psyt 301: issues in drug dependence midterm lecture 3-5

what is a stimulant?

• increases catecholamine transmission (DA, NE. E)

• increases alertness / energy / mood / appeal of drug-paired events

• acts on catecholamine transporters by blocking uptake / inducing transmission

Stimulants =

1) Plant-based

2) Synthetic

Plant based vs. synthetic stimulants

Plant based:

• Cocaine

  • Comes form coca plant

  • Crack cocaine = cocaine boiled with baking soda

  • Snorted, IV, smoked

• Ephedra

  • pills, drunk

  • Europe, Asia, South Americas

• Khat - Cathinone

  • Khat plant - active ingredient: Cathinone

  • drunk, chewed, smoked

  • East Africa

Synthetic:

• d-Amphetamine, meth-amphetamine, methylphenidate

  • Pills, smoked, IV, intranasal, “crystal”

• MDMA, modafinil

motivation / market for new/stronger psychoactive substances?

easier to smuggle, bc/ stronger substance = more potent (more addictive), requires less amount to smuggle (easier transport)

highest probability drug to get a dependence?

nicotine (> alcohol > cocaine > cannabis)

which highly addictive drug has the highest remission rate (decreased use / “easiest” to get over addiction)

Cocaine (next is cannabis > alcohol > nicotine)

• 50% of people recover after being a cocaine user

• “It was a fun phase in my life, but that’s all it was”

3 factors according to Leyton why “drug users can’t stop”

1) Increased goal-directed approach

• Motivation to approach the reward increases because of its conditioned and sensitized incentive salience (conditioned cues because more salient, and sensitization increases cravings)

2) Development of compulsions

• Inability to stop/disengage from drug seeking behaviour

3) Switch from approach to avoidance

• Taking drug not because you want to but in order to stop stress / withdrawal effects

triggers of drug use (Leyton)

• Already having one drink

• socializing cues, availability of drug, mood

what 4 factors induce reinstatement (return to drug-seeking habits after period of abstinence), and that are the same in rats

1) The drug itself (resuming drug-taking

2) Drug cues (they become more salient, the more you are exposed to cues)

3) Stress

4) Withdrawal (only when it is paired with the learned expectation that a drug is coming

True or false: Most goal-directed behaviour is about avoidance (escaping deficits like withdrawal) > approach (motivation to get the rewards)

FALSE: most goal-directed behaviour = about approach > avoidance

besides dopamine, what other molecules are relevant in addiction?

serotonin, glutamate, ACh, endogenous opioids, endocannabinoids

Why is dopamine the key molecule involved in addiction?

1) The most brain activity occurs in the NAcc (which is DA release) in response to reward

2) DA antagonists (which block DA release) stop reward-seeking behaviour (stop goal-oriented approach behaviour for drugs)

• DA antagonists also lower Progressive Ratio Breakpoint (lowers lever pressing motivation)

• DA antagonists lower reinstatement caused bye drug, drug cues, or stress

True or false: being in withdrawal state induces. DA release

FALSE —> withdrawal state alone does not induce DA release, it’s only when withdrawal state is paired with learning association of “drug anticipation” = induces DA release

how do dopamine antagonists work?

they block DA release by blocking dopamine autoreceptors

• Can’t just use DA antagonists to cure addiction, bc/ sometimes DA antagonists actually induce more DA release, causing more drug-seeking motivation and behaviour

where do humans show DA release (analagouse to the NAcc in rats)

Ventral striatum

What association did Leyton find vs. the study that replicated his study?

Leyton’s findings:

• 2 way association: novelty seeking and drug-taking (strong correlation)

Replicated finding:

• 3 way association: lower inhibitory DA autoreceptors = greater trait impulsivity = greater DA release

If dopamine is not linked to pleasure, what is it linked to?

Behaviour (specifically motivation behaviour / reward-seeking behaviour)

is pleasure required to change motivational states?

No, only dopamine pathways

naloxone-induced withdrawal findings on the dorsal striatum vs. ventral striatum

Naloxone-induced withdrawal caused:

• increase in dorsal striatum activity (wants the person to take drugs to escape aversion > simply seeking out reward)

  • Dorsal striatum, the brain’s habit center, tells you to compulsively carry out actions to escape the dysphoria of withdrawal

• decrease in ventral striatum activity (lowered craving/wanting behaviour to seek out reward)

  • Ventral striatum = reward center, high DA release = high reward-seeking behaviour (so withdrawal lowers any of this activity)

overall do people with severe drug addictions show higher or smaller dopamine responses? than those with less severe / no SUDs?

smaller DA responses due to down-regulated DA receptors (they need much more drug to actually feel something - related to built up tolerance)

• however, re-exposure (reinstatement) of drug cues cause heightened DA responses again

• people with SUD can be described as showing heightened DA response against a low reward system and high stress neurobiological background

how is the human brain different from the rat brain in terms of drug addiction

human brain = much larger, more expanded cortex and humans can have comorbidities with their drug addiction

is it shared or non-shared environments that foster comorbidity with drug addiction?

Shared environments

• Ex. women who have similarly gone through sexual trauma tend to more likely fall into drug addiction and also display internalizing and externalizing behaviours

what is the general factor that relates to likelihood of obtaining a psychopathology, especially if you already have 1 psychopathology?

“p” factor

• high p factor = high risk of comorbidity (of psychopathologies)

what is integration theory (Leyton)

integration theory includes the 3-factor diatheses model that explains how mental disorders can arise from an interaction between stress and pre-existing biological/psychological vulnerabilities:

1) early life trauma (stress)

2) adolescent externalizing behaviour (pre-existing vulnerability)

3) low dopamine autoreceptor transmission (pre-existing vulnerability)

Leyton found significant results for these factors in explaining future mental disorders using PET scan data, to map DA transmission and excitation (except the sample size was limited)

Follow up-study on Leyton’s Integration theory / Diatheses stress model (how did it differ)

Another study replicated Leyton’s results and found a 4th factor in the interaction between stress and pre-existing biopsycho vulunerability:

• 4th factor: Sex (gender significantly predicted who was more vulnerable to mental disorders in combination with the other factors)

• Better/stronger sample size: used IMAGEN database

• Used fMRI BOLD signal (to map whole brain activity, not just DA activity)

What important pattern did the follow-up study find about BOLD (brain) responses and early life adversity?

There is a moderating effect between early life trauma/adversity and brain activity (which can be either adaptive or maladaptive:

1) Maladaptive: The person’s brain becomes low reward functioning (low brain activation to reward cues) - higher risk for mental illness

2) Adaptive / Protective: The person’s brain becomes high reward functioning (high brain activation to reward cues) -- lowers risk for mental illness

What were overall the two study’s results (PET study vs. fMRI study)

(Contradicting results)

PET Study:

• Low DA inhibition (meaning high DA excitation in the striatum)

fMRI Study:

• Low brain activitation (wouldn’t this imply low DA excitation?)

Takeaway:

• Overall, in people more at risk for drug addiction, there is high DA dysregulation (results in high DA responses) against a background of low brain activation (a low functioning reward system)

• Bc/ over time, a lower-activity reward system (low DA autoreceptors) is highly sensitive to addictive drugs that can produce high DA responses

  • In the absence of drug cues, the brain is low-reward functioning, low motivational state

  • In the presence of drug cues, the brain gets spiked by DA responses

• Alternating motivational state between low and high DA responses in chronic drug users

explain the relationship between alcohol and juice cues and predicting drinking problems 7 years later

adolescents that show high striatal activation to alcohol > juice cues = higher predictor of drinking problems 7 years later

• as well: adolescent externalizing behaviour = predictor of drinking problems 7 years later too

• Note: Childhood trauma DID NOT significantly show as being a predictor of drinking problems 7 years later in this study (yes in other studies)

Summary of adolescent drug use / predisposition to drug/alcohol problems

Young adults at risk for SUDs show altered meso-corticolimbic (MCL) dopamine

• PET data more accurately shows this relationship (and has higher sensitivity) > fMRI data

What are the alternatives to drug treatment and how do they compare in terms of investment to society?

From lowest investment return to society vs. highest return to society:

Source country control (get rid of the drugs being made in the country) < Interdiction (kill the drug sellers) < Domestic enforcement (imprison the drug sellers) < Treatment

different types of drug treatment

Treatment’s return rate to society: $7.46 back for every $7 spent on drug treatment

• Group + individual therapy:

  • Contingency therapy (reducing amount of drug in exchange for rewards each time)

  • Motivational therapy (CBT)

  • Twelve Step Facilitation (ex. AA)

• Replacement therapy:

  • Replacing illicit strong drug with a lesser legal drug (ex. replacing fentanyl with methadone / nicotine)

• Potential treatments

  • TMS (transcranial magentic stimulation)

  • Psychedlics

  • Amphetamines GLP-1A agonists (reduces cravings - “I don’t need as much”)

Where do opioid drugs come from?

The poppy plant - originally used for pain relief and psychoactive properties

Opium = the dried juice/latex from the poppy plant

• contains alkaloid compounds

what are the 3 naturally producing neuropeptides that bind our natural opioid receptors?

1) B-endorphins

2) Enkephalins

3) Dynorphins

These neuropeptides bind 3 types of receptors: mu (MOR), kappa (KOR), or delta (DOR)

where are neuropeptides widely expressed?

CNS and PNS

• found in regions that regulate pain, mood, stress, pleasure

What opioid receptor do most exogenous drugs bind to?

MOR (mu opioid receptor)

weakest vs. strongest types of opioids/medications

weakest: codeine, tramadol

strongest: methadone, fentanyl

What are two common modes of pain administration

1) Oral

2) Transdermal (ex. patches)

why are opioids for acute pain used? (and give an example of acute pain)

for pain relief (acts as an analgesic = pain reliever)

• example: pain caused by big surgeries = acute pain (temporary)

• Acute pain is any pain lasting less than 1 month

• Note: sub-acute pain = pain within 1-3 months

a large portion of pain relief opioid medications are used to treat what?

dental pain (20% of opioid meds prescribed post-dental surgery)

What is chronic pain?

defined as pain symptoms last > over 3 months

• ex. muskoskeletal pain, visceral pain, orofacial pain

why may adolescents use opioids > other drugs

easier access (parents’ cabinets, from friends)

thought of as safer (bc/ they were prescribed by a doctor)

what were the 3 waves of opioid-related deaths between 1999-2020?

Wave 1: Prescription opioid crisis (caused by Oxycontin and other semi-synthetics on the market by Purdue Pharma, falsely advertised as “non-addictive”)

Wave 2: Heroin opioid crisis (Oxycontin removed from market, illicit heroin overdose rates rise)

Wave 3: Synthetic opioid crisis (illicit fentanyl sold on the street, 50x stronger than heroin)

What areas / provinces in Canada = associated with higher opioid-related deaths?

West Canada (BC > Alberta etc.)

Least amount of opioid-related overdoses: Quebec / Eastern Canada

Do men or women experience more opioid related deaths?

Men (men aged 30-50 experience more opioid-related deaths (account for 70% of opioid deaths) over women

Do most opioid related deaths come from pharmaceutical made drugs or non-pharmaceutical made drugs (illicit / not approved)

Non-pharamaceutical drugs (accounts for 77% of opioid related deaths)

what factors increase risk of opioid-related deaths? (6)

1. Mixing drugs

2. Differences in Opioid strength and content

3. Opioid tolerance shift

   1. Losing your tolerance after period of abstinence makes you more susceptible to overdose by taking same drug dosage you took when you had a higher tolerance can be fatal

4. Opioid Administration route (injection = more unsafe)

5. Using Alone (no one can help you if you overdose)

Is pain subjective or objective?

Subjective

• same injury can evoke different pain ratings by different people (on self-reports)

True/false Pain = biopsychosocial process

TRUE

SUDs and people with chronic pain

30% of people with chronic pain are tobacco users

20% of people with chronic pain are cannabis users

10% of people with chronic pain are sedative users

people with chronic pain = 2x more likely to have alcohol problems

• 25% of sedative users with chronic pain mix their sedatives with alcohol

how many days is required for long term opioid therapy (LTOT)?

daily opioid use for = / > (equal or over) 90 days (> 3 months)

How did opioids become common medical treatment (describe key factors)

1) originally used to treat cancer patients with chronic pain

• idea: it’s unethical to let dying cancer pains experience chronic pain with no pain relief

• this arguement extended to apply to chronic non-cancer pain patients (CNCP) bc/ non cancer chronic pain is of similar intensity to cancer chronic pain

2) scientific publications and professional societies published that opioid addiction is rare and opioid therapy is safe (popularizing opioid therapy)

3) Pharmaceutical industries started manufactuering and advertising more opioids to treat pain

• Ex. Purdue Pharma and OxyContin controversy

4) Lack of education

• graduates / undergrads weren’t educated on addictiveness of certain opioids and believed Pharma industries were advertising the right drugs (Pharma exploitation)

5) Insurers / Payers

• Insurance companies and payers didn’t / don’t offer enough coverage for pain treatment beyond pills (psychotherapy, physical therapy), so people resort to opioid pills (even if they can get addicted more likely)

Are opioids scientifically proven as effective for long-term chronic pain?

No, but studies show that for less than 3 months (short-term, acute pain), opioids DO reduce pain (by 0.69 on a 10-point scale), but studies like this are limited bc/ they only test for less than 3 months = not true LTOT (which is > 90 days)

Benefits for chronic pain opioid use is based on:

• anecdotes, qualitative studies, and patient beliefs

What are the 4 common problems associated with opioid use for chronic pain?

1) Adverse side effects

2) Physical dependence

3) Opioid misuse

4) Opioid use disorder

What tools assess physical dependence?

Self-report tools (SOWS)

Clinical administered tools (COWS)

How to measure opioid misuse

• self reports

• clinical interviews

• medical records

• urine tox screens

What is OUD characterized by?

social problems, psychological problems from use, occupational problems, failure to fulfill life role obligations, risky use, taken in larger amounts than intended, compulsive use, craving, unsuccessful efforts to cut down

what are the socio-demographic factors that lead to opioid misuse/addiction

men, younger, unemployed

describe prevention and opioid harm reduction strategies

1. safe opioid disposal locations

2. drug testing

   1. Confidential drug testing to see if you have any specific drugs in your system, free of judgment

3. syringe-exchange programs (SEPs)

   1. safe injection

4. supervised consumption sites

5. naloxone distribution

all of these above policies = safer and legal

how is naloxone administered in the body?

intranasal, intravenous, intramuscular, subcutaneous routes

what are the treatment options for people with opioid use disorder (OUD)

OAT = most effective opioid therapy

• Opioid agonist treatment —> opioid agonist (either buprenorphine (suboxone) or methadone, or slow-release oral morphine) being administered to control opioid cravings while preventing withdrawal effects

What is buprenorphine-naloxone OAT?

A type of opioid therapy where buprenorphine (a partial opioid agonist) is combined with naloxone (an opioid antagonist) —> buprenorphine binds opioid receptors to produce a lesser high but works to manage cravings

• if people misuse this treatment (inject > taking orally), naloxone will kick in and send them into severe withdrawal = incentive to NOT misuse

Suboxone (bup-nal):

• Drug administration: under the tongue tablet / film

• Suboxone enables take-home dosage (flexibility and independence for users)

• And taking more of the medication WONT make you more high, bc/ buprenorphine = only partially agonizes

what is methadone OAT

• Methadone = full opioid agonist, mainly used for highly tolerant chronic drug users

• Drug administration: liquid formulation

• People can be on methadone for years

What is slow-releasing oral morphine

A daily capsule = often offered if drug user is not benefiting from other OAT treatments like bup-nal (suboxone)

what do all OAT techniques have in common?

They block cravings and reduce addiction over time by producing less rapid highs

Most advantageous OAT technique

Buprenorphine

• less side effects, lowest risk of overdose due to partial antagonism

• lower risk of public safety harms

• milder withdrawal symptoms after discontinuing use

• optimal for rural remote locations where patient can’t always be watched by professional

If harms of opioid therapy outweigh the benefits, what approach is best to mitigate/prevent opioid use problems?

Opioid tapering

When should evaluating risks/harms occur during OAT?

Before and during therapy

What was the negative outcome caused by the implementation of the Center for Disease (CDC) Control in 2016?

The CDC stated that recommended doses of opioids shouldn’t exceed 90 mg, but this was a recommendation and not a strict cutoff

• clinicians viewed this as a strict cutoff, and stopped administering pain meds above 90 mg to patients which caused severe problems (ex. withdrawal) for dependent patients (and under treatment of pain), higher suicide, mental health crises, and more patients sourced out illicit pain relief methods

describe opioid tapering (which is not OAT)

slow gradual dose reduction that is voluntary, consensual, individual, and patient-centered

• tapering pace (slowing down dosage reduction, accelerating dosage reduction, pausing dosage reduction etc.) is based on each individual patient

• often accompanied by psychosocial support (unlike some OAT therapies)

what barriers contribute to opioid related harms

Lack of clinician training in switching from one opioid to another (ex. buprenorphine rotation)

Receiving fragmented care (patient takes meds from pain specialist for chronic pain, but also takes meds for mental illness from psychiatrist)

what psychological interventions are becoming more popular in treating OUDs?

1. CBT

2. Acceptance and Commitment Therapy (ACT)

3. Mindfulness-based interventions

How is CBT helpful for opioid misuse prevention and OUDs?

• Educates patients on opioid misuse / SUDs

• Enhances and maintains motivation to be compliant

• Includes cognitive restructuring (helping patients identify high risk situations)

• Helps patients cope with cravings and urges to misuse opioids