15 Appendices

15.1 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

Drug

Uses

P450-2D Enzymes

Potency

Ref

ajmalicine

2D6

strongest

(164)

carbon monoxide

poison

2D6

(160)

chloroquine

antiparasitic

2D6

med-low

(172)

chlorpheniramine

antihistamine

2D

med-high

(151)

citalopram

antidepressant

2D6

med-low

(166)

clozapine

antipsychotic

2D6

low

(171)

desipramine

antidepressant

2D6

low

(152)

diphenhydramine

antihistamine

2D

med-high

(151)

doxorubicin

anticancer

2D6

med-low

(165)

fluoxetine

antidepressant

2D6

med-high

(152)

fluvoxamine

antidepressant

2D6

med-high

(152)

imipramine

antidepressant

2D6

med

(152)

lomustine

anticancer

2D6

med

(165)

mepyramine

antihistamine

2D6

high

(151)

methadone

addiction treatment

2D6

med

(162)

moclobemide

MAO-A Inh. (reversible)

2D6, also 2C19, 1A2

(147)

nortryptiline

antidepressant

2D6

med-low

(155)

oxamniquine

antiparasitic

2D6

med-low

(172)

paroxetine

antidepressant

2D6

high

(152)

PCP

recreational

2D

(150)

primaquine

antiparasitic

2D6

med-low

(172)

propranolol

beta-blocker

2D6

low

(156)

quinidine

2D6

(148)

quinine

antiparasitic

2D

(151)

sertraline

antidepressant

2D6

med-high

(167)

triprolidine

antihistamine

2D

med-high

(151)

vinblastine

anticancer

2D6

med-low

(165)

vinorelbine

anticancer

2D6

med-low

(165)

Drug

Uses

P450-3A Enzymes

Potency

Ref

7,8-benzoflavone

3A4 (activator)

(153)

cannabidiol

component of marijuana

3A

med

(161)

cocaine

recreational

3A

low

(157)

clotrimazole

agricultural fungicide

3A (activator)

very high

(154)

cyclophosphamide

3A

low?

(158)

ifosfamide

3A

low?

(158)

ketoconazole

3A

(145)

pilocarpine

cholinomimetic

3A

low

(149)

Drug

Uses

P450-3A Enzymes

Potency

Ref

1-aminobenzotriazole

Nonspecific

med-high

(159)

chlorophyllin

geriatric

Nonspecific

(146)

general anaesthetics

Nonspecific

(163)

P450 Inhibitors
Drug	Uses	P450-2D Enzymes	Potency	Ref
ajmalicine		2D6	strongest	(164)
carbon monoxide	poison	2D6		(160)
chloroquine	antiparasitic	2D6	med-low	(172)
chlorpheniramine	antihistamine	2D	med-high	(151)
citalopram	antidepressant	2D6	med-low	(166)
clozapine	antipsychotic	2D6	low	(171)
desipramine	antidepressant	2D6	low	(152)
diphenhydramine	antihistamine	2D	med-high	(151)
doxorubicin	anticancer	2D6	med-low	(165)
fluoxetine	antidepressant	2D6	med-high	(152)
fluvoxamine	antidepressant	2D6	med-high	(152)
imipramine	antidepressant	2D6	med	(152)
lomustine	anticancer	2D6	med	(165)
mepyramine	antihistamine	2D6	high	(151)
methadone	addiction treatment	2D6	med	(162)
moclobemide	MAO-A Inh. (reversible)	2D6, also 2C19, 1A2		(147)
nortryptiline	antidepressant	2D6	med-low	(155)
oxamniquine	antiparasitic	2D6	med-low	(172)
paroxetine	antidepressant	2D6	high	(152)
PCP	recreational	2D		(150)
primaquine	antiparasitic	2D6	med-low	(172)
propranolol	beta-blocker	2D6	low	(156)
quinidine		2D6		(148)
quinine	antiparasitic	2D		(151)
sertraline	antidepressant	2D6	med-high	(167)
triprolidine	antihistamine	2D	med-high	(151)
vinblastine	anticancer	2D6	med-low	(165)
vinorelbine	anticancer	2D6	med-low	(165)

Drug	Uses	P450-3A Enzymes	Potency	Ref
7,8-benzoflavone		3A4 (activator)		(153)
cannabidiol	component of marijuana	3A	med	(161)
cocaine	recreational	3A	low	(157)
clotrimazole	agricultural fungicide	3A (activator)	very high	(154)
cyclophosphamide		3A	low?	(158)
ifosfamide		3A	low?	(158)
ketoconazole		3A		(145)
pilocarpine	cholinomimetic	3A	low	(149)

Drug	Uses	P450-3A Enzymes	Potency	Ref
1-aminobenzotriazole		Nonspecific	med-high	(159)
chlorophyllin	geriatric	Nonspecific		(146)
general anaesthetics		Nonspecific		(163)

One reference ((164)) 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 ((170)).

15.2 Appendix 2: Neuropharmacology of Recreational Drugs

2CB: Like many phenethylamines, has mixed properties of a dopamine releasing agent, serotonin (5HT) releasing agent, and probably binding specifically to 5HT receptors (likely including 5HT2A and 5HT2C). Compare amphetamine, MDA.
alcohol: Mechanism unknown; may affect membrane permeability or alter ion channel function. Functionally potentiates GABAergic activity and blocks NMDA receptors, and also has actions on other ion channel receptors.
amyl nitrate: Vasodilator; recreational effects probably derive from this effect rather than being specific to a set of receptors.
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 (called the picrotoxin site) on GABA receptors, which activates them. 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, although most think it is an agonist.
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.
ketamine: Blocks NMDA receptors at the same site as DXM and PCP.
LSD: Targets 5HT_2A and 5HT_2C, 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.
nicotine: Stimulates and then blocks nicotinic acetylcholine receptors.
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.
PCP (phencyclidine): PCP and related cycloarylpiperidines block NMDA receptors, as well as having a variety of other effects, including sigma agonism, dopamine reuptake inhibition, and specific effects on an unknown cerebellar receptor.
Poppers: See amyl nitrate
Psilocybin (mushrooms): Similar to LSD; acts via 5HT2A and 2C receptors and possibly additional ones.
Quaaludes (methaqualone): See barbiturates.
Ritalin: Similar to cocaine, but less potent.
Rohypnol: See benzodiazepines.
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.

15.3 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:

(+)-pentazocine
haloperidol
DTG
(+)-3-PPP
DXM
(+)-SKF 10,047
(+)-cyclazocine
(-)-pentazocine
PCP
(-)-SKF 10,047

Sigma₂ ligands in rough order of potency:

DTG
haloperidol
(+)-3-PPP
(-)-pentazocine
PCP
(+)-pentazocine
(-)-SKF 10,047

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.