receptors become saturated and the main experiential effects become defined by increasing sigma₁ binding.  The sigma₁ receptor is functionally coupled with nicotinic acetylcholine and NMDA receptors.  Sigma₁ agonists have been shown to protect hippocampal cells from hypoxia and hypoglycemia by regulating excitatory amino acids released from presynaptic sites.  However, sigma₁ agonism does not reduce NMDA-induced neurotoxicity (Nakazawa et al, 1998).  Sigma₁ receptors are located in the cerebellum, nucleus accumbens, and the cortex.  There are also sigma₁ receptors located (in lower density) in the limbic areas and in the extrapyramidal motor system (Gonzalez-Alvear et al, 1995).  Some novel sigma₁-related behavioral effects begin to emerge starting at the “level 2” dose range.  One predominant effect is a change in the sense of bodily motion, or having “sea legs”.  This is likely due to sigma₁ receptor stimulation in the cerebellum and motor system.  Also, the psychomimetic effects of DXM begin to emerge at this dosage level, likely due to sigma₁ receptor stimulation.  Support for this brain-psychotomimetic-behavior link comes from studies which have shown that chronic amphetamine use increases the amount of sigma₁ receptors (Itzhak, 1993), and from research that suggests that everything from amphetamine psychosis to schizophrenia may be due, in part, to sigma₁ activity (Simpson et al., 1991).  Along with sigma₁ agonism at this dose level, DXM’s active metabolite, dextrorphan (DXO), begins to block a growing number of NMDA channels.  When DXO binds inside an open NMDA channel, it blocks the channel, preventing sodium, calcium, or any other excitatory chemical from entering the neuron.  Combining sigma₁ activation with this NMDA antagonism, intermediate and working memory become impaired.  This effect may contribute to losing one’s sense of time.  In addition, sigma₁ and NMDA blockade may be responsible for the common sensation amongst DXM users that repetitive tasks never get boring.  This effect may be due to a combination of short-term memory impairment coupled with dopaminergic-related reward and increased motor activity.  Also likely due to both sigma₁ binding and increasing NMDA antagonism, many users report that hyper-abstraction begins in this dose range.  User reports suggest that thoughts become abstract to the point where they seem absurd to an outside observer, and the concept of cause and effect can disappear completely (White, 2001, Section 5.3).  These quotes give two examples of hyper-abstraction reported by anonymous DXM users:

[One] user wrote of thinking about convergent infinite sums (e.g., 1/2 + 1/4 + 1/8 + etc., which sums up to 1). Although one can add these terms up forever, it's easier to abstract the process and get the answer that way. This user imagined an infinite series of abstractions, and then imagined abstracting that infinite series to get a new level or plane of abstraction (White, 2001, Section 9.2.8).

Many DXM thought patterns involve what some have called "Strange Loops" in logic (Godel, Escher, Bach, 1979). Like the self-contradicting statement "this statement is false", some of them cannot be embodied in logical form; others can be, but cannot be derived without presenting them as hypothesis. Thinking at this degree of abstraction is very difficult (unless you are fortunate enough to be Kurt Gödel) (White, 2001, Section 9.2.8).

When sigma₁ modulation is combined with NMDA antagonism, sensory input starts to become “choppy”.  Depth perception fails, and the ability to coordinate incoming sensory information with a continuous perception of time disappears.  This leads to two opposite sensory alterations: that many events are happening “at once”, or that several concurrent events are processed seconds after each is actually experienced.  This can lead to an experience of viewing the world through a sensory “strobe-light effect” (White, 2001, Section 5.3).  Sigma₁ receptors are also located throughout the body.  Research suggests sigma₁ receptors can inhibit tumor growth (Brent and Pang, 1995), as well as inhibit the immune system.

At higher doses (7.5 to 15mg/kg), or “level 3”, the PCP₂ and sigma₁ receptors have saturated, so any new effects that emerge are the result of increasing dose-related antagonism of NMDA receptors by DXO (DXM’s active metabolite).  Increasing NMDA blockade in the prefrontal cortex leads to severe thought distortion and deficit in higher cognitive function.  The massive blockade of NMDA receptor channels at this dose level also leads to severe inhibition of long-term potentiation in the hippocampus, which is involved in memory formation.  Thus, the user who takes this higher dose may retain only small fragments of the experience after-the-fact.  The increasing NMDA blockade coupled with saturated sigma₁ receptors causes an elevation in dopamine activity in the striatum, nucleus accumbens, olfactory tubercule, and the prefrontal cortex (Wedzony and Golembiowska, 1993).  This dopaminergic activity in the nucleus accumbens may increase the rewarding effects and the addictive potential.  The increasing dopamine levels in the prefrontal cortex may lead to an increase in psychotomimetic effects.  Also, dopamine increase may also contribute to some of the more obscure reported experiential effects at this level of dosage, such as an enhancement of smell (possible hypothesis: via dopamine in the olfactory tubercule?).  Some users report near-death or out-of-body experiences at this high dose level, which might be explained by the extreme disruption of sensory input to the temporal lobe (and other limbic areas) caused by NMDA blockade.  DXM becomes toxic for many individuals starting around 20mg/kg, at which total separation from reality and any sensory input occurs, also known as disassociative anesthesia.  These high doses can also lead to excitotoxicity, or cell death.  Normal NMDA activity keeps other neurotransmitters, including glutamate, from being over-secreted in certain areas of the brain.  So, when NMDA channels are blocked by DXM’s metabolite, DXO, glutamate levels can increase to the point where neuronal hyperactivity can occur, possibly leading to cell death.  Long term lesions in the brain, known as Olney’s lesions, are caused by this glutamate-induced excitotoxicity (Rothman and Olney, 1995).  Interestingly enough, DXM was studied as a post-stroke treatment (similar to hypoxic-ischemic injury) because of its apparent neuroprotective value at lower doses.  Because high doses cause toxicity and seizure, DXM and other disassociative anesthetics were rejected as post-stroke treatment drugs.  However, a 3-amino analog of DXM (AHN649) with low-affinity NMDA antagonistic properties, has been shown to be effective at protecting from ischemic injury.  AHN649 is also devoid of DXM’s negative side effects (seizure and neurotoxicity), even at high doses (Tortella et al, 1999).

Pharmacokinetics

DXM, in the form of hydrobromide salt, is quickly absorbed by the gastro-intestinal tract when taken orally, and can fully enter the bloodstream in as little as 30 minutes.  Once in the bloodstream, DXM easily passes through the blood-brain barrier into the brain.  DXM’s primary route of metabolism is through the liver.  In normal individuals, liver enzyme cytochrome P450-2D6 converts approximately 90% of DXM into dextrorphan, or DXO, DXM’s primary psychoactive metabolite.                The remaining 10% of DXM is converted into 3-methoxymorphinan (3MM) by liver enzyme cytochrome P450-3A.  From there, both DXO and 3MM are converted (by the liver) into 3-hydroxymorphinan (3HM) by P450-3A and P450-2D6 respectively.  3MM and 3HM have no psychoactive properties (McEnvoy, 1993).   7% of Caucasians (and 0.5% of Asians) have a genetic difference which makes their cytochrome P450-2D6 enzymes about 70 times less efficient (Jacqz-Aigrain and Cresteil, 1992).  Because 3MM and 3HM are not psychoactive, the individuals who have slower P450-2D6-related metabolism will experience greatly reduced effects, due to much lower concentrations of DXM’s primary NMDA-antagonist metabolite, DXO (Jacqz-Aigrain et al, 1993).

Many other drugs also inhibit the P450-2D6 enzyme, including most antidepressants and many antihistamines.  Therefore, taking these drugs before ingesting a dose of DXM will greatly reduce the effects of the drug by competing for the 2D6 enzyme (White, 2001, Appendix 15.1).  Because both DXM and DXO compete for the 2D6 enzyme, taking a “booster” dose of the drug causes a lengthening of effect, but very little increase in psychoactive effect.  This occurs because DXO is being actively metabolized into 3HM by P450-2D6, so there is less of the liver enzyme available to convert the new DXM to DXO (Jacqz-Aigrain et al, 1993).