Lecture 6 - Cannabis cont. and Caffeine

Question 1

Age of initiation

Answer 1

• Most widely used illicit drug in UK and US (4.6% in UK, 14 million in US)
• Brooke et al. (1999) = longitudinal study of 776 ss from New York state
• Age of initial use peaks at approx. 17 years old (Brooks et al., 1999) – impact on developing brain

Question 2

Is cannabis a gateway drug?

Answer 2

• Gateway into stronger, more potent substances
• Difficult to assess
• Some users may be disposed to try harder drugs
• Progression from initial to regular user?
• Risk factors = family disturbances, drug use by family/peers, school performance, age of onset (Gruber & Pope, 2002)
• (can’t pin it down to cannabis being a gateway drug)

Question 3

Tolerance

Answer 3

Needing a greater dose to achieve the same effect

Question 4

Dependence

Answer 4

• Difficulty stopping taking cannabis
• Craving for cannabis
• Withdrawal symptoms

Question 5

Tolerance in human studies

Answer 5

• Mixed results in human studies
• Compton et al. (1990) = tolerance observed following repeated administration of marijuana or pure THC
• Kirk and de Wit (1999) = same ‘high’ in light/infrequent users relative to heavy/frequent users

Question 6

Tolerance in animal studies

Answer 6

• Animal studies more consistent (objective measures of CB1 receptor activity in the brain)
• Breivogel et al. (1999): rats
• Daily injections of THC (10mg/kg) over 3 weeks
• Progressive reduction in CB1 receptor density and activity
• Some brain areas totally desensitized in 3 weeks

Question 7

Dependence studies

Answer 7

• Budney et al. (2003); Kouri et al. (1999)
• Abstinence triggers irritability, anxiety, depression, sleep disturbance, aggressiveness, decrease appetite
• Resemble nicotine withdrawal symptoms
• Worst in first 2 weeks – can last for over a month

Question 8

Dependence animal studies

Answer 8

• Early studies found no effect of drug withdrawal
• But THC has a long half-life, so may still be present in the system
• Aceto et al. (1996) = precipitated (sudden) withdrawal
• Rats given twice daily THC injections
• Then given SR141716 (CB1 receptor antagonist)
• Symptoms of hyperactivity: shaking, face rubbing, scratching (symptoms of withdrawal)
• Induce withdrawal by introducing antagonist alongside THC
• De Fonesca (1997) = possibly a consequence of rats being stressed rather than withdrawal
• Increased corticotrophin-releasing hormone (CRH) in precipitated withdrawal rats

Question 9

Treatment of cannabis use disorder

Answer 9

• Cycle of tolerance leading to higher doses and making withdrawal difficult
• CBT
• Participants rewarded with vouchers for providing cannabis-use urine samples
• Significant relapse (Moore & Budney, 2003)
• Withdrawal symptoms may be eased by oral consumption of THC (reducing dose over time to make it more manageable) (Haney et al., 2004)
• Useful in the short-term, difficult to achieve long-term abstinence

Question 10

Behavioural effects

Answer 10

• Lynsky and Hall (2000)
• Chronic cannabis use associated with poor education performance
• More negative attitudes about school
• Poorer grades
• Increased absenteeism
• Amotivational syndrome = apathy, aimlessness, lack of productivity, long term planning and motivation
• Regular cannabis use early in life predicts poor school performance and drop-out rates (Fergusson et al., 2003)

Question 11

Cognitive effects

Answer 11

• Cognitive deficits in long term users (Solowjj et al., 2002)
• Standardised tests of learning, memory and attention
• Long-term user deficient 1 and 7 days after exposure
• No difference between heavy users and controls after 28 days of abstinence (Pope et al., 2001)
• Cognitive deficits linked to recent use – reversible over time

Question 12

Health

Answer 12

• Higher concentrations of carcinogens in cannabis smoke than tobacco
• More tar and carbon monoxide in a joint than a cigarette
• Cardiovascular disorders (Rezkalla and Kloner, 2019; Latif and Garg, 2020)
• Cerebrovascular disorders (Archie and Cucullo, 2019)
• Immune system (Cabreal & Pettit, 1998)
• THC suppresses immune function
• Increase risk of viral and bacterial infection
• Reproductive function (Smith & Asch, 1987)
• Smoking in women suppresses luteinizing hormone release (but can be tolerated)
• Reduced sperm count in men (but only in heavy users)

Question 13

Clinical applications of cannabis

Answer 13

• Can be tracked back hundreds/thousands of yeas
• Late 19th century and early 20th century = crude extracts used in US and European treatments
• Identification of THC -> research involving manufacture of synthetic compounds
• Select for properties which have clinical effects (remove psychoactive elements to reduce side effects)

Question 14

Analgesia

Answer 14

• Cannabis also used for treatment of chronic pain:
• Multiple sclerosis
• Spinal cord injury
• Glaucoma
• Limited widespread use (especially in US)
• Side effects
• Joints more effective than synthetics
• HU-211 = a cannabinoid that doesn’t activate CB1 receptors (no side effects) undergoing clinical trials

Question 15

Anti-emetic

Answer 15

• Dronabinol = antiemetic for chemotherapy patients
• Nabilone = appetite stimulant on AIDS patients
• Anecdotal evidence/limited clinical studies

Question 16

Caffeine: background

Answer 16

• Sources of caffeine include coffee, tea, chocolate and energy and carbonated drinks
• 80-90% of people consume regularly
• Average adult daily intake = 200-400mg
• One cup of coffee approx. 80-100mg

Question 17

Pharmacology of caffeine

Answer 17

• Caffeine absorbed through the gastrointestinal tract in about 30-60 minutes
• Plasma half-life of around 4 hours, but usually topped up
• People have a rising concentration of caffeine in the blood plasma throughout the day
• Caffeine converted to metabolites by the liver
• 95% excreted in urine, 2-5% in faeces, rest through saliva
• Caffeine (and its metabolites) act primarily by blocking adenosine (A1 , A2A) receptors in the brain

Question 18

Behavioural effects in rodents

Answer 18

• Caffeine has a biphasic effect in rats and mice:
• Low dose - stimulant, ↑ locomotor activity
• High dose - reversed, ↓ locomotor activity
• In humans, low-to-intermediate doses results in a variety of positive subjective effects

Question 19

Behavioural effects in humans

Answer 19

• Increased alertness
• Reduced tension
• Reduced reaction time
• Enhance sports performance
• Modest but significant benefits to muscle strength, power and endurance (Grgic et al., 2018, 2019,2020)
• Mechanism of effect still under investigation: could be mediated by effects of alertness and reduced muscle tension, placebo effect (Elhaj et al., 2021)
• Negative effects
• Disruption to sleep:
• Particularly in older adults (Clark et al., 2017)
• When consumed within 6 hours before going to sleep (Drake et al., 2013)
• Negative effects at higher doses (>400mg; Nehlig, 2010):
• Tension
• Jitteriness
• Anxiety
• Panic disorder patients may be hypersensitive -> can induce panic attacks

Question 20

Tolerance and dependence of caffeine

Answer 20

• Tolerance to subjective effects of caffeine (Griffiths & Mumford, 1995)
• Heavy drinkers can consume coffee before bed
• Abstinence → withdrawal symptoms
  (Griffiths et al., 1990)
• Even in >100mg/day drinkers (1 cup a day)
• Headache, drowsiness, fatigue, impaired concentration & psychomotor performance
• Withdrawal effects lasts a few days of consecutive abstinence but will dissipate

Question 21

Health effects of caffeine

Answer 21

• Little to no risk to healthy, non-pregnant adults (Nehlig, 2016)
• Acute consumption effects for non-consumers (van Dam et al., 2020)
• ↑ blood pressure
• ↑ respiratory rate
• ↑ water excretion
• Risk to pregnancy
• Association with infant birth weight (Qian et al., 2020, James, 2021)
• Dose-dependent increase in risk of stillbirths (Greenwood et al., 2014)
• Prenatal exposure is associated with developmental effects such as childhood obesity
• Current guideline <200mg per day
• If not, complete abstinence from caffeine during pregnancy