Mednotes

L6 Clinical Pharmacology Drug Tolerance and dependence

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tagsclinicalpharmacology, lecture, neuropharmacology, addiction
aliasesDrug tolerance, dependence, and abuse

21 min read

Overview

This lecture covers the pharmacology underlying drug dependence and substance use disorder: how common substance use disorder is and how much societal harm it causes; the formal definitions of physical dependence, psychological dependence, and tolerance; the shared neurobiological mechanism (phasic dopamine release in the reward pathway) that links most addictive drugs; how the specific molecular actions of stimulants, opioids, and alcohol drive euphoria, tolerance, and withdrawal; and how the route and speed of drug delivery independently affects addiction risk. It closes with dependence-risk statistics for opioids and alcohol and a note on the distinct subjective effects of psychedelics versus cocaine.

Epidemiology and burden of drug harm

  • Drug use is a top risk factor for death in both New Zealand and the US (2023 data); on both countries’ ranked risk-factor charts, smoking, high alcohol use, and drug use are highlighted as major contributors to total deaths [flag: exact ordering/spelling of the lower-ranked, smaller-font risk factor labels was difficult to fully verify at rendered resolution, though the highlighted items are clearly legible].
  • US opioid epidemic: 12-month overdose death counts rose from ~48,000 (2015) to a peak of ~115,000 (around 2022–2023), then declined to ~72,000 by 2025. Drug overdoses are the 8th most common cause of death in the US, behind heart disease (695,547), cancer (605,213), COVID-19 (416,893), accidents (224,935), stroke (162,890), chronic lower respiratory disease (142,342), and Alzheimer’s disease (119,399), and ahead of diabetes (103,294), chronic liver disease/cirrhosis (56,585), and nephritis/nephrotic syndrome/nephrosis (54,358).
  • The New Zealand drug harms ranking study (Crossin et al., 2023) scored drugs by weighted harm to self and others: Alcohol 88, Methamphetamine 71, Synthetic cannabinoids 50, Tobacco 49, Non-prescription opioids 44, Illegal fentanyls 42, Opioid substitution products 42, Prescription opioids 42, Cannabis 32, Solvents & fuels 29, Benzodiazepines 19, Amphetamine-type substances 18, Cocaine 16, GHB/GBL 12, Synthetic cathinones 10, Ketamine 8, MDMA 7, NPS 7 [flag: this item is labelled “PIEDs” (performance and image enhancing drugs) on the slide, which seems out of place between MDMA and nitrite inhalants — flagged for verification], Nitrite-based inhalants 5, ENDs/vapes 4, Hallucinogens 4, Kava 4, Nitrous oxide 3.
  • NZ recreational drug use (2013–2024): cannabis use is far the highest and rising (~9.5% to ~15.5% of the population using in the past 12 months); all other drugs tracked (hallucinogens, MDMA, amphetamine-type stimulants, sedatives, cocaine, opioids) stay under ~5%, with MDMA the second-highest of these.
  • Wastewater-derived methamphetamine and cocaine consumption both show sharp rises into 2024–2025 after several years of relative stability.
  • Historical cocaine use: heavy use in the US in the 1980s. A 1975 US government report described cocaine as used occasionally and “not physically addictive.” Prevalence data show 12-month cocaine use in young adult age groups peaked around 1980–1986 (roughly 19–24%) before declining to roughly 4–8% by 1993–2001 [flag: this is a dense scanned data table; full row-by-row transcription for all years was not completed, and part of the slide contains an unrendered/shaded area of unclear content].

Defining dependence, tolerance, and substance use disorder

  • Severe substance use disorder is the clinical term for addiction.
  • 13% of adults have mild-to-moderate substance use disorder (2–5 DSM-5 criteria); most societal drug harm (drunk driving, domestic violence, loss of work productivity) comes from this larger group, not from the severe group.
  • 3–5% of adults meet 6 or more criteria (severe substance use disorder).
  • Risk factors for substance use disorder: mental disorders, early substance use, childhood trauma, impulsivity, weak parental support, lower education.

DSM-5 substance use disorder criteria (severity: 2–3 = mild, 4–5 = moderate, 6+ = severe)

  1. Taking the substance in larger amounts or for longer than intended
  2. Wanting to cut down or stop but not managing to
  3. Spending a lot of time getting, using, or recovering from the substance
  4. Cravings and urges to use
  5. Not managing responsibilities at home, work, or school
  6. Continuing to use despite relationship problems it causes
  7. Giving up important activities because of use
  8. Repeated use in physically dangerous situations
  9. Continuing to use despite a physical or psychological problem caused/worsened by the substance
  10. Tolerance (needing more for the same effect)*
  11. Withdrawal symptoms, relieved by taking more*
    *Criteria 10–11 are not counted if the drugs are prescribed and taken under supervision.
  • Physical dependence: marked by withdrawal symptoms if drug use stops.
  • Psychological dependence: drug-taking becomes compulsive and takes precedence over other needs; the urge to use can persist long after physical dependence has resolved. Includes behavioural addictions (food, sex, gambling, social media).
  • Drug tolerance: a decrease in the effect of a drug with repeated use.

Dopamine and the mechanisms of stimulant dependence

  • The dopamine theory of addiction: most, but not all, dependence-causing drugs increase brain dopamine levels. Phasic (“burst”) firing of dopamine neurons is more strongly linked to dependence than steady/tonic release. Reuptake inhibitors and releasing agents help distinguish the effects of specific neurotransmitter release.
  • Noradrenaline and dopamine releasing agents (NDRAs) — mechanism of amphetamine and methamphetamine:
    1. Amphetamines act as substrates for monoamine transporters and for VMAT (vesicular monoamine transporter).
    2. They enter storage vesicles and displace dopamine (and noradrenaline).
    3. This drives reverse transport, pushing dopamine and noradrenaline out into the synapse.
    4. The resulting high synaptic neurotransmitter levels bind dopamine and noradrenaline receptors (D1, D2, D3–5).
    • Methamphetamine enters the brain more rapidly than amphetamine, which is why it carries a higher dependence risk.
  • Cocaine is an NDRI (noradrenaline and dopamine reuptake inhibitor): it blocks NET and DAT, which normally recycle dopamine/noradrenaline out of the synapse. This increases noradrenaline binding at α2 receptors and dopamine binding at D1 receptors in the nucleus accumbens. Cocaine’s effects are not long-lasting, which may contribute to its addictive potential; smoking cocaine (crack) is much more addictive than intranasal use. Acute cocaine toxicity/overdose relates to noradrenergic activity — increased heart rate, blood pressure, and vasoconstriction.
  • Relative potency at monoamine systems (EC50/IC50 in nM; a lower value means a more potent drug):
DrugDA release EC50NA release EC505-HT release EC50DAT IC50NET IC50SERT IC50
Methamphetamine1113695100064—
Amphetamine1322—130094—
MDMA1420490160410108362
Cocaine———260250320
Methcathinone236085—112085—
Cathinone (khat)56004000——199—

Corresponding harm ranking (max possible harm rating of 100): methamphetamine (~33) > cocaine (~28) > amphetamine (~24) > ecstasy (~9) ≈ khat (~9).

  • D1 versus D2 dopamine receptors: D1 receptors are responsible for the dopamine “high” but have lower affinity than D2 receptors (affinity = how tightly a drug or neurotransmitter binds a receptor). D2 receptors are occupied first; high synaptic dopamine concentrations are then needed to activate the remaining D1 receptors. Phasic (burst) dopamine firing is required to activate D1 receptors, so rapid drug delivery — which produces such bursts — increases D1 receptor activation and reward.

Route and speed of administration

  • Smoking or injecting a drug (versus snorting or swallowing it) is associated with more frequent use, more money spent on drugs, greater loss of control, and a higher likelihood of overdose.
  • 12-month cocaine dependence incidence: 5% for intranasal use versus 22% for inhaled (smoked) use.
  • Plasma cocaine concentration by route (from lowest to highest peak speed): oral and intranasal routes rise slowly to a broad peak (~280 ng/ml and ~340 ng/ml respectively, around 60–90 minutes); smoked cocaine spikes early to ~220 ng/ml; intravenous cocaine spikes sharply to ~550 ng/ml within minutes, then declines rapidly. Harm rating for crack cocaine (~54) is roughly double that of cocaine (~27).
  • Faster delivery more closely mimics the phasic dopamine release pattern linked to dependence. In animal studies, faster drug delivery leads to higher total self-administered doses, differing patterns of dopamine receptor downregulation (rapid vs slow cocaine delivery), and altered gene expression pathways in neurons.
  • Methylphenidate (Ritalin) is an NDRI like cocaine. IV versus oral delivery in humans produces different patterns of brain activation: there is a significant correlation between subjective “high” rating and dorsal anterior cingulate cortex (dACC)–striatum (caudate nucleus + nucleus accumbens) functional connectivity, and both connectivity and subjective high rise higher and faster with IV delivery than with oral delivery.

Across stimulants, the speed of drug delivery — not just the drug itself — independently raises dependence risk by producing sharper, more phasic dopamine surges.

Dependence to stimulants

  • Prolonged, repeated stimulation of the dopaminergic reward pathway can lead to physical and psychological dependence, which can progress to a substance use disorder (addiction).
  • Roughly 20–30% of people who use methamphetamine even once go on to develop a substance use disorder.
  • Physical dependence is caused by withdrawal symptoms on cessation of use. Long-term stimulant abuse is associated with decreased impulse control, verbal learning, and working memory; tolerance to methamphetamine can be a contributing factor to continued/escalating use.
  • Drugs that increase more dopamine in the synapse reinforce reward more strongly than drugs that mainly increase noradrenaline or serotonin. Drugs that preferentially increase dopamine are called stimulants; drugs that preferentially increase serotonin are called entactogens/empathogens (MDMA-like).

Opioids

  • Opioid euphoria, like analgesia, is mediated through the μ-opioid receptor. Diamorphine (heroin) produces an intense rush when given IV; codeine produces a lower degree of euphoria.
  • Reward circuit: morphine acts at μ receptors on GABA interneurons in the ventral tegmental area (VTA), disinhibiting dopamine neurons there and increasing dopamine release into the nucleus accumbens (reward). The brain stem region governs breathing, which is relevant to opioid respiratory depression.
  • Mechanism of opioid tolerance, in order:
    1. Agonist activates the opioid receptor.
    2. The receptor is phosphorylated by GRK (a GPCR kinase), reducing ligand affinity.
    3. β-arrestin binds the phosphorylated receptor, preventing further receptor signalling.
    4. The receptor undergoes endocytosis (internalisation).
    5. Rather than being dephosphorylated and recycled back to the surface, the receptor is tagged for degradation.
    6. Net result: fewer opioid receptors on the cell surface.
    • As a result of this tolerance, people with opioid addiction can take 50–100x a therapeutic dose.
  • Treatments for opioid addiction often use partial agonists at the μ-opioid receptor: these cause less euphoria but still cause physical dependence. Opioids are not as toxic as other drugs of abuse but cause severe physical dependence and withdrawal.
  • Heroin (IV) versus methadone (oral) illustrate the rationale for opioid substitution therapy: heroin produces a sharp, high-intensity drug effect that falls off by ~8 hours, with withdrawal spiking sharply around day 3–4 and resolving by ~day 8; methadone produces a slower-onset, lower-peak, more gradually declining effect (lasting to ~32 hours) and a lower, broader, more prolonged withdrawal extending to ~day 20.
  • Dependence risk of prescription opioids (meta-analyses): overall ~3.3–4.7%. Strong opioids were associated with a lower dependence incidence (0.7%) than weak opioids (5.5%) or a mix of both (6.1%). Opioids prescribed for more than 3 months were associated with a significantly lower incidence of dependence (2.3%) [as stated in the source]. A more recent study found dependence and opioid use disorder in chronic non-cancer pain patients at 9.3%.
  • Non-prescription opioid use (other than heroin) among young people (19–30) has declined nearly 20x over the past 15 years, from ~8.5% (around 2005) to ~0.5% (2024); among 35–50 year-olds it declined from ~4.5–5.5% (2008–2018) to ~2% (2024).

Alcohol

  • The dose of alcohol reached in the body is roughly 100 times greater than that of most pharmaceutical drugs.
  • Mechanism: alcohol is a positive allosteric modulator at GABA-A receptors and reduces NMDA receptor activity; this indirectly increases dopamine release from the VTA into the nucleus accumbens.
  • Alcohol acts at both nonspecific and specific membrane sites: nonspecific effects include altering lipid composition, interacting with phospholipid polar heads, and disturbing the arrangement of membrane proteins; specific effects include acting at neurotransmitter binding sites, modifying channel gating mechanisms, interacting directly with channel proteins, and stimulating Gs (linked to adenylyl cyclase).
  • Acute tolerance: after peak blood alcohol concentration, subjective intoxication (feeling drunk) decreases even though coordination remains impaired — i.e., a given blood alcohol concentration can feel “intoxicated” on the way up and “sober” on the way down.
  • Increased confidence and risk-taking accompany decreased skill; 15% of college students have experienced an alcohol-related injury.
  • Physiological effects: decreased sleep quality, cirrhosis, carcinogenicity, thiamine depletion.

Long-term heavy alcohol consumption causes thiamine deficiency, leading to neuron cell death and Wernicke's encephalopathy, along with reduced brain mass in the frontal lobe and other regions.

  • A UK Biobank study (Topiwala et al., 25,378 participants) found alcohol consumption as low as 7 units/week is correlated with less grey matter; the effect worsens with dose (beta from roughly −0.07 at 7–12 units/week to roughly −0.30 in males / −0.28 in females at >28 units/week). One can of 5% beer contains 1.7 units of alcohol.
  • Alcohol and health debate: low alcohol consumption may have some positive effects on stress reduction and cardiovascular health, and in people with a familial risk of heart disease (but not cancer) low-dose alcohol may improve longevity — but the current public health recommendation is that there is no safe level of alcohol consumption. Dose–response data show a “protective” curve dipping slightly below relative risk 1.0 at very low consumption before rising, and a “harmful” curve rising steadily to a relative risk of ~1.85 at around 10 standard drinks/day.
  • Alcohol mechanism of euphoria: increases firing rate of VTA neurons, raising dopamine in the nucleus accumbens. During alcohol withdrawal in dependent states, dopamine and its metabolites (DOPAC, HVA) in the mesolimbic pathway fall over the following ~8–12 hours (compared with stable levels in controls). Alcohol also increases brain opioid release; opioid antagonists (e.g. naloxone) reduce alcohol self-administration in animals, and clinical trials of opioid antagonists in alcohol use disorder patients found reductions in alcohol consumption, relapse, craving, and subjective “high.”
  • Alcohol dependence occurs in ~22% of drinkers; when it becomes pathological it is defined as alcohol use disorder (AUD). Risk factors include acute and chronic stress and genetics — AUD occurs in 54% of monozygotic twins versus 28% of dizygotic twins, giving a heritability of 38%. Withdrawal symptoms from alcohol dependence are severe and life-threatening.
  • Alcohol is commonly among the top 7 leading causes of death, contributing via driving accidents, liver disease, and cancer. US survey data (2009–2024) show most respondents report 0–1 sexual partners in the past 12 months; binge drinking (“5+ drinks”) prevalence declined among 19–30 year-olds (~37% to ~24%, with a rise to ~32% around 2021–2022) but rose slightly among 35–50 year-olds (~22% to ~26%) [flag: the exact axis units for this chart were not labelled on the slide beyond the numeric scale; presumed to be percentage].

Subjective effects: psychedelics versus cocaine

  • Using the Ego-Dissolution Inventory, increasing LSD-equivalent dose of psychedelic drugs is associated with rising “ego-dissolution” scores, while “ego-inflation” scores stay flat.
  • Increasing cocaine dose (grams) is associated with rising “ego-inflation” scores, while “ego-dissolution” scores stay low and flat.
  • This suggests psychedelics and cocaine produce distinct, near-opposite subjective effects on the sense of self, each of which could separately motivate continued use.

Summary and lecture takeaways

Stated takeaways: describe drug pharmacology that increases the risk of drug harm; describe physical dependence of drugs; consider how the delivery method of drugs affects drug harm; consider abuse potential when prescribing medication.

Closing summary

  • Substance use disorder is common.
  • Physical and psychological dependence both contribute to substance use disorder.
  • Drugs that increase the phasic release of dopamine are more likely to be addictive.
  • Some drugs (e.g. opioids) have harm reduction options; others (e.g. methamphetamine) do not.
  • Drugs that can be effective medicines can also be addictive (e.g. amphetamine, fentanyl).
  • Opioids should not be prescribed long term because of addiction risk.

Transcript flags carried through from source (7 total, slides 5, 8, 15, 19, 29, 37, 45)

  • Slide 5: exact ordering/spelling of lower, smaller-font risk-factor labels on the NZ/US mortality charts not fully verifiable at rendered resolution (highlighted items are legible).
  • Slide 8: the NZ drug harms ranking chart labels an item “PIEDs” between MDMA and nitrite inhalants — seems out of place, unverified.
  • Slide 15: several study citation labels on the dopamine-binding chart are small and partly illegible.
  • Slide 19: dense scanned cocaine prevalence table only partially transcribed (selected/highlighted years); part of the slide image is an unrendered/shaded area of unclear content.
  • Slide 29: a full-slide photograph with no caption or citation; its relevance to the lecture content is not stated on the slide.
  • Slide 37: axis units for the “5+ drinks” prevalence chart are not explicitly labelled (presumed percentage).
  • Slide 45: a full-slide scenic photograph with no caption or stated connection to the lecture content.

Self-test

  1. Define drug tolerance.
  2. Distinguish physical dependence from psychological dependence.
  3. What DSM-5 criteria count thresholds define mild, moderate, and severe substance use disorder?
  4. What proportion of adults meet 2–5 DSM-5 criteria (mild–moderate SUD) versus 6 or more criteria (severe)? Which group accounts for most societal drug harm, and why?
  5. List the risk factors for developing substance use disorder given in the lecture.
  6. Explain the dopamine theory of addiction: which pattern of dopamine neuron firing is most strongly linked to dependence risk?
  7. Describe, in order, the steps by which amphetamine and methamphetamine increase synaptic dopamine and noradrenaline (the NDRA mechanism).
  8. Why does methamphetamine carry a higher dependence risk than amphetamine?
  9. Describe cocaine’s mechanism of action, and explain why smoked cocaine (crack) is more addictive than intranasal cocaine.
  10. Distinguish D1 from D2 dopamine receptors in terms of affinity and their respective roles in producing the dopamine “high.”
  11. Explain why rapid drug delivery increases D1 receptor activation and therefore dependence risk.
  12. A patient reports using cocaine intranasally, while another uses it by smoking (inhalation). Using the 12-month dependence figures from the lecture, predict which patient has the higher dependence risk and by roughly how much.
  13. Describe, in order, the receptor-level steps of opioid tolerance, from receptor activation through to reduced surface receptor number.
  14. Why do partial μ-opioid receptor agonists used in opioid addiction treatment cause less euphoria, and why do they still produce physical dependence?
  15. Using the heroin-versus-methadone pharmacokinetic and withdrawal comparison, explain why methadone substitution reduces the severity of opioid withdrawal compared to abrupt heroin cessation.
  16. By what mechanism does alcohol increase dopamine release in the reward pathway, and what other neurotransmitter system does it act on to help produce euphoria?
  17. Explain the phenomenon of acute tolerance to alcohol, using the relationship between blood ethanol concentration and subjective intoxication described in the lecture.
  18. What did the UK Biobank study find about alcohol consumption and brain grey matter, and what is the current public health recommendation on a “safe” level of alcohol consumption?
  19. State the twin-study heritability figures for alcohol use disorder given in the lecture.
  20. Distinguish stimulants from entactogens/empathogens in terms of which neurotransmitter each preferentially increases in the synapse.
  21. Distinguish the subjective self-related effects of psychedelic drugs from those of cocaine as dose increases (in terms of ego-dissolution versus ego-inflation).
  22. A patient has been prescribed a strong opioid for chronic non-cancer pain for 4 months. Using the dependence-risk figures given in the lecture, would you expect their dependence risk to be closer to that of “strong opioids” or of the more recent “chronic non-cancer pain” study estimate, and what are those two figures?
  23. Integrative: explain how the concept of “speed of drug administration” links the pharmacokinetics of cocaine and methylphenidate to the phasic dopamine/D1 receptor mechanism, to produce a unified explanation of addiction risk across different routes of use.
  24. What proportion of people who use methamphetamine even once go on to develop a substance use disorder, and which cognitive domains are impaired by long-term stimulant abuse?

Answers

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