Drugs of Abuse Opiates (briefly) Hallucinogens Cannabinoids LSD and other psychedelics Ecstasy PCP

Opiates Discussed in a previous lecture Heroin is the prototypical member of the class Strongly addictive Potent 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 laughter Relaxation, sleepiness when alone Sensory stimuli have novel quality Altered perception of time Depersonalization Short term memory impairment Inability to perform complex tasks “amotivational” syndrome

Effects of Cannabinoids Cardiovascular Tachycardia: block with propranolol and clonidine Other Immunosuppression Inhibition of spermatogenesis Anovullatory menstrual cycles

Toxicity Apparently impossible to OD with cannabinoids. No known deaths due to direct action of cannabinoids. Lack of cannabinoid receptors in CNS breathing centers. Psychotoxicity Hallucinations, delusions, paranoia Confusion, severe depersonalization, anxiety Excacerbation of schizophrenia Effects of Cannabinoids

Cannabinoids Tolerance can develop after repeated use. Mild withdrawal symptoms after prolonged use: irritability nervousness insomnia

Cannabinoids Administration Usually inhalation of smoke, but also active after oral administration Peak plasma concentration in 7-10 minutes Peak subjective effects in minutes Subjective effects persist for 2-3 hours Deficits in attention, perception and information processing persist for 4-8 hours Elimination  9 -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 input enhanced sense of clarity diminished control over what is experienced slow passage of time synesthesia: 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 psilocin not between LSD and amphetamines or cocaine not between LSD and cannabinoids Flashbacks: recurrence of drug effects without drug occurs in about 15% of users excacerbated by phenothiazines, cannabinoids, stress, fatigue mechanism unknown

Psychedelics Mechanism: Psychedelics act of serotonin (5-HT) receptors (G-protein coupled) LSD is a partial agonist at 5-HT 2A and 5-HT 2C 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 NC

3,4-methylenedioxymethamphetamine (MDMA) C C C NC O O

Ecstasy C C C NC O O

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: tachycardia agitation hyperthermia panic 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 Ricaurte Journal of Neuroscience 19: (1999)

Other Ecstasy-like Drugs 3,4-methylenedioxyethamphetamine (MDE, Eve) Dimethyl tryptamine (DMT) Gamma hydroxybutyrate (GHB) CNS depressant, sedative may act on GABA receptors may be a precurser for GABA may have it’s own receptors may be a neurotransmitter As a drug of abuse: Club drug Body Builders (increases releas of growth hormone from pituitary) Date Rape

Phencyclidine (PCP), “Angel Dust” A dissociative anesthetic, discontinued for human use General Effects:CNS stimulant CNS depressant Hallucinogenic Analgesic “High” last 4-6 hours, t1/2 in body ~3 days Accelerate elimination by gastric suction

Phencyclidine (PCP), “Angel Dust” Low Doses:intoxication, staggering slurred speech, numbness Moderate Doses:muscle rigidity, sweating disorganized thoughts, disorientation hostile and bizarre behavior amnesia High Doses:Anesthesia Stupor Coma Convulsions

Phencyclidine (PCP), “Angel Dust” Proposed Mechanism: 1) Channel blocker of ligand gated ion channels primary target is NMDA-type glutamate receptors these receptors have various roles in CNS, including learning and memory 2) Sigma Opioid sites mysterious 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?