chapter 6 all arounders. hallucinogens/psychedelics alterations in cortical functions cognition...

CHAPTER 6 All Arounders

Hallucinogens/Psychedelics

Alterations in cortical functions Cognition Perception Mood


Tetrahydrocannabinol (THC)From Cannabis sativa

Active ingredients 9-tetrahydrocannabinol (major component) Cannabinol Cannabidiol

Marijuana.Bhang – lower grade leaves/stems 2-5% THC

Hashish/charas – resin of female flowers 10-20% THC

Ganja/sinsemilla – tops of female plants 5-8% THC


THCPrimary effects

Disruption of attention Impaired short-term memory Altered sensory awareness Analgesia Altered motor/posture control Immunosuppressive?

Structurally unrelated to other drugs Binds to specific cannabinoid receptors

Hallucinogens/PsychedelicsTHC

History Millennia – used as mild intoxicant Few native cultures use medicinally Introduced to West in mid-19th century 1920s-40s – Reefer Madness 1990s – medical marijuana laws

Future Have current laws been effective? Should THC be available for medical use? In what form? Recreational THC? What would be the effect of legal THC? What to do?????


THCCannabinoid Receptor

Inhibits adenylate cyclase Receptors found on presynaptic terminals Inhibit Ca ions Facilitate K channels Stimulation of these receptors inhibits release of

neurotransmitters Huge number of receptors – 10-20x opioid receptors –

may be most common receptor in brain


THC ReceptorNatural ligand (agonist): anandamide

Partial agonist similar to THC Chemically dissimilar, but 3-D structure very similar Inhibits glutamate release

Cannabinoid1 Hippocampus - memory Cerebral cortex - psychoactivity Cerebellum – movement/posture Basal ganglia – movement/posture

Cannabinoid2 Peripheral Lymphoid system immunosuppression?


Pharamcokinetics Average dose 0.4-10 mg - smoked Time to peak ~10 min Blood level 80-150 ng/mL Detectable 12hr Rapid onset high lasts ~12hr Oral dose

Absorption abut 30-60 min Peak 2-3 hr post 1st pass metabolism? Distributed quickly Highly lipophilic Crosses b/b and b/p barriers Metabolites: 11-hydroxy-9-THC, 11-nor-9-THC-

carboxylic acid


THCElimination

Primarily as COOH in urine t1/2 ~30hr Excretion time depends on previous history with

drug


Pharmacological Effects – animals - Humans Memory disruption Analgesic Decreased body temp Calming agent Decreases aggression Impairs behavioral tasks Hallucinations Temporal distortions Depress ovarian function? Decrease sperm production? Induce over eating Euphoria


THCCardiovascular system

Increase heart rate, BP Corneal vessels dilate

Pulmonary system Toxins in smoke very dangerous Similar to tobacco toxins, likely same carcinogenic

effects


THCReproductive system

Reduces testosterone and sperm levels FSH/LH decreased - females May disrupt menstrual cycle Pregnancy? Little data on fetal/infant development issues


THCSide effects

Sedation Impaired motor skills Impaired cognition Impaired memory Impaired driving Impairment may last hours beyond feeling


Tolerance/dependence Desensitization of receptors Preoccupation, compulsive use, relapse

Withdrawal Restlessness Irritability Agitation Anxiety Depression Reduced appetite Insomnia/sleep disorders Nausea/cramping Starts within 48hr, lasts 2-6 days


THCTherapeutic uses

Appetite stimulant for AIDS patients Anti-nausea – chemotherapy

Not as effective as prescribed antiemetics Potential

MS Glaucoma Brain protection – trauma, stroke, ischemia LOTS of research needed


Other drugsMost psychedelics mimic

Acetylcholine – anticholinergic Norepinephrine/dopamine – catecholamine-like Serotonin-like


ScopolamineFrom

Atropa belladonna - nightshade Datura stanonium – jimson weed Mandragora officinarum – mandrake Above plants may also include atropine


ScopolaminePharmacological effects

Anticholinergic Dry mouth Reduced sweating Dry skin Increased body temperature Dilated pupils Blurred vision Tachycardia Hypertension

Hallucinogens/PsychedelicsScopolamine

CNS effects Delirium Intoxication Drowsiness Euphoria Amnesia – profound Fatigue Mental confusion Dreamless sleep Loss of attention Clouds consciousness Restlessness/excitement Hallucinations Disorientation


ScopolamineHigher/toxic doses

Delusions Mental confusion Stupor Coma Respiratory depression

“hot as a hare, blind as a bat, dry as a bone, red as a beet, and mad as a hen.”


Catecholamine-likePhenylethylamines – amphetamine familyStimulants – Catecholamine actionPsychedelics – serotonin action5-HT2 serotonin receptor

Emotional responses Sensory-perception/color distortion Dreamlike feeling Depersonalization Somatic effects (tingling, tremor, etc.)


MescalinePeyote cactus – Laphaphora williansiiUsed in SW Native American religious rites

Generally taken orally Rapid, complete absorption 1-2 hr to significant brain levels 3.5-4 hr to peak effect, particularly visual Other effects: anxiety, stimulation, increased reflexes,

tremors

Seldom abused?


Synthetic AmphetaminesDOM, MDA, DMA,MDE, TMA, MDMAClose relatives to methamphetamine and

mescaline with similar effects


MDMA – prototypical syntheticMetabolizes to MDA (more hallucinogenic)NeurotoxinDamage to serotonin transportAttention impairedIncreased impulsivityTypical amphetamine-like side effectsSevere toxicity - can cause fatalities


Myristin/ElemicinNutmeg/Mace

Unreality Confusion Disorientation Euphoria Visual hallucinations Acute psychotic reactions Unpleasant side-effects: nausea/vomiting/tremors Usually only use once


Serotonin-likeLSDPsilocbinPsilocinDimethyltryptamineBufotemine


Serotonin-likeVery similar structure to serotoninSuspected serotonin agonistPossible dopamine agonistPossible interruption of “filtering” or sorting of

sensory inputSerotonin itself does not display similar effects


Lysergic acid diethyl amide – LSDSynthesized 1938Very low dose required for effect - 25 ugVery strong visual/perceptional hallucinations


LSDPharmacokinetics

Taken orally Rapidly absorbed Peak levels in about 3 hr Readily diffuses to brain and across placenta Duration 6-8 hr Difficult to detect in drug tests due to very low

concentration and instability


LSDPhysiological effects

Slight body temp increase Dilation of pupils Slightly increased heart rate/BP Low level of toxicity


LSDPsychological effects

Altered Perception Thinking Emotion Arousal Self image Time Sensory input (intensified)


LSD Psychological effects

3-phases of LSD experience1. Somatic phase – CNS stimulation2. Sensory phase – sensory distortions,

pseudohallucinations3. Psychic phase – maximum drug effect – bad trip

Tolerance/Dependence Rapid tolerance – physiological and psychological Little to no dependence


LSDAdverse reactions/Toxicity

Chronic or intermittent psychotic states Major effective disorder (depression) Exacerbation of preexisting condition Disruption of personality (burnout) Flashbacks


DMTSimilar effects as LSDVery short duration – 30 min

BufotemineAlso similar2hr t1/2Related to autism/depression??

Hallucinogens/PsychedelicsPsilocybin/Psilocin

From many mushroom speciesLSD-like effectsActive drug is psilocinCan produce psychosis

OloliuquiMorning Glory seedsActive drug - Relative of LSDSevere unpleasant side effects

HarmineSimilar action to LSD and DMTAlso severe side effects


Phencyclidine/KetamineDeveloped as anestheticsPCP no longer used due to severe psychiatric

reactions, but more commonly abused Agitation Excitement Delirium Disorientation Hallucinations Similar to schizophrenia


PCP/KetaminePharmocokinetics

Smoked - peak reached in 15 min - ~40% of dose absorbed

Oral – peak reached in ~2 hr Elimination t1/2 about 18hr

Hallucinogens/PsychedelicsPCP/Ketamine

Mechanism of action Antagonist to NMDA/Glutamate

Psychotomimetic Analgesic Amnesia Schizophrenic

Psychological effects Dissociation of individual from self and environment Intense analgesia and amnesia – blank stare Low (recreational0 dose – agitation, euphoria, disinhibition,

excitement, gross drunkenness Coma, stupor BP elevated Exaggerated/violent reaction to outside stimuli

Hallucinogens/PsychedelicsPCP/Ketamine

Side effects/Toxicity Severe anxiety, aggression, panic, paranoia, rage Violent reactions to sensory input Self inflicted injuries - Lack of response to pain Respiratory depression, Seizure, Pulmonary edema

Tolerance/Dependence/Abuse Compulsive abuse – stimulates reward areas

Therapy for PCP intoxication Minimize sensory input – isolate Activated charcoal Physical restraint Sedation – benzodiazepine and/or antipsychotic Supportive therapy

chapter 6 all arounders. hallucinogens/psychedelics alterations in cortical functions cognition...

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