LSD and Other Hallucinogens Study Notes

Chapter 6 LSD and Other Hallucinogens

  • Albert Hofmann's Accidental Discovery

    • In 1943, chemist Albert Hofmann at Sandoz Pharmaceuticals accidentally experienced the first LSD trip after contact with a trace amount of the chemical, lysergic acid diethylamide (LSD).

  • Initial Experimentation

    • Hofmann conducted a deliberate experiment with a 0.25 mg dose of LSD, initially believed to be ineffective.

    • This dose was approximately five times greater than the average dose, resulting in intense hallucinations and sensory distortions.

  • Effects of LSD

    • Hofmann's experience revealed key effects of hallucinogenic drugs, including:

    • Visual distortions

    • Altered body sense

    • Blending of visual and auditory sensations

    • Effects can vary from frightening to pleasant, illustrated by Hofmann's shifting perceptions.

  • Cultural and Historical Context

    • Hallucinogenic drugs like LSD have origins in both ancient and modern contexts.

    • Basic materials like fungi have existed for millions of years.

    • An estimated 6000 plant species worldwide exhibit psychoactive properties.

  • A Matter of Definition

  • Terminology and Attitudes

    • Terminology often reflects the user's attitude:

    • Positive terms:

      • "Psychedelic" (mind-expanding)

      • "Entheogenic" (generating the divine within)

    • Negative terms:

      • "Psychotomimetic" (appearance of psychosis)

      • "Psychodysleptic" (mind-disrupting)

      • "Psycholytic" (mind-dissolving)

    • Neutral term:

    • "Hallucinogenic" meaning "hallucination-producing" describes the effects of these drugs.

  • Hallucinations vs. Illusions

    • Hallucinations: Perceptions of nonexistent entities.

    • Hallucinogens: Typically alter perception of existing environments; the term "illusionogenic" is suggested as more accurate.

Classifying Hallucinogens

  • Hallucinogens Classification

    • Classified based on chemical similarity to brain neurotransmitters, affecting:

    • Serotonin

    • Norepinephrine

    • Acetylcholine

    • Glutamate

    • GABA receptors.

  • Acetylcholine-related Hallucinogens

    • Includes atropine, scopolamine, and hyoscyamine (muscarinic acetylcholine antagonists) derived from plants like deadly nightshade and mandrake.

  • Indolamine Hallucinogens

    • Chemically similar to serotonin; includes:

    • LSD

    • Psilocybin

    • Morning glory seeds

    • DMT

    • Harmine

    • They act as 5-HT2 agonists.

  • Phenethylamine Hallucinogens

    • Related to norepinephrine; includes mescaline, DOM, MDMA, and MDA, which also act as 5-HT2 agonists.

  • Miscellaneous Hallucinogens

    • Diverse group including muscimol, ibotenic acid, PCP, ketamine, Salvia divinorum; varying mechanisms include:

    • GABAA agonism

    • NMDA antagonism

    • Kappa opioid agonism.

Lysergic Acid Diethylamide (LSD)

  • LSD Origins and Ergotism

    • A synthetic hallucinogen derived from ergot, a fungus found in moldy grains.

    • Ergot contains lysergic acid, toxic and historically associated with ergotism

    • Two forms of ergotism:

      • One causing gangrene/loss of limbs

      • The other leading to hallucinations and convulsions.

  • Albert Hofmann and LSD Development

    • Hofmann synthesized LSD while investigating lysergic acid for reducing bleeding and aiding childbirth.

    • Initially synthesized in 1938, LSD-25 was the 25th compound in his series of experiments, set aside until revisited in 1943.

  • LSD's Structure and Serotonin

    • LSD closely resembles serotonin in molecular structure, enabling it to act as an agonist on serotonin-sensitive receptors in the brain.

The Beginning of the Psychedelic Era

  • LSD's Initial Scientific Exploration

    • Sandoz Pharmaceuticals sought FDA approval for LSD in 1953, distributing samples for research into possible treatments for schizophrenia.

  • Psychedelic Research and Influence

    • Psychiatrist Humphrey Osmond, who coined the term "psychedelic," researched LSD and other hallucinogens like mescaline.

    • Introduced Aldous Huxley to mescaline, leading to Huxley’s essay "The Doors of Perception."

  • CIA Experiments and Public Awareness

    • LSD was involved in secret CIA experiments for espionage, with effects becoming known and influencing figures like Timothy Leary.

  • Timothy Leary's Role

    • A Harvard psychologist, Leary reported a profound religious experience with psilocybin in 1960.

    • Conducted psilocybin and LSD sessions with Richard Alpert, initially monitored scientifically but oversight later decreased.

  • Controversy and Dismissal

    • Leary's radical ideas, including suggesting LSD in water supplies, led to his and Alpert’s dismissal from Harvard in 1963, notable for media exposure and public awareness of LSD.

  • Cultural Impact of LSD

    • Became a symbol of 1960s cultural rebellion; Leary popularized “turn on, tune in, and drop out.”

    • Psychedelic culture flourished, featuring churches, festivals, and media.

  • Legal and Social Backlash

    • Panic surrounding LSD effects resulted in alarmist media coverage and congressional hearings.

    • Sandoz distanced from LSD, and it was declared illegal in the U.S. in 1966 and Canada in 1967, affecting research and relegating LSD to illicit drug culture.

How LSD Works in the Brain and Body

  • Serotonin-2A Receptors

    • The primary hallucinogenic effects of LSD arise from its stimulation of serotonin-2A (5-HT2A) receptors.

  • Serotonin Receptor Subtypes

    • There are 15 subtypes of serotonin receptors, classified into seven groups (5-HT1−7), most linked to G-proteins affecting second messenger systems, except for 5-HT3 family, which is ionotropic.

  • Hallucinogens and Receptor Excitation

    • Many hallucinogens can excite serotonin-2A receptor sites, irrespective of structural similarity to serotonin.

  • Blocking Hallucinogenic Effects

    • Drugs that block 5-HT2A receptors can prevent hallucinogenic effects, highlighting receptor importance in hallucinogenic experiences.

  • Binding and Hallucinogenic Potency

    • The potency of hallucinogenic effects is directly related to a drug's binding affinity for 5-HT2A receptors.

6.4.1 Acute Effects of LSD

  • LSD Potency and Dosage

    • LSD is highly potent, effective in doses measured in micrograms; typical street doses range from 50 to 150 micrograms, with effective doses as low as 10 micrograms.

    • For comparison, 325,000 micrograms is the amount in a standard aspirin tablet.

  • Absorption and Duration

    • LSD is rapidly absorbed when taken orally, with effects onset within 30 to 60 minutes, peaking in 2 to 4 hours, lasting 4 to 12 hours.

  • Toxicity and Safety

    • Despite high potency, LSD has low toxicity, with estimated lethal doses being 300 to 600 times the effective dose.

    • Only one confirmed case of death from LSD overdose is documented.

  • Forms and Appearance

    • LSD is odorless, tasteless, and colorless, commonly sold as microdots, windowpanes, or blotters, often adorned with images.

  • Initial Physical Effects

    • Initial effects of LSD include:

    • Increased heart rate

    • Elevated blood pressure

    • Dilated pupils

    • Slight rise in body temperature

    • Feelings of restlessness, euphoria, tension release.

  • Psychedelic Trip Features

    • The experience begins 30 minutes to 2 hours post-ingestion, characterized by:

    • Closed-eye visuals: Vivid colors and patterns seen with eyes closed.

    • Synesthesia: Cross-sensory perceptions (e.g., seeing sounds).

    • Multilevel reality perception: Seeing into objects’ molecular structures.

    • Exaggerated perceptions: Distortion of common objects.

  • Later Phase Effects

    • Three to five hours after ingestion, users may observe:

    • Emotional swings: Rapid emotional changes from joy to panic.

    • Timelessness: Distorted sense of time.

    • Ego disintegration: Sense of unity with the universe and loss of self-boundaries.

  • Influence of Set and Setting

    • The LSD experience’s nature, whether positive or negative, is influenced by users' expectations, environment, and psychological health.

6.4.2 Patterns of LSD Use

  • LSD Usage Trends

    • Changes in LSD usage since the 1960s show modern users typically taking it less frequently and in lower doses, resulting in shorter high durations.

    • Motivation has shifted from consciousness exploration to recreational use as a club drug.

  • Microdosing

    • A trend involving “microdoses” of LSD or psilocybin, too low to induce hallucinations but potentially enhancing mood, energy, and cognition.

    • Effects vary among individuals as this practice lacks extensive study.

  • Reported Effects of Microdosing

    • In a study:

    • 26% reported improved mood

    • 15% indicated improved focus

    • 13% noted increased creativity

    • However, 18% experienced physiological discomfort, and 8.8% reported impaired focus.

  • Potential Therapeutic Uses

    • Microdosing is being examined for treating depression, anxiety disorders, PTSD, and drug addiction; further research is necessary.

    • Experts recommend against unsupervised microdosing.

6.5.1 Will LSD Produce Substance Dependence?

  • Rapid Tolerance Build-Up

    • LSD causes rapid tolerance development, limiting continuous use over extended periods.

  • Intense Experience

    • The LSD experience is demanding and exhausting involving intense sensory and emotional experiences.

  • Lack of Control

    • Users find predicting LSD effects challenging, making it less appealing for those seeking a consistent high.

6.5.2 Will LSD Produce a Panic Attack or Psychotic Behaviour?

  • Bad Trips and Panic Reactions

    • Bad trips can occur even when users are aware they are taking the drug; companionship and reassurance help manage adverse effects.

  • Risk Factors for Adverse Effects

    • Those unaware of taking LSD, with unstable personality traits, or in hostile environments are more likely to experience negative incidents.

    • Long-term psychiatric issues are rare; no strong evidence links LSD use to permanent psychiatric conditions.

  • Comparison with Schizophrenia

    • While effects of LSD and schizophrenia share superficial similarities, they differ significantly:

    • LSD hallucinations: Primarily visual, often in the dark.

    • Schizophrenic hallucinations: Auditory, typically with open eyes.

    • LSD users are communicative and open to suggestion, contrasting with the withdrawn nature of most schizophrenic individuals, suggesting LSD does not mimic schizophrenia.

6.5.3 Will LSD Increase Your Creativity?

  • LSD and Perceived Creativity

    • Under LSD's influence, individuals often feel creative enhancement, although this perception does not hold in objective evaluations.

  • Professional Artists' Experience

    • Artists/musicians feel their work is superior while on LSD, yet this belief fades after the drug’s effects diminish.

  • Controlled Studies

    • Research indicates no significant increase in creative output objectively compared to baseline levels of creativity.

6.5.7 LSD as a Medical Treatment

  • Early LSD Research

    • Initial explorations by Osmond and Hoffer looked at LSD for alcoholism treatment; results were not analyzed collectively until later.

  • Meta-Analysis Findings

    • A 2012 meta-analysis of six trials (536 participants) showed that a single LSD dose significantly reduced alcohol misuse in treatment programs.

  • Resurgence of Interest

    • Following a decline in the 1960s, interest in psychedelics including LSD increased, with clinical trials indicating potential benefits for anxiety related to terminal illnesses and palliative care.

  • Future Research

    • As stigma diminishes, further research is anticipated to explore LSD's therapeutic potential.

6.6 Psilocybin and Other Hallucinogens Related to Serotonin

  • Psilocybin Source and History

    • Derived from mushrooms in southern Mexico and Central America, historically revered by the Aztecs for their visionary properties. Ancient carvings depict their use.

  • Discovery and Chemical Properties

    • Documented hallucinogenic effects of Psilocybe mexicana in 1955; Hofmann identified psilocybin as the active ingredient.

    • Psilocybin converts to psilocin in the body, the psychoactive compound affecting the brain.

  • Effects and Dosage

    • Psilocybin is less potent than LSD; effective dosages vary:

    • 4-5 mg induces relaxation

    • 15 mg or more causes hallucinations, altering perceptions.

    • A psilocybin trip lasts 2-5 hours, shorter than LSD’s duration, characterized by more visual effects and lower emotional intensity along with fewer panic reactions.

  • Psychotic Experience and Therapeutic Use

    • High doses can lead to significant mood and perception changes, qualifying as psychotic experiences, with increasing recreational use and therapeutic research benefits in conditions like OCD, anxiety, depression, nicotine addiction, and treatment-resistant depression.

6.6.1 Lysergic Acid Amide (LAA)

  • Cultural Use of Morning Glory Seeds

    • Morning glory seeds (ololuiqui) have a history of use in religious and healing practices among the Aztecs.

  • Active Ingredient Discovery

    • Hofmann identified the active ingredient in morning glory seeds as LAA, chemically related to LSD.

  • Effects

    • Similar effects to LSD but much less potent (1/10th to 1/30th) with more auditory than visual hallucinations.

  • Commercial Coating

    • To prevent abuse, commercial morning glory seeds are often coated to induce nausea/vomiting if ingested.

6.6.2 Dimethyltryptamine (DMT)

  • Source and Derivation

    • Primarily extracted from tree bark/resin in the West Indies, Central, and South America; typically inhaled as snuff.

  • Historical Synthesis

    • First synthesized by Richard Manske in 1931; structurally related to LSD and other serotonin-like hallucinogens.

  • Psychoactive Effects

    • DMT is active when inhaled but not when taken orally; known for rapid onset and short effect duration, dubbed "businessman’s LSD."

  • Effects Timeline

    • A 30 mg inhaled dose leads to physiological changes within 10 seconds, with peak effects at 10-15 minutes, subsiding within one hour.

  • Side Effects

    • Users may experience paranoia, anxiety, and panic during peak effects.

  • Chemical Similarity

    • A chemical found in Bufo toads resembles DMT structurally.

6.6.3 Harmine

  • Harmine and Ayahuasca

    • Derived from Banisteriopsis vine bark in the Amazon, harmine is the primary psychoactive in ayahuasca, used by Indigenous shamans in healing rites.

  • Chemical and Psychological Similarity

    • Harmine is chemically similar to serotonin; it produces different psychological effects compared to LSD.

  • Effects

    • Instead of LSD-like experiences, harmine induces trance-like states alongside dreamlike hallucinatory images, often involving animals and supernatural beings.

  • Additional Components

    • Some ayahuasca preparations contain DMT, enhancing experiences with sensations of flying and spatial detachment.

6.7 Hallucinogens Related to Norepinephrine

  • Chemical Composition

    • Some hallucinogens bear structural similarities to norepinephrine, influencing arousal and alertness.

  • Stimulant Effects

    • Certain hallucinogens produce stimulant effects akin to amphetamines due to norepinephrine similarity.

  • MDMA (Ecstasy)

    • Capable of amphetamine-like stimulant effects due to chemical similarity to norepinephrine.

  • Mescaline and DOM

    • Unlike MDMA, these do not exhibit significant stimulant effects despite norepinephrine resemblance.

6.7.1 Mescaline

  • Source and Preparation

    • Derived from the peyote plant, a spineless cactus; cactus crowns are cut, dried, and consumed in disk-like buttons (an effective dose is about 200 mg or five buttons).

  • Effects and Usage

    • Similar to LSD, peaking 30 minutes to 2 hours post-consumption; used in religious ceremonies by Indigenous Peoples in the U.S. and Canada.

    • Studies show that mescaline hallucinations feel more sensual; individuals cannot distinguish between LSD and mescaline effects at equivalent doses.

  • Physiological Reactions

    • Consumption can result in bitter taste, vomiting, headaches, and nausea, especially when the stomach is full.

  • Chemical Structure and Mechanism

    • Mescaline can be synthesized and also resembles norepinephrine in structure, stimulating serotonin-2A receptors like LSD, indicating a shared brain mechanism.

6.7.2 DOM

  • Synthetic Hallucinogens

    • A class of synthetic hallucinogens, including DOM, resembles mescaline and amphetamine but lack strong stimulant effects.

  • Potency and Effects

    • DOM is around 80 times more potent than mescaline but weaker than LSD; lower doses (3-5 mg) induce euphoria, while higher doses (10 mg or more) lead to intense hallucinations lasting up to 25 hours.

  • Adverse Reactions

    • Associated with a higher incidence of panic attacks and psychotic episodes compared to LSD, often called a “bad trip.”

  • Adulteration

    • Instances exist of DOM being used as an adulterant in marijuana.

6.7.3 MDMA (Ecstasy)

  • History and Development

    • MDMA (3,4-methylenedioxy-N-methylamphetamine) was first synthesized in 1914 by Anton Kollisch and later patented by Merck. Initial use aimed to suppress appetites in soldiers but gained interest in the 1970s for enhancing empathy in therapy.

  • Therapeutic Use

    • Considered an entactogen for its introspective and emotional connectivity effects; explored for treating PTSD, especially among veterans, facilitating trauma processing without retraumatization.

  • Recreational Use and Risks

    • Popular in clubs and rave scenes; street ecstasy often contains additives causing severe health risks (hyperthermia, dehydration, cognitive impairments).

    • "Ecstasy stacking" increases these risks.

  • Gender Differences and Recommendations

    • Women may face greater behavioral effects from chronic ecstasy use; pregnant women are advised against its use due to potential risks.

  • Pure MDMA vs. Street Ecstasy

    • Pure MDMA is viewed as safer under controlled conditions. Most dangers arise from impurities/adulterants added by street sources. Pure MDMA produced in legitimate labs shows future therapeutic potential.

6.8.1 The Hexing Drugs and Witchcraft

  • Anticholinergic Drugs

    • These drugs block parasympathetic acetylcholine effects, causing

    • Reduced mucus and saliva production

    • Elevated body temperature, increased heart rate, blood pressure, pupil dilation.

    • Psychological effects include delirium, confusion, and memory loss.

  • Key Anticholinergic Drugs

    • Atropine, scopolamine, and hyoscyamine, derived from various psychoactive plants.

  • Atropine

    • Derived from Atropa belladonna (deadly nightshade); antagonizes muscarinic acetylcholine receptors affecting both peripheral and central nervous systems.

    • Historically utilized for poisoning; associated with pupil dilation and heart-rate acceleration at lower doses, facilitating arousal.

  • Mandrake

    • Contains atropine, scopolamine, and hyoscyamine; functions as a sedative-hypnotic at low doses, causing hallucinations and paralysis at higher doses.

  • Henbane

    • Contains scopolamine and hyoscyamine; known for anesthetic and pain-killing properties at lower doses, lethal at higher doses.

  • Datura (Jimsonweed)

    • Notable for hypnotic and hallucinogenic effects; can induce disorientation and memory loss, toxic at high doses resulting in hospitalizations/deaths.

  • Historical Context

    • In medieval times, combinations of deadly nightshade, mandrake, and henbane were central to witches' potions, producing physiological and psychological effects believed to induce hallucinations of flight and communion with the Devil.

6.9.1 Amanita muscaria

  • Amanita muscaria Description

    • Known as the fly agaric mushroom, characterized by its bright red cap with white dots; historically used as an intoxicant.

  • Hypothesized Historical Significance

    • Possibly the basis for ancient soma in Hindu texts and utilized in Greek mystery cults.

  • Active Ingredients

    • Muscimol acts on GABAA receptors by opening Cl− channels, functioning independently of normal GABA release.

    • Ibotenic acid, converted to muscimol in the body, is a potent neurotoxin used in research for creating chemical lesions via increasing glutamatergic neurotransmission.

  • Effects

    • Includes muscular twitching, hallucinations, dizziness, and aggression; historical accounts suggest usage among Viking warriors for enhancing strength and aggression.

  • Ibotenic Acid Mechanism

    • Acts on NMDA receptors causing Ca2+ influx, which may lead to apoptosis upon overstimulation.

Phencyclidine (PCP)

  • Originally a synthetic depressant and surgical anesthetic

  • PCP was withdrawn due to severe side effects like delirium and hallucinations - only in veterinary medicine.

  • Classification Challenges

    • PCP exhibits a mix of stimulant, depressant, and hallucinogenic effects,

    • Dissociative anesthetic due to induced detachment feelings from the environment.

  • Mechanism of Action

    • Acts as a noncompetitive antagonist on NMDA receptors, disrupting Na+ and Ca2+ ion movement into neurons, affecting memory/cognitive process.

  • Acute Effects

    • Administered orally, intravenously, or through inhalation

    • effects may include manic excitement, severe anxiety, mood changes, and hallucinations altering body image

  • Duration and Aftereffects

    • Effects can last several hours to two weeks, often followed by amnesia and dissociation

    Street Names

    • PCP is known by various names like Angel Dust, Jet Fuel, and Zombie Dust, reflecting its potent and unpredictable effects.

Ketamine

  • Ketamine Properties

    • A dissociative anesthetic hallucinogen similar to PCP with both stimulant and depressant characteristics

  • Medical Use and Side Effects

    • Emergency anesthetic

      • limited therapeutic use due to side effects like violent jerking, vivid dreams, disorientation, and hallucinations.

  • Recreational Use and Risks

    • Known as "Special K" or "Vitamin K,"

      • dreamlike intoxication and amnesia

  • Controlled Substance and Therapeutic Potential

    • A Schedule I controlled substance used in Canada to treat mental illnesses, including severe anxiety and treatment-resistant depression

Salvia divinorum

  • Salvia divinorum Overview

    • A Mexican herb previously used to remedy ailments like diarrhea and headache; produces intense visual hallucinations and dissociative experiences akin to psilocybin mushrooms.

  • Active Ingredient

    • Salvinorin-A, acting as an agonist at kappa opioid receptors

  • Effects Duration

    • Potent but short-lived effects - 15 minutes.

Classifying Hallucinogens

  • Hallucinogens Classification

    • Hallucinogens divided into four primary groups based on similarity to major neurotransmitters:

    • Analogous to acetylcholine.

    • Resembling serotonin.

    • Related to norepinephrine.

    • Miscellaneous Group: Includes synthetic hallucinogens like PCP and ketamine, lacking resemblance to any known neurotransmitter.

Lysergic Acid Diethylamide (LSD)

  • LSD Overview

    • A hallucinogenic drug belonging to the serotonin group, synthetically derived from ergot, a toxic rye fungus.

    • Hofmann synthesized LSD in 1943; gained popularity in the 1960s as part of the psychedelic movement led by Timothy Leary.

  • Common Effects of LSD

    • Effects encompass:

    • Colorful hallucinations

    • Synesthesia (sounds perceived as visual)

    • Perceptual distortions

    • Emotional swings

    • Delayed sense of time

    • Perceived mind-body separations.

6.4 How LSD Works in the Brain and Body

  • Mechanism of LSD

    • LSD's effects are predominately due to stimulating serotonin-2A receptors in the brain.

  • Physiological Impact

    • Enhanced sympathetic autonomic activity resulting in increased heart rate, elevated blood pressure, dilated pupils, and slight body temperature rises.