Drugs & Behavior - Class #11 (Hallucinogens)

Ketamine

- "Special K" - Developed to replace PCP - Veterinary use for its anesthetic effects (by injection) - Liquid is colorless and tasteless - Swallowed or injected, or converted to powder and snorted

LSD Interest: Phase 2

- 1953: proposed to be a potentially useful adjunct to psychotherapeutic techniques

Mescaline

- A psychedelic found in a small cactus called peyote (contains 1.5% mescaline) - Historically, the drug is dried and eaten - Native American tribes use(d) mescaline during sacred ceremonies - Not often used recreationally beacuse it takes up to 15 years for a single dose to mature - Categorized as schedule 1 (little research has been done) - Catecholamine-like in molecular structure (similar to the catecholamines dopamine and norepinephrine) - Chemically related to norepinephrine, but 5-HT2A receptors are responsible for its hallucinogenic effects, which may last 8-10 hr - Effects include dilation of the pupils, increase in body temperature, anxiety, visual hallucinations, vomiting, muscular relaxation - High doses may cause death - Street samples are rarely authentic

LSD: Harmful Effects

- Acute psychotic reaction - Flashbacks - Trailing phenomena - No recorded death from overdose

GHB: Effects on Behavior

- Alcohol-like intoxication - Relaxation, euphoria, anxiolytics - Amnesia for events during and after drug use - Treatment for narcolepsy

LSD: Sensory and Psychological Effects - Sol Snyder (1974)

- Altered perception of senses, including synesthesia - Self-reflection: value noted by psychotherapists (Snyder referred to Freud's goal of making "conscious the "unconscious") - Loss of identity and cosmic merging

Hallucinogens related to Acetylcholine

- Anticholingergic hallucinogens diminish the effects of ACh in the parasympathetic nervous system - Long history: so-called "hexing drugs" that have been involved in sorcery and witchcraft since the Middle Ages (common ingredients in witches brews) - Contain a combination of atropine (in eye drops that dilate the pupil), scopolamine (in patch form for motion sickness), hyoscyamine (from henbane) - Sources: deadly nightshade plant, mandrake roots, henbane seeds, angel's trumpets - Effects of ingesting higher doses (due to accidental or intentional ingestion of the plants): anticholingergic delirium: a complete inability to differentiate reality from fantasy (contrasted to hallucination); hyperthermia; tachycardia; bizarre behavior - Most describe effects as extremely mentally and physically unpleasant

MDMA: Benefits (?)

- As with many hallucinogens, some psychiatrists have found them effective for use during psychotherapy

GHB: Neuropharmacology

- Binds to its own receptors and in high doses to GABA-B - Perhaps also specific GABA-A receptors

PCP and Ketamine: Neuropharmacology

- Both are NMDA receptor antagonists

MDMA: Lethal Effects

- Causes of death: heart and circulatory problems, liver damage, swelling of the brain, overheating - quality control (may be adulterated with drugs such as amphetamine, ephedrine, and PMA) - consumption of alcohol and other drugs

LSD: Stage 4

- Comedown phase (2-3 hr)

Dextromethorphan: Effects

- Cough suppresant - High doses, effects are similar to PCP and ketamine - Ataxia, dizziness, euphoria, tactile and visual hallucinations

Lysergic Acid Diethylamide (LSD)

- Derived from ergot, a toxic rye/grain fungus that has been responsible for thousands of deaths over the years - Ergotism

LSD: Tolerance

- Develops rapidy - If LSD is taken repeatedly, its effects disappear within 2 or 3 days - No amount of the drug will be effective - Tolerance dissipates quickly - Cross tolerance with other hallucinogens excluding THC

LSD: Facts and Fiction

- Does not produce psychological or physical dependence - Chance of inducing panic or psychotic state is slight (providing it is taken in a "supportive" setting) - No evidence LSD elevates one's level of creativity - Although sensory perceptions are altered, whether they are enhanced is unclear - Reaction times are impaired - Does not damage chromosomes - Possible birth defects?

Hyoscyamine

- Drug that acts on acetylcholine receptors - From henbane

Scopolamine

- Drug that acts on acetylcholine receptors - Used for motion sickness

Atropine (Belladonna)

- Drug that acts on acetylcholine receptors - Used in eye drops by ophtamologists

PCP and Ketamine: Tolerance and Withdrawal

- Drugs not typically used every day, so tolerance may not develop (develops when drug is used consistently, just rarely happens because people tend to use it sporadically) - When withdrawal effects are seen: physical distress, lack of energy, depression, anxiety, confusion, tremors, diarrhea

Psychedelics

- Drugs that change level of consciousness - "Mind-manifester"

Empathogens

- Drugs that induce feelings of empathy - "empathy enhancers"

Psychotomimetics

- Drugs that induce psychosis (loss of touch with reality) - including delirium - "Psychosis mimic"

Phantasticant

- Drugs that induce vivid perceptual experiences or phantasmagoria

Hallucinogens

- Drugs that produce distortions of perception and of one's sense of reality - Other classes of drugs may produce hallucinations at high dose levels, but hallucinogens produce these effects at low or moderate levels

Salvia: Pharmacokinetics

- Effective only for a short time (5-30 minutes) - Salvinorin A metabolized to the inactive salvinorin B

LSD: Neuropharmacology

- Effects on the nervous system are still not clear - Agonist of serotonin receptors, primarily 5-HT2A receptors - Effects on 5-HT receptors in the following areas: Locus coeruleus (LC), cortex, raphe nuclei - In particular, the 5-HT2A receptor is involved in the hallucinogenic effects

LSD: Animal Studies Run Amok

- Experiment with elephant - "LSD-induced effects in elephants: comparisons with musth behavior"

GHB

- Gamma-hydroxybutyrate - GABA metabolite - Used clinically as Xyrem (treatment for narcolepsy) - dietary supplement - Street use increase in 1990's: by body builders for growth promotion; as a sedative and a recreational drug; date rape drug - FDA banned it from public sale (1990) - GBL kits (not illegal), liquid X, scoop, cherry meth, blue nitro, easy lay, etc. - Schedule I drug (2000)

LSD: Stage 1

- Heightened, exaggerated senses (30-60 min) - Visual hallucinations, appearance of geometric patterns

LSD: Effects on Performance

- Impairs reaction time - Performance on a "pursuit rotor task" may be improved by LSD - Functioning on intellectual tasks impaired - Impairment of problem-solving and cognitive functions

LSD in the 60's

- In the 1960's, usage of LSD was used as a true psychedelic drug at higher doses to achieve hallucinations and "cosmic" experiences - Meanwhile, the CIA and military conducted experiments in the 1950's and 1960's (looking for "non-lethal incapacitating agents); CIA program MK-Ultra - 1962: The FDA restricts LSD research & the first LSD related arrests are made - 1963: LSD is found on the streets for the first time in the form of liquid or sugar cubes - 1967: Federal government bans LSD in the US - 1970: LSD is placed in Schedule 1 of the Controlled Substances Act

MDMA: Effects on the body

- Increase muscular tension (bruxism) - Increase in body temperature, headache, nausea, blurred vision, insomnia, difficulty in concentration, fatigue, depression

MDMA: Neuropharmacology

- Increased transmission at synapses that use serotonin (also norepinephrine) - Blocks reuptake of the neurotransmitter - Also enhances the release of the neurotransmitter - Increases levels of oxycotin

Bufo frogs/Buotenine

- Indoleamine-like drug - High concentrations in the parotid glands of the Colorado River Toad (among others) - Contains bufotenin(e) but any intoxication is primarily from a related compound (Schedule I) - Users apply pressure to the parotid glands, located behind the ears, causing a milk substances to ooze onto the size - People have been known to directly lick off the amphibian or collect to dry and eventually smoke

Psilocybe Mushrooms

- Indoleamine-like drug - LSD-like - Small and brown (magic mushrooms) that stain blue to the touch - classified by the DEA as a Schedule 1 Controlled Substance - Usually eaten whole after drying, drunk as a tea or soup, or ground to a powder and smoked (typically with marijuana) - There are nearly 200 species with psychoactive components - Effects: dream-like states with hallucinations, perceptual alterations (especially slowing of time), synesthesia, euphoria, lethargy and many other highly individual effects - Recently researchers have examined potential benefits of controlled psilocybin administration on treating PTSD, depression and anxiety - Other studies have examined brain activity and subjective effects in people - Studies conclude that psilocybin decreases activity throughout the brain and reduces synchronized activity

Dimethyltryptamine (DMT)

- Indoleamine-like drug - Short-acting hallucinogen similar in structure to bufotenin (5-OH-DMT) and psilocin (4-OH-DMT) - Serotonin-like compound found in a variety of plants - It is the primary mind-altering component of anyahuasca, used by native peoples of Peru - The hallucinatory effects of ayahuasca requires a MAOI from another plant to be added (typically harmine and harmaline) - Synthesized in the lab in 1931; only later was it identified in a variety of S. American plants - By itself, it must be inhaled or taken as snuff (if taken orally, it is combined with an MAOI, as with ayahuasca) - Produces classic auditory and visual hallucinogenic effects - Lots of sources: "canary grass", Prairie Bundle-flowers, etc. (mostly in S. America)

GHB: Withdrawal

- Insomnia, anxiety, delirium with hallucination

LSD Interest: Phase 1

- Interest in LSD's potential for revealing the biochemical basis of psychosis - This phase waned in the mid '50s primarily because it was determined that the effects did not mimic the symptoms of any natural psychosis

MDMA: Negative Effects

- Jaw clenching, anxiety, paranoia, insomnia, dry mouth, increased body temperature

Salvia: Neuropharmacology

- Kappa-opiod receptor agonist

LSD: Effects on Perception

- Keener perceptions - Sight and sound become more acute - Slowing down oftime

LSD Interest: Phase 3

- LSD and similar drugs became just another class of abusable drugs

Indoleamine-like drugs

- LSD is similar to serotonin, as are... - Psilocybin (from "magic mushrooms") - Lysergic Acid Amide (from morning glory seeds) - DMT (from a variety of South Americans plants) - Bufotenine (plants, venom from toad skin) - Harmine and harmaline (in Ayahuasca)

LSD: Dosages and Sources

- LSD: hits - Today: About 200 micrograms needed for full effect - 1970's: 100 micrograms - gel tab, window pane, microdots - mescaline: dried peyote cactus

MDMA: Withdrawal

- Lack of repeated usage prevents withdrawal symptoms from occurring...except for: - Hang over effects

MDMA: Neurotoxicity

- Long term serotonin neurotoxicity 1) One notable study in monkeys: - Serotonin depletion due to loss of nerve terminals - Decreased levels of SERT (serotonin transporter) - Compensatory (?) increases in 5-HT2A receptor level - many cognitive deficits However, many human studies are confounded with other drug use In humans: - Decreased serotonin transporter levels in cortex and hippocampus - Some studies report that memory, attention and decision-making are impaired in MDMA users at low doses

LSD: Stage 2

- Loss of control (next 2 hrs) - Time slows, more intense visual effects

Studying Hallucinations

- Moreau, 1845: took hashish and self-analyzed his hallucinatory state (conclusion: hallucinations result from brain excitation) - Kluver, 1926: mescaline-induced imagery produced 4 constant (geometric) types, many in vibrant colors --> he discovered that these constants appear in other hallucinatory conditions - Kluver did not describe a 2nd stage involving animals, people and places that are seen by 60-70% of subjects

LSD: Subjective Effects

- Motivation issues - Hallucinogenic effects: verbal reports, hypnogogic states (state of transition from wakefulness to sleep) - Phantasticant and perceptual effects: can produce experiences with great emotional significance (used in religion) - Entactogenic and empathogenic effects: insight into one's past and one's own mind

Dextromethorphan: Neuropharmacology

- NMDA receptor antagonist - Sigma receptor agonist - Antitussive effect - Decreases opioid reward - Pharmacological properties similar to the dissociative anesthetics and alcohol

LSD: Withdrawal

- No withdrawal symptoms

Dextromethorphan: Pharmacokinetics

- Oral consumption - Converted rapidly to dextrorphan during the first pass through the liver

PCP and Ketamine: Harmful Effects

- PCP: psychotic behavior (similar to schizophrenia) that can last months - Ketamine (chronic use): loss of gray matter in frontal cortex

Dissociative Anesthetics

- Phencyclidine (PCP) - Ketamine

Salvia Dinorum

- Plant indigenous to Mexico - Regarded by the DEA as a "drug of concern", although it is not presently legal - Salvinorin A is the active compound

Salvia: Behavioral Effects

- Produces intense hallucinations, laughter, loss of motor coordination, perceptual changes, emotional swings, synesthesia

Common themes of hallucinations

- R.K. Siegel (1977) - similar across culture - drug and non-drug hallucinations are similar - concluded that nature and structure of hallucinations are determined by brain activity, not the drug itself

MDMA: Sought-after effects (on behavior/performance)

- Rapid sought-after effects, 4-6 hr in duration - Euphoria, increased confidence, increased perception of closeness to others, visual hallucinations, wakefulness, endurance, energy, sharpened sensory perception, extroversion - Subjectively MDMA induces both amphetamine-like and LSD-like effects, but is relatively free of the hallucinations produced by LSD-related compounds - A dose of 75-100 mg induces a state similar to that cause which is caused by marijuana or low doses of PCP

Club drugs

- Recreational drugs used at dance clubs/"raves" to enhance experience and pleasure - Used to achieve one or more of the above states

PCP and Ketamine: Behavior and Performance

- Relaxation, warmth, numbness - Euphoric feeling, distortions in body image, floating in space - Mild depression after use (24 hrs to a week) Higher doses: - immobile, comatose, dramatic mood swings, disorientation, motor disturbances (that include catatonia or stereotypy), amnesia, schizophrenic behavior, coma, depression, weight loss - Can last many months after cessation of use

Entactogens

- Same as empathogen - "Touching within"

LSD: Stage 3

- Self-reflection (3-5 hr) - Time suspended - Continuous stream of distorted images (may be pleasant or menacing) - Synesthesia: crossing over of the senses - Sense of "cosmic merging"

Bufotenine

- Similar to DMT, but found in the dermal glands of frog species - Not well studied, bu hallucinatory effects have been described anecdotally - Used in China as "Ch'an su" (Ingested orally or applied topically to reduce swelling and alleviate pain)

LSD: Effects on the body

- Stimulates the autonomic nervous system - Dilates the pupils - Increases body temperature - Nausea

Albert Hofmann's discovery of LSD

- Synthesized LSD in 1938 - Did this by synthesizing lysergic acid derivatives that were known to stimulate uterine contractions - Took a "small" "accidental" sample of the 25th derivative, LSD-25 several times (1943) = first LSD "trip" - Following Hofmann's discovery of LSD, interest went through 3 distinct phases

MDMA ("Ecstasy")

- Synthetic Mescaline-like drug - Synthetic amphetamine derivative, usually sold as small tablets or capsules - Many street names (X, Adam, etc, et, etc) - Originally synthesized by Merck drug company in 1912 - Merck studied its properties sporadically through 1960 (minimal research) - Sasha Shulgin said to have synthesized the drug for Dow in 1965; began to use and pass on to friends (increased general interest) - 1970's: psychotherapists give drug to patients (to enhance intimacy and communication) - Usage was popularized in the 1980's by people selling it openly - Reclassified in 1985 as Schedule I (banned due to stated neurotoxic effects) - despite much evidence arguing against the drug's danger

Dextromethorphan

- Synthetic cough suppressant - Opioid-like in structure, but different mechanism - Robitussin - "Roboing"

Phencyclidine (PCP)

- Synthetic drug developed in 1963 as an anesthetic - Dissociative anesthetic (i.e., separation from sensory experience) - withdrawn from the market due to delirium, disorientation, and agitation that occurred after people were recovering from the drug, called "emergence delirium" - continued to be sold on the streets as: crystal, angel dust, hob

GHB: Pharmacokinetics and Dose

- Taken orally (rapidly absorbed) - Effects begin within 15-30 min; peak effects at about 30 min - half-life of 40 min - Therapeutic index: 20-30 - Can be lethal when mixed with other drugs

MDMA: Pharmacokinetics

- Taken orally; peak level in 2 hours - Half-life: about 8 hrs - Metabolized to MDA (similar potency) - Excreted in urine

Timothy Leary and LSD

- Timothy Leary led the psychedelic movement that popularized LSD use in the 1960's - He was a Harvard lecturer; began to experiment with magic mushrooms on a trip to Mexico; returned and provided it to others - He discovered and began to use LSD after his return, and made it the basis of a new philosophy, characterized by the phrase, "turn on, tune in, drop out" - He was dismissed from Harvard in 1963

MDMA: Tolerance

- Tolerance can develop rapidly

GHB: Tolerance

- Tolerance to motor-impairing, sedating, and anesthetic effects

Ayahuasca

- Used in shamanic ceremonies in S. America

LSD: Pharmacokinetics

- Usually taken orally - Effects begin between 30-90 min. after ingestion - Metabolized in the liver - Easily crosses BBB - Half-life: 175-300 min in humans (about 3 hours) - Excreted in the feces (90% excreted within 24 hrs) - Effects can last 2-12 hours - Tolerance develops quickly - No withdrawal symptoms noted - Flashback experiences possible (DSM-IV: "Hallucinogen Persisting Perception Disorder" (HPPD))

PCP and Ketamine: Pharmacokinetics

- Weak, lipid soluble bases - Effective orally, inhaled, injected - PCP peaks in about 10 to 90 minutes, last 4-8 hours - Ketamine can be snorted, injected, or taken orally (oral administration has slow absorption: typically dried to powder and used intranasally; effects last from 35-40 min)

Mescaline-induced geometric imagery

- grating/lattice/ honeycomb - cobwebs - tunnel/funnel/alley - spiral

LSD Use Today

- today, LSD is used at somewhat lower doses and is more of a phantasticant or enactogen than a hallucinogen

MDMA: Harmful Effects

1) Depletion in serotonin: - Sleep disorders, depression, persistent anxiety, impulsiveness, hostility, memory impairment - Effects dissipate after about 6 months once drug is stopped 2) Heat regulation - Increase in body temperature may lead to heatstroke, muscle tissue damage, kidney failure, liver damage, and may cause the brain to swell resulting in epileptic-like seizures 3) Toxicity: MDMA overdose is rare - intense sympathomimetic responses and active hallucinations as well as thermoregulatory, cardiovascular, hepatic and electrolyte altering (due to water consumption)

LSD: 4 stages of Sensory and Psychological Effects

1) Heightened, exaggerated sense (30-60 min) 2) Loss of control (next 2 hr) 3) Self-reflection (3-5 hr) 4) Comedown phase (2-3 hr)

Phantasmagoria

A confusing scene that is like a dream because it is always changing in an odd way

GHB: Patterns of Self-Administration

Animals: - No evidence that rats or monkeys will reliably self-administer GHB Humans: - Drastic increase in use

LSD: Patterns of Self-Administration

Animals: - Not self-administered by non-humans - Adverse effects - Exception with monkeys with a history of administering MDMA Humans: - Never continuously consumed

Ergo Fungus: Ergotism

Behavioral and psychological effects - St. Anthony's fire: sense of heat due to constriction of blood vessels - led to gangrene - Convulsions, delirium, hallucinations - Contained various compounds similar to lysergic acid - Named for 12th century monks who treated it - Clams have been made that ergot infestations of food supplies may explain unusual behaviors historically (such as Salem witch trials)

Drug Induced Hallucinations

Experiments with Psilocybin: - The Default Mode Network (DMN): - Psilocybin reliably reduces acitivity in the DMN; these high-level networks also become disorganized under psilocybin

Scintillating scotomas

Migraine auras

Hallucination model

Model by Bressloff, Cowan, et al: "Hallucinatory images in the brain could be understood in terms of spontaneous pattern formation in the brain...the brain makes patterns of activity when it goes unstable."

Salvia: Tolerance and Withdrawal

None