Ch 12 TB: Hallucinogens 

Hallucinogens

  • alter the state of consciousness
  • drugs that radically change the mental state by distorting the perception of reality to the point where hallucinations occur
    • illusionogenic
    • psychotomimetic: mimic psychosis inducing state
    • psychedelic
    • mind expanding
  • mimic symptoms of functional psychoses such as schizophrenia
  • rare usage today
  • do not fit in the same category
  • the effects of hallucinogens differ from natural psychosis
  • psychedelic: mind expanding or mind revealing
  • affect mood, thinking processes, and physiological processes
  • alter nearly all aspects of psychological functioning
  • ==four subgroups of hallucinogens==: serotonergic hallucinogens, methylated amphetamines, anticholinergic hallucinogens, and dissociative anesthetics
  • ==delusions==: thought process/belief that did not exist
Serotonergic Hallucinogens
  • Class of drugs that includes ==LSD== and drugs with similar effects and mechanisms of actions
  • ==mescaline (peyote cactus)==
    • Peyote= most widespread hallucinogenic drug in the New World
  • ==psilocybin== (from certain mushrooms)
  • produce vivid visual hallucinations + variety of effects on consciousness
  • have differing chemical structures, but all drugs influence serotonergic transmission in the brain
  • Activation of 5HT 2A receptor is a key factor in producing visual hallucinations
Methylated Amphetamines
  • Includes MDA and MDMA (ecstasy)
  • structurally related to amphetamine
  • produce alterations in mood and consciousness with little or no sensory change
  • act on DA, norepinephrine, and 5HT synapses
  • effects are most potent on the serotonergic system
  • do not bind selectively to the 5-HT 2A receptor
Anticholinergic Hallucinogens
  • Class of drugs including atropine and scopolamine found in plants such as mandrake, henbane, belladonna, and jimsonweed
  • produce dreamlike trances, awaken with little or no memory of the experience
  • antagonists
Dissociative Anesthetics
  • class of drugs including PCP (angel dust) and ketamine
  • produces surgical anesthesia while individuals remains at least semiconscious
Salvia divinorum (salvinorin A)
  • most widely used hallucinogens
  • chemical found in a plant in the sage family
  • not a federal controlled substance, but some states have banned it
  • acts differently on the brain when compared to other hallucinogens
  • affects kappa receptors, classified as the kappa hallucinogen

Serotonergic Hallucinogens: LSD and Related Compounds

Early History
  • Spanish conquistadores explored and colonized Mexico and other parts of Central and S America
  • used for religious/ritualistic practices; mind expansion, vision, prophecy
  • plants produced vivid visual hallucinations
  • Indigenous people took visions as oracles that could reveal the future and aid in decision making
  • mushrooms were viewed as sacred
  • still used in Mexico today
Recent History
  • drugs had no impact on mainstream European or American culture until 1960s
  • {{Psychedelic movement{{
    • Basel Switzerland; Albert Hofmann discovered LSD in 1938
    • He perceived an uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors
    • Normal effective dose: 25 to 125 micrograms; can be as low as 10 micro grams
    • LSD began to be distributed as an adjunct to psychotherapy
    • LSD would break down the patient’s normal ego defenses and facilitate the psychotherapy processes
    • LSD is a psychotomimetic; it is mimicked by psychosis
    • LSD became most controversial drug in the world by the 1960s
    • negative claims about LSD: chromosomal damage, resulting in mutant children, insanity, suicide, acts of violence, and homicidal behavior; led to decline in use in 70s and 80s
    • use increased in 90s, especially among high schoolers
  • LSD is the most potent, its effects are experienced within 8-12 hours
Serotonin (5HT)
  • important in regulation of:
    • sleep, mood, impulsivity, and cognition
    • Found in the brain, blood, and GI tract (and Substantia Nigra)
  • Produced in the ==raphe nucleus==
    • projections sent to nerve endings up to the brain or down to the spinal cord
  • depletion
    • prolonged wakefulness
  • stimulation of serotonin rich cells
    • analgesia (inability to feel pain)
    • sleepiness
    • changes in appetite
Mechanisms of Action of LSD-Like Drugs
  • small doses can produce dramatic effects for visual hallucinations and alterations of consciousness remain enigmatic (difficult to understand)
  • alters activity of the brain systems mediated by 5-HT NT
  • ==partial agonist== at serotonin receptors
  • chemical structures of major hallucinogens resemble naturally occurring transmitter 5-HT
    • compounds mimic natural 5-HT and activate 5-HT receptors in the brain
    • LSD elicits behavioral attributes of 5HT 2A receptor
  • Problem: ==Mescaline’s chemical structure is different from the others==
    • mescaline produces vivid visual hallucinations virtually identical in form to those of LSD
    • Cross tolerance between LSD, mescaline, and other serotonergic hallucinogens
    • mescaline and LSD are agonists at the specialized group of serotonin receptor subtypes, 5-HT 2A
  • Many drugs that affect serotonin do NOT produce hallucinations
    • BUT HOW CAN SEROTONERGIC HALLUCINOGENS PRODUCE REMARKABLE EFFECTS ON VISUAL EXPERIENCE?!?!?!?!?!?!?
Pharmacokinetics of LSD-Like Drugs
  • All hallucinogens that act on 5-HT receptors have similar effects
  • What do the drugs vary in?
    • potency
    • LSD is the most potent
    • duration of action
    • other pharmacokinetic variables
  • LSD is rapidly absorbed; subjective effects are noted w/in 20 to 60 mins
  • LSD is distributed throughout the body and penetrates BBB
  • Effects persist for 8 to 12 hours then drug is rapidly metabolized and eliminated from the body
  • Can detect LSD and metabolites in urine for 72 hours after use
  • DMT: dimethyltryptamine; relatively short acting
    • effects begin w/in minutes, but persist for about 60 minutes
  • Chloropromazine is an effective antagonist
    • reverse effects are seen with LSD
Psychotherapeutic Uses
  • LSD produced a model psychosis
  • psychotherapists would benefit from having experiences similar to those of their patients
  • Visual vs. auditory
    • different sensory systems are impacted
    • hallucinations under LSD influence are visual
    • schizophrenics are usually auditory
    • subjective experience is not identical
  • Hallucinogens and use as adjunct to psychotherapy
    • therapists learn important info when patients use LSD and that patients gain better insight into condition b/c LSD could break down ego defenses
  • Moderate dose of psilocybin administered to patients w/advanced stage cancer reduced anxiety and depression
Effects of Serotonergic Hallucinogens
  • {{Physiological effects of LSD{{
    • similar to amphetamine and cocaine
    • they are sympathomimetic
    • pupil dilation
    • increase HR
    • increased BP
    • increased Body Temp, sweating
  • {{Psychological effects{{
    • difficult to characterize due to subjectivity
    • profound visual perception is common among individuals
    • spiral explosions and vortex patterns
    • lattice pattern: checkerboard pattern that appears on plain surface
    • flashing lights
    • increased brightness and saturation of colors
    • sense of movement in stable objects
    • trails or plumes around objects
    • synesthesia: the experience of sensing a sound stimulus as a visual one
    • subject reports “seeing” music
    • {{other effects:{{
    • mood is labile, easily altered
    • bizarre cognitive experiences occur
    • emotional state varies
    • “magical” and thinking
    • “mystical type” experiences are reported under a high dose
Adverse Effects of Serotonergic Hallucinogens
  • Controversy about their potential to produce a variety of adverse effects
  • LSD use produced chromosomal damage
    • individual who had drug would have deformed children
    • THERE IS NO CONVINCING EVIDENCE THAT LSD (OR SEROTONERGIC HALLUCINOGENS) INCREASE BIRTH DEFECTS IN OFFSPRING WHEN TAKEN IN NORMAL DOSES
    • risk of fetal damage if taken by pregnant women
  • Bad trips: leave individual in acute psychotic state, might harm themselves or others
    • Psychological state of the user and environmental setting are important
  • Flashback: sudden recurrence of an LSD-like experience
    • event occurred months or years before
    • nature of experience:
    • visual disturbances, flashes of color, trails in visual field, fleeting perceptions in peripheral field of view
    • flashbacks are brought on by stress, fatigue, entering dark environment, or MJ use
    • it’s difficult to estimate the frequency of flashbacks
    • Treatment- antipsychotics or benzodiazepines
  • difficult to determine whether LSD caused psychosis or person was psychotic to begin with and LSD made symptoms more flagrant
    • generally involves individuals who had already been diagnosed or have psychotic symptoms before drug use

Methylated Amphetamines

Ecstasy (MDMA) Overview
  • most controversial illegal drug in society
  • increase in popularity in late 1990s
  • declined after 2001
    • MDMA claimed to produce brain damage and death
  • influence 5-HT, DA, and norep. transmission
  • mild euphoria (excitement, happiness), openness, feelings of warmth and empathy, lack of defensiveness
History and Epidemiology
  • MDMA patented in 1914 by Merck Pharmaceuticals in Germany
  • known as the love drug
  • MDA and MDMA are Schedule 1
  • rave movement, from Europe to US
  • MDMA remains one of the most popular recreational drugs
  • most widely used illegal drug in Europe after MJ
Effects of Methylated Amphetamines
  • usually taken orally,
  • but can be injected
  • or absorbed intranasally (snorted)
  • rapidly absorbed
  • duration of action: 6 to 8 hours
  • MDMA blocks reuptake of 5-HT and DA
  • Overall: increase in 5-HT and DA activity, several hours later, decrease in 5-HT activity
  • sympathomimetic effects at effective doses
    • pupil dilation
    • increased HR, BP
    • muscle tension
    • teeth grinding
    • increase Body temp
    • appetite suppression
    • insomnia
  • effects very similar to amphetamine
  • stronger reinforcing effects for MDMA than amphetamine at all doses; reported to like MDMA better
  • physical withdrawal symptoms
    • drowsiness
    • muscle pain
    • depression
    • paranoia
    • anxiety
  • ==MDMA does not produce hallucinations== or the dissociation of LSD, less likely to produce adverse reactions
MDMA Toxicity
  • dehydration, heatstroke, heat exhaustion, muscle breakdown, kidney failure, stroke, seizures, heart attacks
  • elevated body temperature
  • most toxic reactions occur at high doses or when multiple doses have been taken, but death can occur at low doses
  • encouraged to drink fluids, but excessive fluids intake can alter the salt balance
Residual Effects of MDMA
  • rats had depletion of serotonin, depletion of serotonergic neuron terminals after many doses of MDA
  • neurotoxic effects can be produced after a single high dose (20 mg/kg), or with several low doses (5 mg/kg) over consecutive days
  • doses considered moderate in animal studies are higher than doses generally used on the street
  • most pills contain an average of 70 to 100 mg MDMA; ==below the dose range that is neurotoxin in humans==
  • ==5-HT modulates sleep, mood, and other functions==; depletion of 5-HT can lead to serious problems
  • there is a reduction in 5-HT functioning between heavy MDMA users and controls
  • the 5-HT system can recover from the effects after a period of abstinence
  • most MDMA users also use other drugs
    • heavy MDMA users showed more evidence of psychopathology (particularly depression) than nonusers
  • MDMA users showed more severe deficits on memory and other cognitive tasks than control participants matched for drug use other than MDMA
  • Still debating long term effects of MDMA use
    • MDMA and related drugs pose risks of acute toxic effects and possible deficits in neuropsychological functioning, particularly among heavy users

Anticholinergic Hallucinogens

  • Atropine and scopolamine: anticholinergic hallucinogens found in certain plants
  • Plants: belladonna (deadly nightshade); mandrake, henbane, jimsonweed
    • block metabotropic (slow acting) acetylcholine receptors in the brain
    • used in “witchcraft”
  • Physiological effects:
    • dry mouth
    • blurred vision
    • loss of motor control
    • increased HR and Body Temp
    • cause respiratory failure (cessation of breathing) at doses higher than the effective dose
  • Psychological experience:
    • dreamlike trance or stupor
    • seem delirious and confused
    • can describe their visions if asked
    • memory of the drug experience is poor; users may be unable to recall any details of the experience
  • rarely seen on the street today
  • Amanita muscaria: fly agaric mushroom
    • contains several different hallucinogenic chemicals, including muscarine
    • muscarine: cholinergic agonist
    • muscimole: hallucinogen similar to LSD-like drugs
    • only hallucinogen known to pass unchanged through the system into the urine

Dissociative Anesthetic Hallucinogens

History
  • Phencyclidine (PCP, angel dust), ketamine, and methoxetamine
  • PCP
    • first synthesized in 1956
    • tested as an anesthetic, produced tranquilizing effects
    • produced general anesthesia for animals, did not feel pain
    • with humans: experienced hyperexcitability, delirium, and visual disturbances
    • more than 20% of US high school students tried PCP
    • no longer used extensively in veterinary medicine
  • Ketamine
    • “special K”
    • seen in crystalline powder or in solution
    • can be snorted, injected, taken orally, or smoked
    • one of the most popular club drugs used for 18 to 32 year olds
  • Pharmacokinetics
    • mechanism: antagonism of NMDA receptors for glutamate (excitatory amino acid)
    • absorbed rapidly after smoking or injection
    • peak [blood] noted 5 to 15 mins after smoking
    • oral administration
    • peak [blood] noted after 2 hours
    • remains in the system unmetabolized for more than 2 days
    • PCP is detectable in urine for several weeks after a single use
  • Effects of PCP and Ketamine
    • moderate dose (1 to 10 mg) produces feelings of euphoria and numbness resembling OH intoxication
    • slurred speech
    • motor discoordination
    • users are catatonic (ability to move in a normal way is affected) and rigid
    • blank stare, may be aggressive and hyperactive
    • profuse sweating
    • increased HR, BP,
    • Nystagmus: rapid jerky eye movements
    • blurred vision or double vision
    • rarely reported hallucinations
    • dreamlike visions
    • changes in perception of body image, elastigirl
    • distortions of tactile senses
    • effects last 4 to 6 hours, but are variable; may persist for days or weeks at high doses
    • overdoses (more than 20 mg): result in seizures, prolonged coma, death from respiratory failure
    • bad trips: toxic psychosis characterized by paranoia and violence
    • may persist for several days
    • dissociative anesthetics are more likely than other hallucinogens to produce medical or psychiatric complications
    • Ketamine intoxications can create symptoms similar to schizophrenia
    • Ketamine can reduce symptoms of depressions
    • single dose of ketamine can improve symptoms within a few hours

Salvinorin A (Salvia)

  • plant in the sage family
  • Salvinorin A is the active chemical in Salvia
  • southern Mexico, used in religious ceremonies
  • ingested by chewing leaves or drinking tea
  • Now, leaves are dried and smoked; concentrated extracts are available for oral use or smoking
  • Not a scheduled drug at the Federal level
    • regulated at the state level
    • sold in some states, banned in others
  • generally smoked b/c appears to be inactive when taken orally
  • short term hallucinogenic effects
    • less than 30 mins in duration; intense trance like state
    • effects: visual hallucinations, sensory disturbances, impaired motor control
  • effective doses (100 to 500 micrograms)
    • {{most potent naturally occurring hallucinogen{{
    • agonist of a subset of kappa opioid receptors
    • not the same receptors that produce pleasurable effects of opiate drugs
    • involved in regulating pain