drugs of abuse opiates (briefly) hallucinogens cannabinoids lsd and other psychedelics ecstasy pcp
TRANSCRIPT
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?