Transcript Cannabinoids

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:
D9-THC (tetrahydrocannabinol)
11-hydroxy-D9-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
Effects of Cannabinoids
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
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 20-30 minutes
Subjective effects persist for 2-3 hours
Deficits in attention, perception and information processing
persist for 4-8 hours
Elimination
D9-THC is metabolized to inactive forms and then excreted in the
urine (for at least a week)
Cannabinoids
Potential Therapeutic Uses
Anti-emetic: D9-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
D9-THC, nabilone and 11-hydroxy- D9-THC act at
these receptors to inhibit adenylate cyclase activity
What is the endogenous ligand?
Are these receptors responsible for the CNS effects of D9THC?
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-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 N
C
Methamphetamine
C C N C
C
3,4-methylenedioxymethamphetamine
(MDMA)
O
O
C C N C
C
Ecstasy
O
O
C C N C
C
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:
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 19:5096-5107 (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?