Drugs of Abuse

Opiates (briefly)

HallucinogensCannabinoidsLSD and other psychedelicsEcstasyPCP

Opiates

Discussed in a previous lecture

Heroin is the prototypical member of the class

Strongly addictivePotent effects on the VTA-NAc pathway

Tolerance to “desirable” effects (such as euphoria) develops quickly. Users require ever higher doses to achieve “desirable”effects and avoid withdrawal, increasing the risk of a fatal overdose

Cannabinoids

Most commonly used illicit drug in the U.S.

Most potent cannabinoids:

9-THC (tetrahydrocannabinol)

11-hydroxy-9-THC (a metabolite)

Effects of Cannabinoids

CNS:

Sense of well-being, euphoria, spontaneous laughterRelaxation, sleepiness when aloneSensory stimuli have novel qualityAltered perception of timeDepersonalizationShort term memory impairmentInability to perform complex tasks“amotivational” syndrome

Effects of Cannabinoids

CardiovascularTachycardia: block with propranolol and clonidine

OtherImmunosuppressionInhibition of spermatogenesisAnovullatory menstrual cycles

ToxicityApparently impossible to OD with cannabinoids.No known deaths due to direct action of cannabinoids.Lack of cannabinoid receptors in CNS breathing centers.

PsychotoxicityHallucinations, delusions, paranoiaConfusion, severe depersonalization, anxietyExcacerbation of schizophrenia

Effects of Cannabinoids

Cannabinoids

Tolerance can develop after repeated use.

Mild withdrawal symptoms after prolonged use:irritabilitynervousnessinsomnia

Cannabinoids

AdministrationUsually inhalation of smoke, but also active after oral administration

Peak plasma concentration in 7-10 minutesPeak subjective effects in 20-30 minutesSubjective effects persist for 2-3 hours

Deficits in attention, perception and information processing persist for 4-8 hours

Elimination9-THC is metabolized to inactive forms and then excreted in the urine (for at least a week)

Cannabinoids

Potential Therapeutic Uses

Anti-emetic: 9-THC (MARINOL) and nabilone (CESAMET, a synthetic cannabinoid) have been used to treat nausea during chemotherapy

Appetite stimulant

Glaucoma: can lower intraocular pressure

Analgesic, anticonvulsant

Cannabinoids

Mechanism

Cannabinoid receptors have been cloned (CB1 and CB2)G-protein coupled 9-THC, nabilone and 11-hydroxy- 9-THC act at these receptors to inhibit adenylate cyclase activity

What is the endogenous ligand?

Are these receptors responsible for the CNS effects of 9-THC?

Psychedelics

LSD (exceptionally potent, doses as low as 20 µg are effective)Mescaline (peyote)Psilocin (mushrooms)

Effects:Low doses: The “psychedelic state”

heightened awareness of sensory inputenhanced sense of claritydiminished control over what is experiencedslow passage of timesynesthesia: hearing colors, seeing sounds

Psychedelics

Effects:

High doses:sympathomimetic effects such as tachycardia, hypertension, tremor, nausea, dizziness

panic, distress

Psychedelics

Tolerance:Can develop after a few daily doses, but sensitivity returns after a few drug free days. May be due to receptor down regulation.

Cross-tolerance develops between LSD, mescaline and psilocinnot between LSD and amphetamines or cocainenot between LSD and cannabinoids

Flashbacks:recurrence of drug effects without drugoccurs in about 15% of usersexcacerbated by phenothiazines, cannabinoids, stress, fatiguemechanism unknown

Psychedelics

Mechanism:Psychedelics act of serotonin (5-HT) receptors (G-protein coupled)LSD is a partial agonist at 5-HT2A and 5-HT2C receptors

Where are the effects?

Dorsal Raphe: exerts some control over processing of sensory input

LSD and 5-HT inhibit firing of neurons

Locus Ceruleus: LSD and mescaline decrease spontaneous neuronal activity, but enhance activation by peripheral stimuli

Cortex

Amphetamine

C C

C

N

Methamphetamine

C C

C

N C

3,4-methylenedioxymethamphetamine(MDMA)

C C

C

N CO

O

Ecstasy

C C

C

N CO

O

Ecstasy

Subjective Effects:a mixture of psychedelic-like and amphetamine-like

Mechanism:causes acute release of serotonin by acting on serotonin transporter

Tolerance to “desirable” effects develops quickly

Acute Toxicity:tachycardiaagitationhyperthermiapanic attacks

Ecstasy

Chronic Toxicity:long-term depletion of serotonin in CNS

morphological damage to serotonergic nerve terminals

Figure 1. ﾊ Dark-field photomicrograph, sagittal plane, of 5-HT immunoreactive axons in the frontal, parietal, and primary visual cortex of a control monkey (A, D, G), a monkey treated with MDMA 2 ﾊ weeks previously (B, E, H), and a monkey treated with MDMA 7 ﾊ years previously (C, F, I). Note the reduction in axon density 2 ﾊ weeks after MDMA exposure and the persistent regional deficits in axon density 7 ﾊ years after MDMA exposure. Scale bar, 100 ﾊｵ m.

Altered Serotonin Innervation Patterns in the Forebrain of Monkeys Treated with (+)3,4-Methylenedioxymethamphetamine Seven Years Previously: Factors Influencing Abnormal Recovery Hatzidimitriou, McCann and RicaurteJournal of Neuroscience 19:5096-5107 (1999)

Other Ecstasy-like Drugs

3,4-methylenedioxyethamphetamine (MDE, Eve)Dimethyl tryptamine (DMT)

Gamma hydroxybutyrate (GHB)

CNS depressant, sedativemay act on GABA receptorsmay be a precurser for GABAmay have it’s own receptorsmay be a neurotransmitter

As a drug of abuse:Club drugBody Builders (increases releas of growth hormone from pituitary)Date Rape

Phencyclidine (PCP), “Angel Dust”

A dissociative anesthetic, discontinued for human use

General Effects: CNS stimulantCNS depressantHallucinogenicAnalgesic

“High” last 4-6 hours, t1/2 in body ~3 days

Accelerate elimination by gastric suction

Phencyclidine (PCP), “Angel Dust”

Low Doses: intoxication, staggeringslurred speech, numbness

Moderate Doses: muscle rigidity, sweatingdisorganized thoughts, disorientationhostile and bizarre behavioramnesia

High Doses: AnesthesiaStuporComaConvulsions

Phencyclidine (PCP), “Angel Dust”

Proposed Mechanism:

1) Channel blocker of ligand gated ion channelsprimary target is NMDA-type glutamate receptorsthese receptors have various roles in CNS, including learning and memory

2) Sigma Opioid sitesmysterious opioid “receptor” that binds n-allylnormetazocine and haloperidol, function unknown

3) Blocker of DA and NE transporters

Are any of these responsible for PCP’s effects?