Psychedelics and LSD

Defining Psychedelics

• Psychedelic drugs generally cause distortions in perception and altered states of consciousness
• These drugs can alter perception and thought
• High doses of psychedelics can induce hallucinations, mimicking psychotic states
• Typical doses of psychedelics distort perception but do NOT cause hallucinations

Serotonergic Psychedelics

• Serotonergic psychedelics are structurally similar to serotonin
• These drugs exert significant effects on the serotonin system

Lysergic Acid Diethylamide (LSD)

• LSD was first synthesized in 1938
• Chemist Albert Hofmann accidentally discovered LSD
• Hofmann isolated lysergic acid from ergot fungus and synthesized LSD while exploring derivatives
• Accidentally ingested LSD caused Hofmann to experience a dreamlike state with exaggerated imagination
• A small dose taken by Hofmann led to distortions of time, vivid hallucinations, and out-of-body experiences
• Hofmann advocated for LSD's therapeutic value
• By the 1960s, government agencies confined LSD to recreational use, making it illegal

LSD Pharmacokinetics: Absorption and Distribution

• LSD is primarily administered orally or mucosally
• Transdermal administration is rare
• A typical dose is 25-300 micrograms because LSD is a potent drug
• A microgram equals one millionth of a gram
• The drug comes attached to a substance such as paper due to the low dose required
• The paper can be placed on the tongue for rapid absorption

LSD Pharmacokinetics: Metabolism and Elimination

• LSD's half-life is 3-5 hours
• The effects can last 8+ hours due to the drugs potency
• Cytochrome p450 enzymes metabolize LSD, but the most important enzyme is unclear
• Small doses make study difficult; the primary identified metabolite is 2-oxo-3-hydroxy-lsd

LSD Pharmacodynamics: Mechanism of Action

• LSD acts as an agonist at serotonin receptors, activating most serotonin receptor subtypes
• LSD also has agonistic effects on dopamine receptors

LSD Pharmacodynamics: Effects of the Drug

• LSD effects vary, depending on the dose, personality, and mood of the user
• Sympathomimetic effects include pupil dilation, increased heart rate, and blood pressure
• The defining result is psychological perceptual effects
• LSD can cause mood fluctuations and distortions in the passage of time
• Perceptual distortions may manifest as an altered perception of existing sounds or objects, not hallucinations
• Users sometimes perceive objects with geometric patterns or pulsations

Negative Effects of LSD

• LSD is considered non-toxic
• The estimated LD50 of LSD is 14,000 micrograms
• Achieving this dose requires 70 individual 200-microgram doses, unlikely except by accident or intent
• LSD is not an addictive drug
• It causes rapid downregulations of serotonin receptors
• Taking the drug two days in a row results in a significantly decreased effect the second day
• Flashbacks occur without warning by re-experiencing effects of a previous LSD trip, long after its use
• Hallucinogen Persisting Perception Disorder (HPPD) induces perceptual effects that persist longer than expected

Psilocybin and Dimethyltryptamine (DMT)

• Psilocybin and dimethyltryptamine are serotonergic psychedelics with similar structural effects to LSD

Psilocybin

• Psilocybin can be found in several mushroom species
• Mushrooms containing psilocybin can be eaten or brewed into tea
• After consumption, psilocybin converts to psilocin or 4-hydroxy-DMT, a psychoactive substance
• Psilocybin acts as an agonist at serotonin receptors similarly to LSD
• The potency is much less than an equivalent dose of LSD

DMT

• DMT is found naturally in both plants and animals
• It can be smoked or administered intranasally
• DMT induces similar experiences as LSD, but with increased intensity
• DMT users may experience hallucinations, rather than perceptual distortions
• Effects are very short-lived, lasting 10-15 minutes, with full effects gone within 30 minutes
• Oral DMT is inactivated by monoamine oxidase (MAO), unless combined with a monoamine oxidase inhibitor (MAOI)
• The South American drink ayahuasca combined with MAOI allows DMT to be taken orally
• Indigenous peoples have consumed an ayahuasca-derivate containing a naturally occurring MAOI called Harmine for centuries
• Consuming DMT orally results in potent psychedelic effects lasting 3-4 hours

Catecholaminergic Psychedelics

• Catecholaminergic psychedelics share structural similarities with catecholamine neurotransmitters and amphetamines
• This class includes norepinephrine and dopamine
• MDMA can be considered a catecholaminergic psychedelic

Mescaline

• Mescaline is found in the peyote cactus of the southwestern United States and Mexico
• Indigenous peoples have used peyote for thousands of years in religious ceremonies of Mexican and American Indians
• The Native American Church is legally permitted to use mescaline in religious ceremonies
• Mescaline has structural similarities to norepinephrine; the difference is presumed to cause psychedelic effects
• Mescaline acts primarily as an agonist at serotonin receptors
• Taken orally, mescaline can produce psychedelic effects similar to LSD lasting for 10 hours

Glutamate Receptor Antagonists

• Glutamate receptor antagonists block glutamate receptors
• Phencyclidine (PCP) and Ketamine are glutamate receptor antagonists
• PCP and ketamine were discovered in 1956 and 1960 as surgical anesthetics
• Today recreational use is common for both
• PCP and ketamine are dissociative anesthetics
• Dissociative anesthetics cause analgesia, amnesia, distorted perceptions, but no loss of consciousness

Glutamate Receptor Antagonists: Effects

• The effects for these drugs are dose-dependent
• Low doses invoke a drunken state with reduced pain sensations, combined with irritability, paranoia, and hallucinations
• Higher doses invoke subject to be withdrawn and non-communicative stupor with catalepsy, can could induce seizures

Glutamate Receptor Antagonists: Risks

• Short term risks involve injuries obtained while under the influence
• PCP can cause unpredictable reactions and dangerous behavior
• PCP psychosis can be mistaken for schizophrenia
• The effects of PCP can last for weeks after drug clearance
• General psychological state when taking the drug and sex can influence PCP effects
• PCP effects cause more dysphoria and aggression between females vs males during periods of use
• PCP-related aggression is influenced by age, frequency of use, suspicion of others, psychiatric history, and assault history
• High doses of PCP can also produce liver failure, a result of PCP-induced hyperthermia

Alcohol Throughout History

• Alcohol production is natural and stumbled upon in prehistoric times
• Alcohol is produced during fermentation by microorganisms like yeast, which metabolize carbohydrates
• Microorganisms produce alcohol as a byproduct
• Fermentation occurs naturally; ancient people noticed fruit exposed to wild yeast and when undisturbed
• Alcoholic beverages were intentionally produced as far back as 7000 BCE
• Beer production uses fermented barely grain, and wine uses fermented grapes
• Distillation can produce purer forms of alcohol, often called spirits or liquor
• The United States attempted to prohibit alcohol sales in the early 20th century through the 18th Amendment
• Prohibition began in 1920, but it did not end alcohol consumption; instead, it caused illegal activity and boomed criminal enterprise
• Prohibition was repealed in 1933

Alcohol Pharmacokinetics: Absorption and Distribution

• Alcohol is primarily administered orally
• Alcohol passes through all cell membranes and is absorbed into the bloodstream via the gastrointestinal tract
• 80% of absorption occurs in the small intestine, and 20% in the stomach
• Alcohol distributes rapidly, crossing the blood-brain barrier easily

Alcohol Pharmacokinetics: Metabolism and Elimination

• Alcohol dehydrogenase (ADH) is the first enzyme found in the stomach and liver that converts alcohol into acetaldehyde
• 85% of ADH metabolism occurs in the liver, with 15% in the stomach
• Stomach metabolism occurs before alcohol reaches the bloodstream
• Some alcohol will be broken down before reaching its target receptors
• Acetaldehyde is a toxic substance metabolized by acetaldehyde dehydrogenase (ALDH)
• ALDH converts acetaldehyde to acetic acid, which is then broken down into carbon dioxide and water
• Alcohol metabolizes at a steady rate close to 1 ounce per hour
• A typical half-life does not apply when determining how long will take for the drug to to leave the user's system; Allow one hour for every typical drink

Alcohol: Metabolic Differences

• Enzyme level differences impact metabolism
• Women have lower stomach ADH levels than men, on average
• More alcohol reaches the bloodstream, giving women higher blood alcohol content (BAC) from same alcohol quantity as men
• Men are larger than women, diluting consumed alcohol to a greater effect
• Men on average have more muscle to fat than ratios than do women
• Alcohol is not readily absorbed by fat, causing higher body fat percentages to retain higher blood alcohol

Alcohol: Genetic Metabolism

• Genetic differences play a role in metabolism
• About 50% of Asians have a genetic polymorphism reducing ALDH activity
• When individuals with reduce of ALDH consume alcohol, ALDH cannot properly metabolized
• Acetaldehyde builds up, causing a variety of side effects including facial flushing, nausea, and headache

Pharmacodynamics of Alcohol: Mechanism of Action

• Alcohol affects the central nervous system
• The prominent effects are associated with allosteric modulation of the GABA receptor
• Alcohol binds to the GABA receptor and causes Gaba to have a greater effect when it binds to the receptor itself
• GABAs effect on neurons is inhibitory; alcohol increases these effects, making it less likely neurons generate action potentials
  • The neurotransmitter GABA inhibits signal-receiving neurons through the GABAA receptor
  • The GABAA receptor is a channel-forming protein that allows chloride ions to pass through cells
  • Excessive GABAA activation may mediate the sedating effects of alcohol and sedating and anesthetic agents
• The GABA receptor has separate binding sites for alcohol, GABA, barbiturates, and benzodiazepine
• Alcohol is a thought to be allosteric modulator of glutamate receptors, reducing the effect glutamate has when it binds to receptors
• Reduced glutamate effects further promotes neuronal inhibition

Pharmacodynamics of Alcohol: Effects of the Drug

• The effects of alcohol are dose-dependent
• Mild doses cause widespread neuronal inhibition, which then causes mild sedation and relaxation
• Social disinhibition and fear reduction occurs because brain circuits related to anxiety and stress are quieted down
• Increased causes effects to be more prominent; individuals may deficits in decision-making ability and impulse control
• Alcohol also inhibits brain areas devoted to movement, like the cerebellum, which causes loss of balance and equillibrium
• Neurons in the hippocampus are inhibited, leading to disrupted memory consolidation
• Increasing dosage can lead to severe sedation and eventually unconciousness

Alcohol: Tolerance

• Pharmacokinetic tolerance occurs when someone consumes alcohol repeatedly; the body initiates mechanisms the help to metabolize alcohol faster, viewing alcohol as a toxin
  • One way this is done is increasing the amount of alcohol dehydrogenase in the stomach a liver
  • This reduces the amount of alcohol reaching the bloodstream because more is metabolized in the stomach
• This causes someone to not obtained desired effects compared to the amount previously needed
• Pharmacodynamic tolerance occur when the rain recognizes that GABA signaling is higher than normal and glutamate signaling is lower than normal with chronic alcohol consumption
  • To regain hemostasis, the brain initiates mechanisms designed to decrease GABA by increase glutamate receptors by reducing GABA and increasing glutamate receptors
  • By removing GABA receptors, alcohol becomes incapable of reducing glutamate signal
  • Since there are more receptors where glutamate signaling can occur
  • The effects of both mechanisms will require someone to require more alcohol intake to achieve there desired intoxicating effects

Hangovers

• Hangovers manifest as unpleasant symptoms that occur after alcohol consumption
• These symptoms include headache, nausea, gastrointestinal disruption, and vomiting occur hours after alcohol consumption
• The exact causes of hangovers are not well understood

Hangovers: Acetaldehyde Accumulation

• The accumulation of acetaldehyde is the most widely accepted explanation for hangovers
• Acetaldehyde is toxic, so people will begin to develop many hangover's symptoms
• Over a prolonged period of drinking acetaldehyde dehydrogenases are unable to efficiently metabolize all acetaldehyde
• Acetaldehyde accumulation is the cause of hangover symptoms
• Over time the body will be able to metabolize all acetaldehyde to dissipate symptoms of a hangover

Hangovers: Congeners

• Contributions may be caused by substances called congeners
• Congeners are byproducts of alcohol fermentation
  • Some can be toxic to the body
  • High volumes of congeners can cause some symptoms of a hangover
• Dark color alcoholic drinks contain more congeners, in which studies have shown to cause more severe hangovers

Hangovers: Other Factors

• Alcohol is a sedative and may promote sleep, but NOT good sleep quality
  • Alcohol disrupts REM sleep; a person may wake up feeling tired
  • Repetitive consumption of alcohol may cause the stomach to release excessive amounts of hydrochloric acid
  • This can cause gastrointestinal

Alcohol Withdrawal

• Repetitive alcohol consumption can lead to the downregulation of GABA and upregulation of glutamate receptors
• The brain changes these receptor levels to maintain baseline levels of neurotransmitter activity; this occurs even when alcohol is present
• Withdrawal: Without alcohol being present, gaba activity will be lower than normal because the body did not maintain itself; where glutamate activity is higher than normal
  • This often times triggers a dysregulation generates negative withdrawal symptoms

Alcohol Withdrawal: Negative Effects

• A patient can experience seizures, tremors, anxiety, and paranoia
  • Seizures can be life threatening
• Benzodiazepines increase Gaba activity
• Anticonvulsants can reduced seizers
• Confusion, dissorientation, and and sometimes has last even hellcuinations last can occur for several days
• Overdosing and BAC's can reduce the function of conscienceness, rate of breaths a heart until one falls into a coma
  • BAC has an average of 0.4% or high

Alcohol: Liver Damage - Cancer

• Alcohol is toxic and can cause the liver to break down
• The liver causes fatty breakdown
• Cancer causes alcohol to have to overwork itself and causes more fatty deposits in people 2 drinks for men and 1 for women a day.
• FASD can form and creates more craniofacilites in people to disform them

Alcohol's Effect on the Fetus

• Fetal alcohol spectrum disorder can be transmitted to the fetus when consuming alcohol while pregnant
• FASDs cause disruption; causes the brain and body to become more and more abnormal and form in this way

Treatments for Alcoholism

• Disulfiram inhibits the activity of acetaldehyde dehydrogenase:
  • Acetaldehyde accumulates system which causes you to become uncomfortable when mixing
  • Deterrant for alcoholic consumption
• Naltrexone acts as the antagonist for the opioid
• Acamprosate is not clear on it's works and creates many nuerotransmitter problems such as the glutamate