Cannabis & Hallucinogens: The Psychedelic Renaissance

By the end of this module, you will be able to:

• Describe the endocannabinoid system and its functions
• Differentiate between THC and CBD effects
• Explain Cannabis Use Disorder and its treatment
• Identify classic and atypical hallucinogens
• Discuss the evidence for psychedelic-assisted therapy

Discovery

The endocannabinoid system was discovered in the 1990s while researchers studied how cannabis affects the brain. It is now recognized as a fundamental regulatory system.

Components

Receptors: | Receptor | Location | Function | |----------|----------|----------| | CB1 | Brain, CNS | Psychoactive effects, memory, appetite, pain | | CB2 | Immune system, periphery | Inflammation, immune response |

Endogenous Cannabinoids (Endocannabinoids):

• Anandamide (AEA): "Bliss molecule"
• 2-Arachidonoylglycerol (2-AG): Most abundant endocannabinoid

Enzymes:

• FAAH: Breaks down anandamide
• MAGL: Breaks down 2-AG

Functions

The endocannabinoid system regulates:

• Pain perception
• Appetite and metabolism
• Mood and stress response
• Memory and learning
• Sleep
• Immune function
• Reproduction

Retrograde Signaling

Unlike most neurotransmitters, endocannabinoids work "backwards":

1. Postsynaptic neuron releases endocannabinoids
2. They travel backward across synapse
3. Bind to CB1 on presynaptic neuron
4. Reduce neurotransmitter release
5. Fine-tune neural activity

Key Cannabinoids

THC (Delta-9-Tetrahydrocannabinol):

• Primary psychoactive component
• Partial agonist at CB1 receptors
• Produces euphoria, altered perception
• Responsible for most intoxication effects

CBD (Cannabidiol):

• Non-intoxicating
• Complex mechanism (not direct CB1 agonist)
• May modulate THC effects
• Anti-anxiety, anti-inflammatory properties
• FDA-approved for certain seizure disorders (Epidiolex)

Other Cannabinoids:

• CBN (Cannabinol): Mildly psychoactive, sedating
• CBG (Cannabigerol): Non-intoxicating, under research
• THCV: May suppress appetite (opposite of THC)

THC vs. CBD Comparison

| Property | THC | CBD | |----------|-----|-----| | Psychoactive | Yes | No | | CB1 binding | Direct agonist | Indirect/modulatory | | Euphoria | Yes | No | | Anxiety | Can increase | Generally decreases | | Legal status | Restricted | More widely legal | | Drug test | Detected | Not typically detected |

Routes of Administration

| Route | Onset | Duration | Bioavailability | |-------|-------|----------|-----------------| | Smoked | Seconds-minutes | 2-3 hours | 10-35% | | Vaporized | Seconds-minutes | 2-3 hours | Higher than smoking | | Edibles | 30-90 minutes | 4-8 hours | 4-12% | | Sublingual | 15-45 minutes | 2-4 hours | Variable | | Topical | Local effect | Variable | Minimal systemic |

Clinical Pearl: Edibles have delayed onset, leading users to consume more while waiting for effects. This is a common cause of cannabis-related ED visits.

Acute Effects

Desired:

• Euphoria, relaxation
• Altered perception (time, sensory)
• Increased appetite
• Enhanced creativity (subjective)
• Social disinhibition

Adverse:

• Anxiety, paranoia
• Impaired memory and concentration
• Impaired motor coordination
• Tachycardia
• Dry mouth, red eyes

Cannabis Use Disorder

DSM-5 Criteria: Same 11 criteria as other SUDs

Prevalence: ~9% of users develop CUD; higher with early onset

Risk Factors:

• Early age of first use
• Frequent use
• High-potency products
• Pre-existing mental health conditions
• Family history

Withdrawal Syndrome (onset 1-2 days, peak 2-6 days):

• Irritability, anger
• Anxiety, restlessness
• Decreased appetite
• Sleep difficulties
• Depressed mood

Long-Term Risks

Cognitive:

• Impaired memory and attention (with heavy use)
• May persist after cessation
• Adolescent use more concerning (developing brain)

Respiratory (smoked):

• Chronic bronchitis symptoms
• Lung cancer risk unclear (confounded by tobacco)

Psychiatric:

• Increased risk of psychosis (especially early use, high THC)
• May worsen existing psychiatric conditions
• Amotivational syndrome (controversial)

Cannabis Hyperemesis Syndrome:

• Cyclic vomiting in chronic heavy users
• Compulsive hot bathing for relief
• Resolves with cessation
• Increasingly recognized

High-Potency Cannabis

Modern cannabis has dramatically higher THC concentrations:

• 1990s: ~4% THC
• Today: 15-25% THC (flower), up to 90% (concentrates)

Concerns:

• Greater addiction potential
• Increased psychosis risk
• More severe withdrawal
• Less CBD to offset THC effects

Classification

Classic (Serotonergic) Hallucinogens:

• LSD (lysergic acid diethylamide)
• Psilocybin (magic mushrooms)
• DMT (ayahuasca)
• Mescaline (peyote)

Dissociatives:

• Ketamine
• PCP
• DXM (dextromethorphan)

Atypical:

• MDMA (mixed stimulant/entactogen)
• Salvia divinorum

Classic Hallucinogens: Mechanism

Primary action: Agonism at 5-HT2A serotonin receptors

Effects:

• Visual hallucinations
• Altered perception of time/space
• Synesthesia (mixing of senses)
• Ego dissolution
• Mystical-type experiences
• Enhanced emotional processing

Pharmacology of Key Substances

Psilocybin (Magic Mushrooms):

• Converted to psilocin (active form)
• Duration: 4-6 hours
• Low physiological toxicity
• No physical dependence

LSD:

• Extremely potent (active in micrograms)
• Duration: 8-12 hours
• No physical dependence
• Long-lasting perceptual changes possible (HPPD)

MDMA:

• Releases serotonin, dopamine, norepinephrine
• Duration: 3-6 hours
• Produces euphoria, empathy, emotional openness
• Neurotoxicity concerns with heavy use
• Hyperthermia risk

Historical Context

1950s-60s: Early research showed promise for:

• Alcoholism treatment
• End-of-life anxiety
• Depression, anxiety

1970s: Controlled Substances Act ended most research

2000s-Present: Renewed scientific interest with rigorous methodology

Current Research

Psilocybin:

• Treatment-resistant depression: FDA "breakthrough therapy" designation
• End-of-life anxiety in cancer patients
• Alcohol use disorder
• Tobacco cessation

MDMA:

• PTSD: FDA "breakthrough therapy" designation
• Phase 3 trials completed with positive results
• Potential FDA approval anticipated

Ketamine:

• Esketamine (Spravato) FDA-approved for treatment-resistant depression
• Rapid-acting antidepressant
• Different mechanism than SSRIs

How Might Psychedelics Work Therapeutically?

Proposed Mechanisms:

• Increased neuroplasticity
• Disruption of rigid thought patterns
• Enhanced emotional processing
• Mystical/meaningful experiences
• "Resetting" default mode network

Critical Elements:

• Set (mindset) and setting (environment)
• Therapeutic support before, during, after
• Integration of experiences
• NOT simply pharmacological effect

Risks and Contraindications

Psychological:

• Bad trips (anxiety, panic, paranoia)
• Psychotic episodes (rare)
• HPPD (Hallucinogen Persisting Perception Disorder)
• Destabilization of existing mental illness

Contraindications:

• Personal/family history of psychosis
• Severe cardiovascular disease (MDMA)
• Certain psychiatric medications (serotonin syndrome risk)
• Pregnancy

Safety Note: Therapeutic use involves careful screening, controlled settings, and professional support—not recreational use.

• The endocannabinoid system regulates pain, mood, appetite, and memory
• THC is psychoactive (CB1 agonist); CBD is non-intoxicating with modulatory effects
• Cannabis Use Disorder affects ~9% of users; higher with early onset and high-potency products
• Cannabis withdrawal is real but not medically dangerous
• Classic hallucinogens work primarily through 5-HT2A receptor agonism
• Psilocybin and MDMA have FDA breakthrough therapy designations for mental health conditions
• Therapeutic psychedelic use requires careful screening, controlled settings, and integration support
• Recreational use carries different risk profiles than therapeutic use

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Part 2 Complete! Next: Part 3: Behavioral Addictions, beginning with Module 11: Technology, Gambling & Gaming →