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APPENDICES


Appendix 1: P450 Inhibiting Drugs

This is a partial list of recreational and medical drugs which inhibit the P450 enzymes 2D6, 3A4, and 3A5. Not all of them will inhibit all of the P450 enzymes, but it's safe to say that a substantial number of these will interact with DXM.

Generally speaking, inhibitors of P450-2D6 include antidepressants (both SSRIs and tricyclics, and possibly MAO inhibitors), antiparasitics (especially antimalarials), antihistamines (both prescription and over-the-counter), neuroleptics, beta blockers (drugs for high blood pressure), and antineoplastics (anti-cancer drugs). Methadone is a P450-2D6 inhibitor, and it is likely that many alkaloids, especially of plant origin, may be mild to moderate P450-2D6 inhibitors.
P450 Inhibitors
DrugUsesP450-2D EnzymesPotencyRef
ajmalicine  2D6 strongest 167
carbon monoxide poison 2D6   163
chloroquine antiparasitic 2D6 med-low 175
chlorpheniramine antihistamine 2D med-high 154
citalopram antidepressant 2D6 med-low 169
clozapine antipsychotic 2D6 low 174
desipramine antidepressant 2D6 low 155
diphenhydramine antihistamine 2D med-high 154
doxorubicin anticancer 2D6 med-low 168
fluoxetine antidepressant 2D6 med-high 155
fluvoxamine antidepressant 2D6 med-high 155
imipramine antidepressant 2D6 med 155
lomustine anticancer 2D6 med 168
mepyramine antihistamine 2D6 high 154
methadone addiction treatment 2D6 med 165
moclobemide MAO-A Inh. (reversible) 2D6, also 2C19, 1A2   150
nortryptiline antidepressant 2D6 med-low 158
oxamniquine antiparasitic 2D6 med-low 175
paroxetine antidepressant 2D6 high 155
PCP recreational 2D   153
primaquine antiparasitic 2D6 med-low 175
propranolol beta-blocker 2D6 low 159
quinidine   2D6   151
quinine antiparasitic 2D   154
sertraline antidepressant 2D6 med-high 170
triprolidine antihistamine 2D med-high 154
vinblastine anticancer 2D6 med-low 168
vinorelbine anticancer 2D6 med-low 168
DrugUsesP450-3A EnzymesPotencyRef
7,8-benzoflavone   3A4 (activator)   156
cannabidiol component of marijuana 3A med 164
cocaine recreational 3A low 160
clotrimazole agricultural fungicide 3A (activator) very high 157
cyclophosphamide   3A low? 161
ifosfamide   3A low? 161
ketoconazole   3A   148
pilocarpine cholinomimetic 3A low 152
DrugUsesP450-3A EnzymesPotencyRef
1-aminobenzotriazole   Nonspecific med-high 162
chlorophyllin geriatric Nonspecific   149
general anaesthetics   Nonspecific   166

One reference (167) gives the general characteristics of P450-2D6 inhibitors as
a positive charge on a nitrogen atom, and a flat hydrophobic region, the plane of which is almost perpendicular to the N-H axis and maximally extends up to a distance of 7.5 A from the nitrogen atom. Compounds with high inhibitory potency had additional functional groups with negative molecular electrostatic potential and hydrogen bond acceptor properties on the opposite side at respective distances of 4.8-5.5A and 6.6-7.5A from the nitrogen atom.
A computer model of the P450-2D6 cytochrome has been constructed (173).


Appendix 2: Receptor Binding of Recreational Drugs

alcohol
Targets and blocks GABA and NMDA channels, as well as probably having an effect on other ion channels (voltage-dependent and receptors). Actually, alcohol is not well understood in comparison to other drugs.
amphetamine
Causes a non-vesicular release of dopamine and noradrenaline by neurons which normally secrete them. May have some direct effect on dopamine and noradrenaline receptors, but this is insignificant compared to its neurotransmitter releasing effect.
barbiturates
Targets and binds to a specific site on GABA receptors, which activates them. This site is called the barbiturate binding site (appropriately enough). This is a different site from alcohol and benzodiazepines, so that if you combine any of these three, they will not compete for the same binding sites. Consequently, there is a synergistic effect, which can be quite dangerous.
benzodiazepines
Similar to barbiturates, except for two factors. First, the binding site is the benzodiazepine site on the GABA receptor. Second, when a benzodiazepine binds to this site, the GABA receptor is not immediately activated; instead, the natural action of GABA is enhanced. This is the main reason benzodiazepines are safer than barbiturates, and have different effects.
"blues"
An antihistamine (targeting and activating the H1 receptor) which probably has sigma1 antagonist properties; when used in combination with pentazocine, it probably blocks the sigma activity of the latter. Rarely found. The only reason I'm mentioning it is because I heard about it in a comedy skit called "Rock and Roll Doctor" and always wondered what "blues" were (until I found out). Well, if you wondered too, now you know.
caffeine
Targets and blocks an adenosine receptor, probably A2 but possibly A1. This is an inhibitory presynaptic receptor, i.e., when activated it decreases the amount of neurotransmitter released by a neuron. Thus, caffeine blocks some of this inhibition, increasing neural activity.
cannabis
Targets a specific receptor (or family of receptors) designated anandamide. It is not yet known whether cannabis (actually, THC) is an agonist or antagonist at this receptor.
codeine
See morphine.
coffee
See caffeine.
cocaine
A dopamine reuptake inhibitor; cocaine blocks the transporter which takes used dopamine out of the way. Thus, dopamine secreted by a neuron keeps activating receptors over and over. Cocaine is also a sigma1 agonist, and has blocking abilities on certain ion channels (by which it exerts its local anesthetic effects).
Demerol
See morphine.
glue
See solvents.
heroin
See morphine.
LSD
Targets 5HT2A and 5HT2C, where it acts either as an antagonist or a partial agonist. Also has some dopaminergic activity; however, the majority of its effects are mediated through the 5HT receptors.
marijuana
See cannabis.
MDA
See MDMA. Release binding spectrum is probably different, and MDA may have additional effects on receptors.
MDMA
Similar to amphetamine, except that MDMA causes a nonvesicular release of dopamine and serotonin (5HT). Probably has other effects as well, some of which may be significant.
methamphetamine
Similar to amphetamine, possibly with more dopamine release.
morphine
Targets opioid receptors mu, kappa, and delta, where it acts as an agonist. Slight differences in binding spectrum to opiate receptors exist among the various natural and synthetic opiates.
nitrous oxide
Seems to affect phospholipid membranes, although some effects may be mediated by NMDA and GABA channels, and other ion channels. General anesthetics are similar to nitrous oxide, although more toxic.
opium
See morphine.
Ritalin
Similar to cocaine, but less potent.
seconal
See barbiturates.
solvents
Same general theory as alcohol and nitrous oxide, but considerably more toxic to neurons (and the liver).
Valium[tm]
See benzodiazepines.
yohimbine
Targets and blocks alpha2 adrenergic receptors. These are autoreceptors, which normally limit the activity of adrenergic neurons. By blocking alpha2 receptors, yohimbine increases the activity of these neurons.


Appendix 3: Other Sigma and NMDA Ligands

Here are a few sigma ligands you may wish to research (if you are interested in that sort of thing):

Sigma1 ligands in rough order of potency:


Sigma2 ligands in rough order of potency:


P> A known sigma antagonist is N-[-2-(3,4-dichlorophenyl)ethyl]- N-methyl-2-[1- pyrimidinyl-1-piperazine] butanol; a sigma1 selective antagonist is (1-(cyclopropylmethyl)- 4-2'4"-fluorophenyl)- (2'-oxoethyl)piperidine HBr.


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