Amphetamines and ADHD Medications

Dextro agonists

- DA transporter is reversed (dumps out DA) - Leaky vesicles so more DA gets dumped, no AP is required for this to happen - NE and DA Levo: induces euphoria (why it is lower percentage in Adderall). This could also be affecting the serotonin system.

What is a secondary effect of amphetamines?

Secondary effect: MAO inhibitor. MAO takes apart dopamine, so more dopamine is present. This acts as an antidepressant.

Difference between r-handed and l-handed molecular structure of amphetamines

r-handed: more potent l-handed: longer lasting

Vigilant concentration

Staying on task - monitoring rules (cognitive) - updating the system and response execution (Switch task show vigilant deficits in ADHD) - reticular activation: locus coeruleus + basal forebrain, not activated in routine behaviour but active when switching between tasks.

Amphetamine tolerance

Tachyphylaxis is possible (within a few hours) - drug of choice for athletes, effects would come back within only a few hours.

taking in a "run-abstinence" cycle

Taken in large quantities for brief periods of time followed by periods of abstinence (not continuous).

People generally prefer ____, which has stronger CNS effects with fewer PNS effects than _____.

methamphetamine, d or l-amphetamines

Excretion of amphetamines depends on _______

pH of the urine. Amphetamines are not reabsorbed from the nephron in acidic urine, but as it becomes more basic, more of the drug gets absorbed and then metabolism of the drug in the liver becomes prominent (longer process)

Drug Holidays

"Drug holidays" = when children stop taking meds over the summer. This is not an addiction, but children become lethargic, lack of motivation, depression. Return of ADHD symptoms. Want for regulated behaviour

What is the street name for amphetamine?

"speed"

Origin of Ephedrine

- Botanical origin (ma huang) • Sympathomimetic - Bronchial dilation • Treat asthma - Increase blood pressure

Behavioural therapies

- CBT (effective for meth) - Contingency management (vouchers for good behaviour) - Community reinforcement (social reinforcement such as praise and encouragement) *combined treatment is most effective

Go no-go task and ADHD

- Continuous response task with intermittent inhibition. - Dynamic adjustment accuracy and RT - mistakes slow down presentation, answers speed up until error Results group: more false alarms in ADHD (no meds) and misses. Not difference in RT between control, ADHD, or ADHD on Ritalin. Those on Ritalin have highest activation on inhibition (more efficient) than control or ADHD non meds. Less activiation required to get the same behavioural results.

Amphetamine action mechanism

- Leaky vesicles (spills out easily into the synaptic cleft), - re-uptake inhibitors (stop autoreceptors from taking up the neurotransmitter, so it lingers in the synapse) - Benzedrine: affects norepinephrine receptors much more than NE neurotransmitter - Increasing dosage creates agonistic effects with serotonin (mechanism not well understood)

15-day residential study

- Participants completed questionnaires and cognitive tasks over 15 days. Days 4-6, 10-12 received meth (placebos the rest) Results: reported positive effects on the first day of taking actual drug, flu-like symptoms on the third day of meth administration. Sleep disrupted and food intake decreased. There is some form of tachyphylaxis. Physiological effects more so than psychological effects (although euphoria is there).

Amphetamine Dependence

- Psychological: craving (depression, anxiety, sleep disturbances) - only meth is incentive salience = "wanting"

Norepinepherine and vigilant concentration

- continuous excessive mental work-loads - depletion of this NT will result in less perseverance (we are not paying attention to change in rules) - lack of reward dependence. Those with ADHD recruit other area (like parietal, language areas) to deal with task changes. Contingent on even small rewards. Rewards do not motivate behaviour.

Characteristics of amphetamine withdrawal

- depression/suicidal thoughts - fatigue - vivid unpleasant dreams - insomnia or hypersomnia - increased appetite - psychomotor agitation

indirect effects of amphetamines

- disease from injection - ability to fight disease is reduced for two reasons: appetite-suppressant means diet is poor, lack of sleep. - people becomes suspicious, antisocial, violent. - higher death rates

Hyperfocus

- getting "locked in" to a task, intense focus, not the kind of perseverance you see in Autism. - studies have documented this in adult-onset - aware of things they ignore, but cannot give up what they are doing - PFC activation in word fluency, depleted serotonin and could also explain sleep disturbances and depressive symptoms

Cocaine schedule 1 abuse potential

- higher abuse problem than Ritalin: shorter time to produce euphoria - less aversive effects then when high on bathsalts - no physical withdrawal symptoms - Ritalin is less dangerous than cocaine

Oral administration of amphetamines

- in the form of pills, - They tend to be ionized in the digestive system, which slows the rate of absorption, - restlessness, excessive talking, confusion, dizziness (short use) - paranoia, punding, irrational thought, sleep problems (with prolonged use). - Benzedrine: decongestant, appetite suppressant but pulled off the market as it was abused as a party drug, - used for treatment for ADHD (1950/60)

direct effects of amphetamines

- irregular heart rate - increased BP - increased risk of stroke - brain damage (deterioration of vessels) - neurotoxic effects (dopamine)

Can ADHD medication be a study aid for typically developing individuals?

- no effects on cognition or LTM - improved performance of boring & difficult tasks - modest effects on working & episodic memory - vigilant attention is not improved: no increase in sensitivity, no vigilance reduction. - sensitivity to feedback, brain responds is hyperactive to positive or negative feedback.

factors influencing oral administration of amphetamines

- presence of food in the stomach - degree of physical activity

Ephedrine

-family class of stimulants - it is an alkaloid

Methylated amphetamines

-street name = cranck, ice, crystal meth - quicker passage across blood-brain barrier (latches onto oxygen as a carrier molecule) - very different effect than other forms of amphetamines

3 subtypes of ADHD

1. ADHD predominantly inattentive (priorly called "ADD") - distracted, disorganized, forgetful, poor concentration, daydreaming - affects EF, memory, attention - vigilant concentration 2. ADHD predominantly hyperactive/impulsive - restlessness, difficulty waiting, immature behaviours - motor and behavioural inhibition - cognitive alertness 3. ADHD combined - most common

Which 3 drug trial have been most successful in treating amphetamine and cocaine addictions?

1. Bupropion 2. Modafinil 3. Naltrexone *behavioural and psychosocial treatment seems to be prominent.

ADHD

1. Impairment of growth/development • Childhood onset - Adult onset not well documented, confound with substance use. • Temporal contiguity - Start and consequence 2. Neurological abnormality resulting in impaired ability to function. • Anatomically based - Differentiate from emotional/cognitive disruption (i.e. "acting out", frustration, ODD) The longer ADHD is untreated, the more out of hand it becomes

Withdrawal in Amphetamine

1. Lethargy 2. Dysthemia (not Depression!)

pKa of amphetamines

19-10 (weak bases)

The "perfect Adderall pill"

75% dexedrine (the treatment of ADHD symtpoms), fast acting 25% levo (midigates Euphoria, makes it last longer), slow acting/long lasting because of the interaction with dexedrine. Allows for taking 1 dose that lasts the day. This proportion could be patented.

buropion

Antidepressant, used in smoking cessation. Only showed success is reducing cravings in light but not heavy meth users.

Cognitive alertness in ADHD

Alertness, noticing Detection: monitoring, orienting, reacting. This is from sensory awareness, inability to ignore stimulus. ADHD people lack inhibition to any stimuli (distracted behaviour), most people have limits to what they can block out. People with ADHD tend to be tired often as a result.

Long-term users of amphetamines shows what?

Amphetamine psychosis. - toxicity levels from chronic use: panic and paranoia is seen, - formication: perceiving bugs crawling under the skin, - compulsions and repetitive behaviour, - delusions and hallucinations, - "tweaking" is irritability, paranoia, violent behaviour (not disorganized like seen in Schizophrenia)(science attributes these symptoms to sleep deprivation)

Withdrawal occurs faster after cocaine or amphetamines?

Cocaine. It occurs within half an hour after cocaine and is delayed for a few hours after amphetamines.

Dextro Amphetamines: Dexedrine

Dexedrine - financed by Air Force, classified military information, - "go pills" = Dexedrine - "no go pills" = sleep aids (Benzo, GABA receptor modulator) - predominantly right-rotating

T of F. Amphetamines are excreted faster than cocaine.

F. Cocaine has faster excretion than amphetamines.

T or F; Amphetamine metabolites are not behaviourally active and have short half-lives.

F. They are behaviourally active and have long half-lives

Do studies show amphetamine effects are higher individually or in a group?

In a group.

If a stimulant treatment drug is addictive, what should it be?

It should be taken orally and have a long half-life. This will keep blood levels constant and prevent fluctuations which could worsen any addictive tendencies.

Brain areas in cognitive alertness

Mesolimbic/mesocortical pathway - Dopamine - motivational significance associated with reward, people with ADHD cannot prioritize actions - set a value on reward

Ritalin

Methylphenidate - phenethylamine is a reuptake inhibitor, more dopamine and norepinephrine in the synapse - more potent inhibitor than cocaine - no euphoria, entered brain slower and has less abuse potential, giving someone Retalin is NOT like giving them cocaine.

Can Ritalin be a "gateway drug"?

No, the opposite. Those who do not get meds were much more likely to seek drugs such as cocaine, but those who were on Ritalin were much less likely to abuse drugs.

naltrexone

Opioid agonist. Reduced cue-induced reinstatement of meth self-administration and block subjective effects.

Discuss the potential use of immunization. What are the difficulties?

The vaccine could stimulate the immune system to create antibodies that would bind to cocaine molecules so they could not pass the BBB. Could be preventative and treatment. It is difficult because vaccines normally only work with large molecules but cocaine is small molecules. Usually a number of vaccinations are needed and it does not last that long. Only works for those who produce high quantities of antibodies.

T or F: amphetamines cause dissociation

True. Learning under the influence of amphetamine results in forgetting that info once it wares off (this is why students should not take amphetamines to study).

Euphoric effects of amphetamines

Usually taken in higher doses and administrated by i.v or inhalation "peak user" "speed freak"

What drug is used as a "replacement" drug during treatment?

amineptine, an antidepressant that inhibits dopamine. May have an abuse potential.

How can amphetamines affect offspring?

behavioural and physical abnormalities. Some studies have found it retards normal growth (more premature- abruptio placentae). No affect on intelligence.

amphetamine effects on sleep

block fatigue, increase concentration, can cause insomnia, can be used to treat narcolepsy and sleep disorder that causes excessive sleepiness.

Amphetamines and sexual activity

both amphetamine and cocaine enhance sexual activity (decrease sexual inhibitions). But crack, freebase, or injection of cocaine lead to disruption of sexual interest.

hyperactivity is referring to...

brain activity, not behavioural activity

"speed ball"

cocaine or amphetamines taken with heroin

Amphetamine allows for _______ blood levels to be _______.

constant, maintained for an extended period of time.

amphetamine isomers

d-amphetamine and l-amphetamine dl-amphetamine (Adderol)

Reinforcement

does not facilitate behaviour changes in ADHD. - not responsive to punishment - not responsive to positive reinforcement - maybe sensitive to a combination of both

modafinil

dopamine, norepinephrine, histamine, and glutamate stimulant. Used for ADHD and narcolepsy. Has a limited abuse potential, but results must be validated.

What administration makes amphetamine the most potent?

injection, inhalation, insufflation. But when amphetamines are taken for medicinal purposes or to prevent sleep, they are taken orally just with a higher dose.

oral d-amphetamine

substituting oral (safer route) for injection.

Amphetamine physiological mechanism

substrate-type releasers. - structural analogs that can enter presynaptic neuron by binding to the transporter - gets packed into vesicles along with the monoamine. - slow reabsorption into the presynaptic cell. - disrupt pH balance - can act as an open channel causing monoamines to exit the cell at a high rate - inhibit activity of MAO enzyme that degrades free floating monoamine

What type of behaviour is associated with repeated amphetamine use?

violent behaviour. - hostile - paranoid - defensive - personality changes, unpredictable and sudden.