Lecture 11 - Hallucinogens

XTC (Ecstasy)

  • Definition: MDMA (methylene-dioxy-metamphetamine), a derivative of amphetamine.

  • Relationship to Amphetamine:

    • Amphetamine chemical structure includes a nitrogen (NH) group and a methyl (CH3) group.

    • Adding a methyl group to amphetamine creates Methamphetamine (MA).

    • MDMA is methamphetamine with methylene and dioxy groups added.

XTC and Neurotransmission

  • Mechanism:

    • XTC causes monoamine release and inhibits reuptake, similar to other amphetamines.

    • It primarily affects serotonin release but also influences acetylcholine.

XTC and Serotonin

  • Serotonin (5-HT):

    • Increases release of serotonin.

    • Blocks serotonin reuptake.

    • Leads to acute depletion of serotonin in the brain.

Serotonin Effect in the Brain

  • Serotonin Pathways:

    • Serotonin pathways are widely spread throughout the brain, originating from the Raphe nuclei.

    • These pathways project to the thalamus, hypothalamus, basal ganglia, cortex, hippocampus, cerebellum, and spinal cord.

Acute Effects of XTC

  • Common Effects:

    • Heightened mood and increased emotional sensitivity.

    • Increased sensory awareness.

    • Reduced appetite.

    • Increased psychomotor drive.

    • Altered sense of time and space.

Brain Activity Imaging

  • Monkeys and MDMA:

    • Studies on conscious monkeys show that several brain areas are activated as blood levels of MDMA increase.

    • Visual stimulation response is stronger when MDMA is administered.

Problems with XTC

  • Toxic Effects:

    • When combined with intense physical activity, it can lead to hyperthermia, tachycardia, arrhythmia, pupil dilation, convulsions, jaw-clenching, and kidney failure.

  • Psychological Disturbances:

    • Depersonalization, paranoia, confusion, anxiety, panic, and suicidal thoughts.

Effects on Mood and Memory

  • Parrott et al. 2002 Study:

    • Examined XTC effects in new, moderate, and heavy users.

    • Heavier use correlated with more symptoms.

  • Short-Term Mood Effects:

    • During ecstasy use, individuals experience elevated mood.

    • After ecstasy, depression-like feelings and irritability can occur due to serotonin depletion.

XTC Effect on Memory

  • Heffernan et al. 2001 Study:

    • Compared 30 regular XTC users with 31 XTC-free controls.

    • XTC users reported more mistakes in prospective memory.

  • Halpern et al. Study:

    • Compared 52 ecstasy users and 59 non-users.

    • Found few consistent differences in verbal and visuospatial memory, verbal fluency, attention, processing speed, manipulative dexterity, and executive cortical functions.

    • Ecstasy users had lower vocabulary scores, possibly indicating pre-morbid ability differences rather than neurotoxicity.
      Note: Not all studies find an effect on memory

Explanation for XTC Effect on Memory

  • Possible Explanations:

    • XTC might destroy serotonergic nerve terminals.

    • Ecstasy can damage brain areas controlling memory, leading to memory impairment.

Serotonergic Neurotoxicity

  • Long-Term Effect:

    • Serotonin levels in cerebral cortex neurons are affected long-term.

    • Studies (Hatzidimitriou et al. 1999) showed reduced serotonin presence in the brain even seven years after ecstasy use.

Serotonergic and Dopaminergic Neurotoxicity

  • Ricaurte et al. Study (Later Retracted):

    • Initial concerns arose from a study suggesting that even single doses of MDMA caused extensive damage to dopaminergic neurons in monkeys, raising fears of increased risk of Parkinson's disease with age.

    • The study was retracted after it was discovered that the drug used was actually methamphetamine, mislabeled as MDMA.

Most Recent Review

  • SERT Binding:

    • Consistent evidence shows that MDMA decreases SERT (Serotonin Transporter) binding.

    • It remains inconclusive whether this decrease is permanent and due to neurotoxicity.

  • Need for Further Research:

    • Large translational studies are needed to determine definitively whether ecstasy use is neurotoxic in humans.

Does XTC Cause Addiction?

  • Cottler et al. 2001 Study:

    • Examined withdrawal symptoms in ecstasy users.

    • Significant withdrawal symptoms were reported, including feeling tired (53%), appetite changes (49%), anxiety/irritability (39%), depression (37%), trouble sleeping (35%), and difficulty concentrating (33%).

XTC: DSM-IV Abuse & Dependence

  • Reports and Studies:

    • Trimbos Institute reported few cases of XTC as a primary drug problem but frequent as a secondary issue.

    • Other studies showed limited evidence of primary addiction.

    • Withdrawal symptoms and continued use despite problems are most common.

Additional Information

  • Ecstasy Dosage and Contamination:

    • Danger stems mainly from unknown dosage and/or contamination with other substances.

    • Reports indicate rising ecstasy deaths due to super-strength pills and child-friendly appearance.

Psychedelics

  • Terminology:

    • Similar terms include hallucinogens, illusionogenic, entheogenic, psychotomimetic, and psychodysleptic.

  • Definition:

    • Psychoactive substances that cause temporary changes in perception, mood, cognition, and sense of self by affecting brain mechanisms.

  • Psychedelic-like Properties:

    • Substances like MDMA and ketamine also exhibit psychedelic-like properties.

  • Categories of Hallucinogens:

    • Serotonin-like / classical: LSD, DMT (in ayahuasca), psilocybin, mescaline.

    • Glutaminergic NMDA receptor antagonists / dissociative anesthetics: PCP, ketamine, dextromethorphan.

    • Anticholinergic: scopolamine, atropine.

    • Empathogens/entactogens: DOM, DMA, MDA, MDMA.

    • Opioid kappa receptor agonist: Salvinorin A.

    • Ibogaine.

Effects of Psychedelic Substances

  • Sensory-Perceptual Distortions:

    • Altered perceptions of colors, sounds, and shapes.

    • Complex hallucinations and synesthesia.

  • Psychological Effects:

    • Dreamlike feelings, depersonalization, and altered affect.

  • Somatic Effects:

  • Therapeutic Potential:

    • Emotional processing, cognitive flexibility, and mystical experiences may lead to therapeutic breakthroughs.

Drug, Set, Setting (Zinberg 1984)

  • Importance of Context:

    • Whether a psychedelic trip is positive or challenging depends on expectations, the environment, and the individual’s psychological state.

  • Drug-Induced Psychosis:

    • NIDA defines it as a distortion or disorganization of a person’s capacity to recognize reality, think rationally, or communicate with others.

History: Psychedelics in the 20th Century

  • LSD Synthesis:

    • 1938: LSD was synthesized by Albert Hoffmann from ergot, a fungus (Claviceps purpurea) that grows on grain.

  • First LSD Trip:

    • April 19, 1943: Albert Hoffmann experienced his first LSD trip.

  • Key Figures:

    • Timothy Leary.

  • War on Drugs:

History: Psychedelics in the 20th Century

  • Timothy Leary’s Research:

    • 1961: Timothy Leary started doing LSD research.

  • Good Friday Experiment:

    • 1962: The Good Friday Experiment was conducted.

  • Leary Fired:

    • 1963: Leary was fired from Harvard.

  • Nixon’s War on Drugs:

    • 1971: LSD was made illegal.

Psychedelic Renaissance

  • Renewed Research:

    • In recent decades, research has revisited the therapeutic use of psychedelics.

  • Therapeutic Effects:

    • In 2016, a study demonstrated the therapeutic effect of psychedelics, and more studies have followed.

Psychedelics and the Brain

  • LSD Pharmacodynamics:

    • Affinity for 5-HT2A, DA-D2, and alpha2 adrenergic receptors.

    • Typical dose ranges from 25 to 100 micrograms taken orally.

    • Effects begin 30 to 90 minutes after ingestion, peaking at 3 hours, and lasting up to 12 hours.

    • Low toxicity; lethal dose in animal studies is 14,000 micrograms. Overdose in humans is practically impossible, but behavioral effects during intoxication pose risks.

  • Psilocybin Pharmacodynamics:

    • Chemically similar to LSD but less potent.

    • Psilocin is the active metabolite, more fat-soluble, and acts quicker in the brain.

    • Dose (dried): 2-4 mg for pleasurable, relaxed effects; >5mg for hallucinations and time distortion.

    • Peak effect at 2 hours, with effects lasting 6 to 10 hours.

Psychedelics and the Brain: Main Theories

  1. 5-HT2A Receptor Agonism:

    • Neuroplasticity.

  2. REBUS Model (Carhart-Harris & Friston, 2019):

    • RElaxed Beliefs Under pSychedelics.

  3. Entropic Brain Hypothesis (Carhart-Harris, 2014).

Psychedelics & Neuroplasticity

  • 5-HT2A Receptor Agonism:

    • Studies (de Vos et al., 2021) show that single and repeated administration of psychedelics increases neuroplasticity one month after administration and enhances learning behavior.

  • Clinical Studies:

    • Single administration leads to rapid neuroplastic changes (BDNF↑).

  • Window of Plasticity:

    • Critical period reopening is proportional to the duration of acute subjective effects (Nardou et al., 2023).

  • Parallel Effects:

    • These effects parallel the clinical effects of psychedelics, potentially underlying them.

Mystical Experience

  • Griffiths et al. 2008 Study:

    • Double-blind design with 36 hallucinogen-naive adults.

    • Participants had sessions with psilocybin vs. methylphenidate.

  • Definition:

    • Profound altered state of consciousness where a person feels deeply connected to something greater than themselves, often with a sense of unity, peace, and insight.

Follow-up Results

  • Meaning and Significance:

    • Mystical-type experiences mediated the attribution of personal meaning and spiritual significance 14 months later.

  • Among Top Experiences:

    • Ranked among the top 5 personally meaningful experiences of a lifetime.

    • Ranked among the top 5 spiritually significant experiences of a lifetime.

  • Increased Well-being:

    • Increased current personal well-being or life satisfaction

  • Positive Behaviour Change

Psychedelics-Assisted Therapy

  • Clinical Research:

    • Used in treating PTSD, depression, end-of-life anxiety, eating disorders, and addiction.

  • Integration:

    • Weeks following the session, the participant meets with a clinician to make sense of their experience and incorporate any insights into their life going forward.

Are Psychedelics Addictive?

  • Addiction Potential:

    • No direct effect on the dopaminergic system, less rapid tolerance, and no withdrawal symptoms result in low abuse potential for classical psychedelics. Abuse potential for substances like ketamine differs.

  • Historical Context:

    • Bill Wilson, founder of Alcoholics Anonymous, explored psychedelics for treating addiction.

Psychedelics to Treat Addiction

  • LSD for Alcoholism:

    • Studies have shown short-term effects (Krebs & Johansen, 2012).

  • Psilocybin:

    • May reduce alcohol and tobacco use in addicted samples (Johnson et al., 2017).

  • Ketamine:

    • Used to treat alcohol dependence (Grabski et al., 2022).

  • Ayahuasca:

    • Observational study showed reductions in alcohol, cocaine, and tobacco use, along with improved wellbeing (Thomas et al., 2013).

  • Ibogaine:

    • Shows promise for opioid addiction but carries risk of extreme physiological reactions.

Psilocybin to Treat Alcohol Use Disorder

  • Bogenschutz et al., 2022 Study:

    • Double-blind, active placebo-controlled clinical trial (n=95).

    • Participants received 2 doses of psilocybin (25-40mg/70kg) + psychotherapy (motivational enhancement therapy and CBT) over 12 weeks.

  • Results:

    • Number of heavy drinking days decreased at 32-week follow-up.

    • Number of standard drinks per day decreased at 32-week follow-up.

    • Psilocybin + psychotherapy produced robust decreases in % of heavy drinking days over and above those produced by active placebo and psychotherapy.

Roadblocks

  • Challenges:

    • Michael Pollan effect, placebo control group issues, therapist training requirements, politics, stigma, legalisation challenges, safety concerns (psychedelics not for everyone).

  • Access and Equity:

    • Need for equitable access for women, BIPOC, non-western, queer people.

  • Commercial Exploitation:

    • Concerns about “psychedelic capitalism”/psychedelic bourgeoise”.

  • Indigenous Traditions:

  • Conclusion:

    • Between hype and hope.

Take Home Messages

  • Unique Alterations:

    • Psychedelics uniquely alter perception, emotion, and self-awareness, enabling insights and therapeutic breakthroughs.

  • Mechanism of Action:

    • They mainly act on serotonin 5-HT2A receptors, boosting brain plasticity and reducing default mode network activity.

  • Theoretical Models:

    • REBUS and Entropic Brain models explain how psychedelics loosen rigid thoughts and increase brain flexibility.

  • Clinical Effectiveness:

    • Clinical research indicates psychedelics can treat depression, PTSD, addiction, and anxiety by enhancing emotional and cognitive change.

  • Risks and Ethics:

    • Use involves risks and ethical challenges, including safety, unequal access, and respect for Indigenous knowledge.d use.