ch 14: cannabis

flowering hemp plant (Cannabis sativa) (2)

• contains over 120 compounds called phytocannabinoids

• psychoactive compound is ∆9-tetrahydrocannabinol (THC) 

marijuana (4)

• mix of dried leaves + flowering tops

• smoked in pipes or bongs of rolled cigarettes (joints)

• sometimes combined with tobacco

• now available as edibles + vaping

how does marijuana potency (THC content) vary (4)

• depending on genetic strain of the plant + growing conditions

• can be increased by preventing pollination + seed production (sinsemilla)

• hashish: concentrated form of cannabis → smoked or eaten

• dabbing: cannabis is extracted w butane to form a waxy residue w high THC content → dap (one dose) is vaporized with a blowtorch or vape pen + inhaled

cannabis sativa vs indica (5)

• sativa: tall, slender light green leaves

• indica: shorter, bushier, darker

  • higher cannabidiol (CBD) to THC ratio 

• almost all strains are hybrids

• growers cultivate different strains to adjust THC/CBD ratio for psychoactivity or therapeutic effects 

phytocannabinoids 

• chemicals unique to cannabis 

• bind to cannabinoid receptors in the body

• THC: most psychoactive → amount varies type of plant, growing conditions, anti-inflammatory, anti-anxiety, anti-psychotic, neuro-protective effects

• CBD: nonpsychoactive → anti-oxidant, anti-convulsant, anti-inflammatory, anti-anxiety, anti-psychotic, neuro-protective effects

cannabis today vs 1960s/70s (3)

• higher THC content

• users can smoke less to obtain the same effect

• higher THC increases risk of adverse reactions

synthetic cannabinoids (4)

• dronabinol (marinol): has been replaced by the synthetic THC analogue nabione (cesamet) and nabiximols (sativex)

• spice (K2): not legal → schedule II

  • binds more fully to brain cannabinoid receptors than THC → produces more intense effects 

  • does not contain CBD → which reduces many of THC’s negative effects 

routes of administration of cannabis + onset rate (5)

• smoked → joints, bongs, pipes

  • easily absorbed by lungs + blood plasma lvls rise quickly 

• vaporizers

• ingested → slower onset of effect + less predictability of action (user less in control)

  • liver metabolizes cannabis before it enters in brain → less THC gets to the brain 

absorption, distribution + metabolism of THC (6)

• rapidly absorbed in blood supply of the lungs

• v. fat-soluble → easily cross BBB

  • gone from brain within a few hours as it accumulates in fatty tissue

• metabolize din liver by CYP450 system → metabolites excreted in urine/feces 

  • complete elimination is slow bc THC persists in fat tissue (20-30 hours half life_

  • THC-COOH can be detected in urine up to 2 weeks 

How do CB1/CB2 receptor signals reduce neurotransmission, and where are CB1 receptors positioned to do this? (4)

• Receptor type: Gi/o-coupled, metabotropic.

• Signaling: ↓ cAMP, ↓ VG Ca²⁺ entry, ↑ K⁺ conductance → hyperpolarization & less vesicular release.

• Localization: Presynaptic CB1 on terminals of ACh, DA, NE, 5-HT, GABA, Glu neurons → broad inhibition of transmitter release.

• Longer-term: MAPK pathway & epigenetic changes → plasticity/learning/memory effects.

Where is CB1 receptor density highest in the brain (per the diagram), and what functions do these regions explain?

• High/medium CB1 density:

  • Basal ganglia: caudate/putamen, globus pallidus, substantia nigra → motor effects (slowed movement, altered initiation).

  • Hippocampus → memory/learning deficits (short-term memory).

  • Cerebellum → coordination/ataxia.

  • Cingulate cortex → attention/affect modulation.

• Implication: Cannabis alters movement, memory, coordination, and emotion via dense CB1 expression in these circuits; CB2 adds immune/microglial modulation.

What are the CB1-mediated behavioral “tetrad” effects of THC in rodents (4), and which drugs are used to prove CB1 involvement? (2)

• Tetrad (CB1): ↓ locomotion,

  • hypothermia,

  • catalepsy,

  • hypophagia

• CB1 antagonists: SR141716A (rimonabant), AM251 → block THC/CB agonist effects

How do CB agonists affect anxiety, and why is the effect dose-dependent? (3)

• Low dose: anxiolytic (network modulation; reduced Glu drive in fear circuits)

• High dose: anxiogenic (broader inhibition incl. GABA, network dysregulation)

• Net result = biphasic dose–response

What is the role of CB1 in cannabis-induced memory impairment, and what does Fig. 14.9 show? (3)

• CB1 activation in hippocampus (CA1) → ↓ LTP → memory impairment

• Fig. 14.9: Vehicle→CP group = high errors; Rimonabant→CP = errors normalized

• Conclusion: CB1 is required for the memory deficit (rimonabant blocks it)

What are key immune effects of CB2 activation? (3)

• ↓ cytokine release (anti-inflammatory)

• Alters immune cell migration to inflammatory sites

• Expressed in immune system, plus microglia & some neurons

cannabidiol (CBD) has a similar structure to ____ but is not ___ or _____ and can act as a ____ of CB1 receptors which inhibits the _____ → enhancing activity of the _____

1. THC

2. intoxicating 

3. dependence-producing

4. negative allosteric modulator

5. breakdown of endogenous cannabinoids

6. endocannabinoid system 

brain imaging shows ___ promotes regional brain activation + _____ → ___ tends to decrease these processes 

• THC 

• enhanced local blood flow

• CBD

what are endocannabinoids + types(6)

• cannabinoid receptor agonists synthesized by the body

  • anandamide: partial agonist 

  • 2-AG: full agonist at CB1 and CH2

• lipid soluble → can’t be stored in vesicles 

• synthesized + released when needed

• triggered by a rise in intracellular Ca2+ lvls

what do endocannabinoids help regulate and what does the endocannabinoid system mediate? (2)

• help regulate mood states, anxiety and fear, reactions to stress → confirmed by rodent studies

• hippocampal endocannabinoid system is an important mediator of anxiety responses

how are endocannabinoids removed + metabolized

• removed from extracellular by an endocannabinoid membrane transporter 

• anandamide metabolized by fatty acid amide hydrolase (FAAH)

• 2-AG by monoacyl-glycerol lipase (MAGL)

mechanism of endocannabinoid signalling

• retrograde signalling (2-AG)

  • DSE: depolarization-induced suppression of excitation

  • DSI: depolarization-induced suppression of inhibition

• non-retrograde signalling → anandamide 

• neuron-astrocyte signalling

What are 3 major functions of the endocannabinoid system highlighted in class? (3)

• Extinction of learned fear → deficits may ↑ PTSD risk

• Regulation of eating/hunger/energy via CB₁ in hypothalamus & reward circuits

• Pain regulation → sensory + affective, esp. neuropathic pain

How do CB₁ receptors promote feeding? (4)

• CB₁ in hypothalamus → ↑ orexigenic peptides (NPY/AgRP, ↓ POMC tone)

• CB₁ in stomach/brain → interacts with ghrelin → hunger signaling

• CB₁ in reward/cortex/OFC → ↑ palatability & food reward

• CB₁ antagonists (rimonabant) → reliably ↓ food intake

Where are CB₁/CB₂ receptors that mediate cannabinoid analgesia? (4)

• PAG / RVM / brainstem pain modulatory regions

• Spinal dorsal horn (primary sensory input)

• Thalamus & limbic areas (amygdala) → ↓ emotional reaction to pain

• Effect: ↓ pain perception and ↓ pain unpleasantness

Why is endocannabinoid signaling a target for PTSD, obesity, and chronic pain? (3)

• PTSD → eCBs facilitate extinction

• Obesity → eCBs drive feeding/reward → block CB₁ to reduce intake

• Chronic/neuropathic pain → eCBs dampen nociceptive transmission at multiple levels

What major processes do endocannabinoids normally regulate? (5)

• Neuroplasticity, learning/memory, neurogenesis, homeostasis

• Stress & emotional regulation, reward signaling

• Pain & appetite

• Anti-inflammatory / antioxidant effects

• ⚠ Cannabis during brain development can disrupt these

What are the main medical/therapeutic cannabinoid options and what are they for? (4)

• Pure THC: dronabinol (Marinol), nabilone (Cesamet) → ↑appetite, anti-nausea

• THC + CBD extract: nabiximols (Sativex) → neuropathic pain, MS spasticity

• CBD only: Epidiolex → pediatric epilepsy

• Medical marijuana: mixed indications (pain, nausea, spasticity)

What are the 4 stages and main acute effects of cannabis? (3)

• 4 stages: buzz → high → stoned → come-down

• Physiologic: ↑HR, ↑BP, ↑appetite

• Magnitude depends on dose, frequency, user characteristics, setting, expectations

How do we know cannabis effects are CB₁-mediated, and what can go wrong at high doses? (4)

• intoxication reduced by CB₁ antagonist rimonabant → CB₁-dependent

• High doses: anxiety, transient psychotic symptoms, paranoia, violent behavior

• Acute toxic reaction = CNS excitation or depression + tachycardia + GI upset

• Rarely life-threatening

How does cannabis affect cognition and driving? What does the THC–crash graph show?

• Impairs learning, memory, attention, decision making (hippocampal-dependent)

• Impairs complex psychomotor tasks → driving gets worse (↑ with alcohol)

• Graph: as blood THC ↑, odds of motor vehicle accident ↑ (rising curve)

• Takeaway: acute THC = cognitive + motor risk

Are cannabinoids rewarding/reinforcing in animals? (4)

• Yes, but weaker than opioids/psychostimulants

• THC = partial CB₁ agonist; some synthetics (WIN55,212-2) = full CB₁ → stronger reinforcement

• CB₁ part of brain reward system and interacts with endogenous opioids

• Still enough for self-administration in animal models

What is the mechanism for cannabinoid reinforcement, and what does the monkey graph show? (3)

• Presynaptic CB₁ on GABAergic terminals in VTA → ↓ GABA on DA neurons → disinhibition → ↑ DA firing → ↑ DA in NAcc

• That DA increase = reinforcing signal

• Monkey self-administration graph: THC injections → responding ↑; vehicle → responding ↓ → THC functions as a reinforcer

How can chronic cannabis use lead to cannabis use disorder (CUD)? (4)

• DSM-5: criteria for intoxication, withdrawal, CUD

• Early start, frequent/heavy use, tobacco co-use, male sex → ↑ risk

• Biological + psychosocial variables (mood/anxiety/personality disorders, availability) also push risk up

• Even though most users don’t develop CUD, a meaningful minority does

What do the cannabis-use pyramid and odds-ratio graph tell us? (4)

• Pyramid: largest layer = low-risk/occasional; smaller layers = hazardous → CUD → dependence

• Shows progression is possible but not inevitable

• Odds-ratio graph: people with CUD have higher odds of other psychiatric conditions (esp. mood/anxiety)

• Takeaway: severity ↑ → comorbidity ↑

What long-term effects can regular cannabis use produce? (3)

• Tolerance: CB₁ receptor desensitization/down-regulation with repeated use

• Dependence: can develop; generally milder than other drugs

• Withdrawal (if present): irritability, sleep disturbance, ↓ appetite, anxiety; usually not severe

What does the “% who progress to dependence” graph show? (4)

• Some who try cannabis eventually develop CUD/dependence

• % is lower than cocaine, heroin, nicotine

• But not zero → cannabis still has real addiction potential

• Takeaway: “less addictive” ≠ “non-addictive”

How is cannabis use disorder (CUD) treated? (4)

• Long-term heavy use → CUD (craving, loss of control, continued use despite problems)

• Best evidence: CBT, relapse-prevention, contingency management

• Meds (dronabinol, nabiximols) haven’t reliably improved long-term abstinence

• Goal: reduce use + prevent relapse

What cognitive/functional problems are linked to chronic cannabis use? (4)

• Impaired attention, working memory, learning (especially with frequent/recent use)

• Heaviest effects when onset is in adolescence and use is sustained

• Linked to lower educational attainment and poorer occupational outcomes

• Some effects may improve with abstinence, but not always fully

What do imaging and animal studies suggest about long-term cannabis exposure? (3)

• Imaging: some users show reduced gray matter / altered activation in PFC and related regions

• Animal/adolescent models: chronic THC → changes in glutamatergic, GABAergic, DA systems and PFC impairments

• Suggests: developing brain is more vulnerable → supports caution with early, heavy use

How does repeated adolescent exposure to a strong CB₁ agonist (CP-55,940) affect PFC structure and plasticity? (4)

• CP = THC-like CB₁ receptor agonist

• Chronic CP in adolescence → PFC dendritic length ↓ (total, apical, basal) vs vehicle

• Same animals → LTP at hippocampus→PFC synapses is blunted after HFS

• Interpretation: early, heavy cannabinoid signaling can weaken PFC wiring + learning-related plasticity → possible basis for cognitive effects of early cannabis use