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tary tooth grinding, known as bruxism,which can deteriorate tooth enamel and

lead to gingivitis.[17]

Additionally,stimulants like cocaine,methamphetamine, and even caffeinecause dehydration and dry mouth. Sincesaliva is an important mechanism inmaintaining one's oral pH level, chronic

stimulant abusers who do not hydratesufficiently may experiencedemineralization of their teeth due to thepH of the tooth surface dropping too low(below 5.5).

Chronic intranasal usage can degradethe cartilageseparatingthe nostrils(the septum nasi), leadingeventually to its complete disappearance.Due to the absorption of the cocaine fromcocaine hydrochloride, the remaininghydrochloride forms a dilute hydrochloricacid.

[18]

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Cocaine may also greatly increase thisrisk of developing rare autoimmune or

connective tissue diseases suchas lupus, Goodpasture'sdisease,vasculitis,glomerulonephritis, StevensJohnson syndromeand otherdiseases.

[19][20][21][22]It can also cause a

wide array of kidney diseases and renal

failure.[23][24]

Cocaine misuse doubles both the risks ofhemorrhagic and ischemic strokes,

[25]as

well as increases the risk of otherinfarctions, such as myocardial

infarction.

[26]

AddictionMain articles: Cocainedependenceand FosB

Cocaine dependence (or addiction) is

psychological dependency on the regularuse of cocaine.

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Signaling cascadein the nucleusaccumbensthat results in

psychostimulant addiction

Note: colored text contains articlelinks.

Nuclear pore

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Nuclear membranePlasma membrane

Cav1.2NMDARAMPAR

DRD1DRD5DRD2

DRD3DRD4

GsGi/o

cAMPcAMPPKACaM

CaMKIIDARPP-32

PP1

PP2BCREBFosBJunD

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c-FosSIRT1

HDAC1[Color legend 1]This diagram depicts the signaling eventsin the brain's reward centerthat areinduced by chronic high-dose exposureto psychostimulants that increase the

concentration of synaptic dopamine,like amphetamine, methylphenidate, phenethylamine, and cocaine. Followingpresynaptic dopamineandglutamateco-releaseby suchpsychostimulants,postsynapticreceptorsforthese neurotransmitterstrigger internalsignaling events througha cAMP pathway and calcium-dependentpathway that ultimately result in

increased CREB phosphorylation.[27][28]

Phosphorylated CREB increases levels ofFosB, which in turn represses the c-fosgene with the help of corepressors.

[28]A

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highly stable (phosphorylated) form ofFosB, one that persists in neurons for

one or two months, slowly accumulatesfollowing repeated exposure to stimulantsthrough this process.

[29][30]FosB

functions as "one of the master controlproteins" that produces addiction-related structural changes in the brain,

and upon sufficient accumulation, withthe help of its downstream targets(e.g., nuclear factor kappa B), it inducesan addictive state.

[29][30]

BiosynthesisMain article: Biosynthesis of cocaine

The first synthesis and elucidation of thecocaine molecule was by RichardWillsttterin 1898.

[31]Willsttter's

synthesis derived cocainefrom tropinone. Since then, RobertRobinsonand Edward Leete have made

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significant contributions to themechanism of the synthesis. (-NO3)

The additional carbon atoms required forthe synthesis of cocaine are derived fromacetyl-CoA, by addition of two acetyl-CoAunits to the N-methyl-

1-pyrrolinium

cation.[32]

The first addition is a Mannich-like reaction with the enolate anion from

acetyl-CoA acting asa nucleophiletowards the pyrroliniumcation. The second addition occursthrough a Claisen condensation. Thisproduces a racemic mixture of the 2-

substituted pyrrolidine, with the retentionof the thioester from the Claisencondensation. In formationof tropinonefrom racemicethyl [2,3-13C2]4(Nmethyl-2-pyrrolidinyl)-3-oxobutanoate there is no preference for

either stereoisomer.[33]In thebiosynthesis of cocaine, however, onlythe (S)-enantiomer can cyclize to formthe tropane ring system of cocaine. The

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stereoselectivity of this reaction wasfurther investigated through study of

prochiral methylene hydrogendiscrimination.[34]

This is due to the extrachiral center at C-2.

[35]This process

occurs through an oxidation, whichregenerates the pyrrolinium cation andformation of an enolate anion, and an

intramolecular Mannich reaction. Thetropane ring systemundergoes hydrolysis, SAM-dependentmethylation, and reductionvia NADPHfor the formation ofmethylecgonine. The benzoylmoietyrequired for the formation of the cocainediester is synthesized from phenylalaninevia cinnamic acid.

[36]Benzoyl-CoA then

combines the two units to form cocaine.

N-methyl-pyrrolinium cation

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Biosynthesis of N-methyl-pyrroliniumcation

Biosynthesis of cocaine

Robinson biosynthesis of tropane

Reduction of tropinone

The biosynthesisbegins with L-Glutamine, which is derived to L-ornithinein plants. The major contributionof L-ornithine and L-arginineas aprecursor to the tropanering was

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confirmed by Edward Leete.[37]

Ornithinethen undergoes aPyridoxal phosphate-

dependent decarboxylation to formputrescine. In animals, however, the ureacycle derives putrescine from ornithine.L-ornithine is converted to L-arginine,

[38]which is then decarboxylated

via PLP to form agmatine. Hydrolysis of

the imine derives N-carbamoylputrescinefollowed with hydrolysis of the urea toform putrescine. The separate pathwaysof converting ornithine to putrescine inplants and animals have converged. ASAM-dependent N-methylation ofputrescine gives the N-methylputrescineproduct, which then undergoes oxidativedeamination by the action of diamineoxidase to yield the aminoaldehyde.Schiff base formation confirms the

biosynthesis of the N-methyl-1

-pyrrolinium cation.

Robert Robinson'sacetonedicarboxylate

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The biosynthesis of the tropane alkaloid,however, is still uncertain. Hemscheidt

proposes that Robinson'sacetonedicarboxylate emerges as apotential intermediate for thisreaction.

[39]Condensation of N-

methylpyrrolinium andacetonedicarboxylate would generate the

oxobutyrate. Decarboxylation leads totropane alkaloid formation.

Reduction of tropinone

The reduction of tropinone is mediatedby NADPH-dependent reductase

enzymes, which have been characterizedin multiple plant species.

[40]These plant

species all contain two types of thereductase enzymes, tropinone reductaseI and tropinone reductase II. TRIproduces tropine and TRII producespseudotropine. Due to differing kineticand pH/activity characteristics of theenzymes and by the 25-fold higheractivity of TRI over TRII, the majority of

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the tropinone reduction is from TRI toform tropine.

[41]

PharmacologyAppearance

A pile of cocaine hydrochloride

A piece of compressed cocaine powder

Cocaine in its purest form is a white,pearly product. Cocaine appearing in

powder form is a salt, typicallycocaine hydrochloride(CAS53-21-4).Street market cocaine is frequentlyadulterated or cut with various powdery

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fillers to increase its weight; thesubstances most commonly used in this

process are baking soda; sugars, suchas lactose, dextrose, inositol,andmannitol; and local anesthetics, suchas lidocaineorbenzocaine, which mimicor add to cocaine's numbing effect onmucous membranes. Cocaine may also

be "cut" with other stimulants suchasmethamphetamine.

[42]Adulterated

cocaine is often a white, off-white orpinkish powder.

The color of crack cocainedepends

upon several factors including the originof the cocaine used, the method ofpreparationwith ammoniaor bakingsodaand the presence of impurities,but will generally range from white to ayellowish cream to a light brown. Its

texture will also depend on theadulterants, origin and processing of thepowdered cocaine, and the method ofconverting the base. It ranges from a

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crumbly texture, sometimes extremelyoily, to a hard, almost crystalline nature.

FormsSalts

Cocaine is a weakly alkaline compound(an "alkaloid"), and can thereforecombine with acidic compounds to form

various salts. The hydrochloride (HCl)salt of cocaine is by far the mostcommonly encountered, although thesulfate (-SO4) and the nitrate (-NO3) areoccasionally seen. Different saltsdissolve to a greater or lesser extent in

various solventsthe hydrochloride saltis polar in character and is quite solublein water.

BasicMain article: Freebase (chemistry)

As the name implies, freebase isthe baseform of cocaine, as opposed tothe saltform. It is practically insoluble in

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water whereas hydrochloride salt is watersoluble.

Smoking freebase cocaine has theadditional effect ofreleasing methylecgonidineinto theuser's system due to the pyrolysisof thesubstance (a side effectwhich insufflatingor injecting powder

cocaine does not create). Some researchsuggests that smoking freebase cocainecan be even more cardiotoxic thanother routes of administration

[43]because

of methylecgonidine's effects on lung

tissue

[44]

and liver tissue.

[45]

Pure cocaine is prepared by neutralizingits compounding salt with an alkalinesolution which will precipitate to non-polar basic cocaine. It is further refinedthrough aqueous-solvent Liquid-liquidextraction.

Crack cocaineMain article: Crack Cocaine

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A woman smoking crack cocaine

"Rocks" of crack cocaine

Crack is a lower purity form of free-basecocaine that is usually produced byneutralization of cocaine hydrochloridewith a solution of baking soda (sodiumbicarbonate, NaHCO3) and water,producing a very hard/brittle, off-white-to-

brown colored, amorphous material thatcontains sodium carbonate, entrappedwater, and other by-products as the mainimpurities.

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The "freebase" and "crack" forms ofcocaine are usually administered by

vaporization of the powdered substanceinto smoke, which is then inhaled.[46]

Theorigin of the name "crack" comes fromthe "crackling" sound (and hencethe onomatopoeicmoniker crack) that isproduced when the cocaine and its

impurities (i.e. water, sodiumbicarbonate) are heated past the point ofvaporization.

[47]Pure cocaine base/crack

can be smoked because it vaporizessmoothly, with little or no decompositionat 98 C (208 F),

[48]which is below the

boiling point of water. The smokeproduced from cocaine base is usuallydescribed as having a very distinctive,pleasant taste.

In contrast, cocaine hydrochloride does

not vaporize until heated to a muchhigher temperature (about 197 C), andconsiderable decomposition/burningoccurs at these high temperatures. This

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effectively destroys some of the cocaine,and yields a sharp, acrid, and foul-tasting

smoke.Smoking or vaporizing cocaine andinhaling it into the lungs produces analmost immediate "high" that can be verypowerful (and addicting) quite rapidlythis initial crescendo of stimulation is

known as a "rush". While the stimulatingeffects may last for hours, the euphoricsensation is very brief, prompting theuser to smoke more immediately.

Coca leaf infusions

This article needs additionalcitationsforverification. Pleasehelp improve thisarticleby adding citations to

reliable sources. Unsourcedmaterial may be challengedand removed. (April 2014)

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Coca herbal infusion(also referred toas coca tea) is used in coca-leaf

producing countries much as any herbalmedicinal infusion would elsewhere in theworld. The free and legalcommercialization of dried coca leavesunder the form of filtration bags to beused as "coca tea" has been actively

promoted by the governmentsof PeruandBoliviafor many years as adrink having medicinal powers. Visitors tothe city of Cuzcoin Peru, and La PazinBolivia are greeted with the offering ofcoca leaf infusions (prepared in tea potswith whole coca leaves) purportedly tohelp the newly arrived traveler overcomethe malaise of high altitude sickness. Theeffects of drinking coca tea are a mildstimulation and mood lift. It does not

produce any significant numbing of themouth nor does it give a rush likesnorting cocaine. In order to prevent thedemonization of this product, its

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promoters publicize the unprovenconcept that much of the effect of the

ingestion of coca leaf infusion wouldcome from the secondary alkaloids, asbeing not only quantitatively differentfrom pure cocaine but also qualitativelydifferent.

It has been promoted as an adjuvant for

the treatment of cocaine dependence. Inone controversial study, coca leafinfusion was usedin addition tocounselingto treat 23 addicted coca-paste smokers in Lima, Peru. Relapses

fell from an average of four times permonth before treatment with coca tea toone during the treatment. The duration ofabstinence increased from an average of32 days prior to treatment to 217 daysduring treatment. These results suggest

that the administration of coca leafinfusion plus counseling would be aneffective method for