Dr. Huberman explains the functioning of medications such as Adderall, Ritalin, Vyvanse, and other stimulants in enhancing focus and treating attention-deficit/hyperactivity disorder (ADHD)
This episode caters to individuals with ADHD, their parents, those currently taking ADHD medications, and anyone curious about the functioning of these medications and their impact on ADHD symptoms
Host- Andrew D. Huberman, Ph.D. (@hubermanlab)
Attention involves cognitive operations such as suppression of noise and focusing on relevant information
Prefrontal cortex plays a critical role in orchestrating neural activity for attention
  • Prefrontal cortex has top-down inhibition, suppressing other brain areas and enhancing salience
ADHD is not necessarily a deficit in prefrontal cortical function but a difficulty in communication with other brain areas
Background chatter in the brain becomes louder in ADHD individuals
The default mode network is active during idle thoughts and imagination, suppressed during focused attention
ADHD individuals often have an overactive default mode network while trying to focus, leading to distractions
Drugs used to treat ADHD work by creating conditions that improve prefrontal cortex functioning
  • The goal is to enhance the prefrontal cortex’s ability to suppress and enhance the activity of various brain networks
  • The use of these drugs during development can teach the prefrontal cortex to become a better conductor
Addressing common questions about ADHD drugs:
  • Are they addictive?
  • Can they be used briefly or intermittently?
  • Long-term effects of using them as a child
  • Considerations for putting children on these drugs
Understanding the biology and potential risks associated with these drugs helps in making informed decisions
Amphetamines, speed, and other stimulants can improve symptoms of ADHD
Increasing activity in the prefrontal cortex alone doesn’t improve attention, as it needs to be flexible and switch between different tasks
Drugs used to treat ADHD fall under the category of stimulants or sympathomimetics
  • Sympathomimetics mimics the activation of the sympathetic arm of the autonomic nervous system, responsible for attention and arousal
The autonomic nervous system has two major components: sympathetic (fight or flight) and parasympathetic (rest and digest)
  • The balance between sympathetic and parasympathetic is always present, even in sleep or panic attacks
ADHD drugs, as sympathomimetics, trigger the release of neurochemicals and activation resembling the sympathetic nervous system
Methamphetamine is a potent sympathomimetic but not commonly prescribed for ADHD due to its high abuse potential and health risks
  • Adderall and Vyvanse have commonly prescribed ADHD drugs that have similar mechanisms of action to methamphetamine but are less potent
Adderall is a combination of amphetamine salts, specifically D-amphetamine and L-amphetamine
  • D-amphetamine is more potent and primarily affects the brain
  • L-amphetamine is less potent and mainly causes peripheral effects like increased heart rate and blood pressure
The major effects of Adderall and other sympathomimetic stimulants are the increased transmission of dopamine and norepinephrine
Dopamine and norepinephrine are neuromodulators that can increase or decrease the electrical activity of specific brain circuits
Dopamine is involved in motivation, pursuit, and mood, while norepinephrine is involved in attention and focus
Dopamine and norepinephrine are released at similar locations in the brain and work together to increase motivation, focus, and alertness
Drugs that treat ADHD effectively increase motivation, focus, and alertness by targeting specific locations in the brain
Synapses are the communication points between neurons, where neurotransmitters are released
Neurons have a cell body, an axon, and synaptic terminals that contain neurotransmitters
Neurotransmitters are packaged into vesicles and released into the synaptic cleft
Transporters in the presynaptic terminal help recycle neurotransmitters back into the neuron
Adderall and other sympathomimetics inhibit the activity of dopamine and norepinephrine transporters, allowing more neurotransmitters to remain in the synaptic cleft
Adderall also disrupts the vesicle monoamine transporter (VMAT), leading to an increased buildup of dopamine and norepinephrine in the presynaptic terminal
These mechanisms result in a higher amount of dopamine and norepinephrine being released when an electrical signal travels down the neuron
Adderall primarily increases dopamine levels, although it also affects norepinephrine
The ability of Adderall to significantly increase dopamine levels is what makes it effective for ADHD treatment and attractive for recreational use or enhancing focus and attention
Adderall contains both L-amphetamine and D-amphetamine, with D-amphetamine being present in a larger amount
Vyvanse is not an extended-release version of Adderall but a separate drug that contains only D-amphetamine
Vyvanse is classified as a prodrug because it is composed of D-amphetamine attached to the amino acid lysine
When Vyvanse is ingested, the lysine is gradually cleaved off in the gut and bloodstream, resulting in timed-release D-amphetamine
Vyvanse was developed to reduce the abuse potential of drugs containing D-amphetamine
D-amphetamine (dextroamfetamine) has been associated with criminal activity and trafficking in the past
  • Despite its historical associations, D-amphetamine has proven to be an effective treatment for ADHD
Vyvanse’s time-release mechanism slows down the absorption of D-amfetamine, leading to a gradual and prolonged increase in dopamine and norepinephrine
The effects of Vyvanse can last anywhere from 12 to 18 hours, depending on individual metabolism
There is no reliable test to predict an individual’s drug metabolism rate, so finding the right dosage and medication type may require trial and error
Some individuals may find that Adderall’s quick time course is too fast or leads to a slump in the afternoon, while others may experience overstimulation with a single dose of Adderall
Adderall and Vyvanse are two different drugs with distinct pharmacological profiles, despite both containing D-amphetamine
The time-release aspect of Vyvanse is achieved by attaching lysine to D-amphetamine
Ritalin (methylphenidate) is a commonly used drug for the treatment of ADHD
Ritalin works by increasing dopamine transmission at synapses and inhibiting the function of the presynaptic dopamine transporter
  • It also disrupts the activity of the noradrenergic transporter, leading to increased norepinephrine at the synapse
However, Ritalin is not as potent in inhibiting the noradrenergic transporter compared to Adderall and Vyvanse
The main effect of Ritalin is increasing dopamine, with some increase in norepinephrine at synapses
Ritalin has a relatively shorter duration of action compared to Adderall, typically lasting about 4 to 6 hours
Ritalin is not equivalent to short-acting Adderall, as it primarily increases dopamine and norepinephrine to a lesser extent
The lower affinity of Ritalin for the noradrenergic transporter contributes to its relatively lower increase in norepinephrine
Adderall and Vyvanse have three mechanisms for increasing dopamine and norepinephrine transmission:
  • Transporter disruption
  • VMAT2 disruption
  • Disruption of protein communication
Ritalin mainly relies on transporter disruption for its effects
The prefrontal cortex plays a key role in coordinating focused attention and task-switching in the brain
Dopamine and norepinephrine, which are affected by ADHD medications, have differential impacts on executive function and attention
Increasing dopamine at specific synapses and networks in the brain helps reduce background noise and distractions, both from the external environment and internal thoughts or bodily sensations
Dopamine facilitates the suppression of signals that would otherwise distract us from focused attention
Norepinephrine, released mainly from the locus coeruleus in the brain, acts as a signal booster at synapses and enhances the amplitude and frequency of communication between neurons
Norepinephrine, when released in the brain networks associated with attention and learning, primarily serves to increase the signal
Medications like Adderall, Vyvanse, and Ritalin increase both dopamine and norepinephrine, leading to a reduction in noise and an amplification of the desired signals in attention-related brain networks
This increase in signal-to-noise ratio enhances the subjective sense of focus and the ability to concentrate on specific tasks
The increase in dopamine and norepinephrine through ADHD medications assumes the dosage is appropriate and tailored to the individual’s needs
Excessive dopamine levels can lead to euphoria, mania, and psychosis, while excessive norepinephrine levels can cause anxiety and panic attacks
Not everyone with ADHD exhibits impulsivity and hyperactivity; some individuals struggle primarily with focus
Children and adults with ADHD can have difficulty entering a focused state, especially for tasks they find uninteresting or challenging
ADHD is characterized by extreme variations in focus ability, with individuals capable of intense concentration on activities they enjoy
ADHD involves challenges in focusing on activities necessary for normal life advancement, such as listening to conversations or sitting still
Dosing of ADHD medications must be carefully calibrated to ensure optimal levels of dopamine and norepinephrine
ADHD is a complex condition with different patterns and variations among individuals
There is a wide range of medications available to treat ADHD, with stimulant drugs like Adderall, Vyvanse, and Ritalin being the most effective
The diversity in ADHD symptoms and individual responses to medications highlights the importance of consulting with a qualified psychiatrist to find the ideal drug and dosage for each person’s specific pattern of ADHD
ADHD symptoms in children and adults are not caused by deficient activity in specific brain circuits but rather by hyperconnectivity between networks
ADHD is not simply a dopamine or norepinephrine deficiency; these neuromodulators modulate neural circuit activity
Medications for ADHD aim to adjust dopamine and norepinephrine levels to achieve a balance and reduce synchronous firing
Stimulants for ADHD don’t calm children down directly but increase overall arousal while activating the prefrontal cortex
Medications help the prefrontal cortex coordinate neural circuit activity like an orchestra conductor or a teacher in the classroom
The goal of ADHD medication is to fine-tune dosage, timing, and duration for optimal neural circuit functioning
Dopamine and norepinephrine enable precise activation of brain networks for improved focus and attention in ADHD
ADHD medications like Adderall, Vyvanse, and Ritalin leverage the neuroplasticity of the brain
  • Neuroplasticity refers to the brain’s ability to change in response to experience
Strongly activating specific brain networks and increasing the release of neuromodulators like dopamine and norepinephrine induce neuroplasticity
Neuromodulators, such as serotonin and acetylcholine, have different roles in the brain
Elevated levels of dopamine and norepinephrine promote neuroplasticity at synapses
Neuromodulators modulate the activity of neurotransmitters, which transmit signals between neurons
Increased dopamine and norepinephrine strengthen connections and make them more easily activated in the future
Prescribing sympathomimetic stimulants for children with ADHD aims to help them focus and promote neuroplasticity in brain networks
Neuroplasticity allows synapses involved in focus to strengthen and function more efficiently even after stopping the medication
Parents and individuals should consider the long-term benefits and potential drawbacks of ADHD medication
Treated children with ADHD show better performance in school, focusing ability, and general outcomes compared to untreated children
Untreated ADHD in childhood increases the risk of illicit drug use and addiction later in life
Children with ADHD who take prescription stimulant drugs do not develop a craving for them in adulthood
Early treatment with these medications leads to the normalization of brain circuits over time
An accurate diagnosis of ADHD is crucial, and a qualified psychiatrist will evaluate the child and consider both pharmacological and behavioral treatments
Treatment for ADHD should involve a comprehensive approach, including behavioral prescriptions, learning tools, nutrition, and supplementation
Treatment plans should be updated as the child progresses through different stages of development
Whether a child needs to continue ADHD medication indefinitely depends on individual circumstances
ADHD medication aims to improve neural circuits for focus and increase their strength
Some individuals may no longer need medication if their circuits have developed sufficiently
Tapering off medication should be done under the guidance of a psychiatrist to minimize withdrawal effects
Dosage reduction over time is often optimal and should be discussed with a psychiatrist
Studies show a broad range of drug doses for Adderall, Ritalin, and Vyvanse
Vyvanse dosages tend to be higher due to the slow-release mechanism
Predicting individual reactions to dosage is challenging, and it varies greatly among patients
  • A patient’s weight, genetics, and enzyme levels can influence their response to medication
Individualized dosage should be based on symptom relief and side-effect considerations
There is no simple test to predict individual response to ADHD medication
  • Starting with the lowest effective dose and adjusting as necessary is a logical and safe approach
Long-term use of ADHD medication does not appear to negatively impact height or overall development
Children with ADHD who are treated with medication may have slightly higher body mass indexes (BMI) compared to their peers
Treatment with appropriate dosages does not stunt development or impair growth
Prolonged sympathetic nervous system activity carries some cardiovascular risk
  • One major study suggested a subtle increase in cardiovascular risk with ADHD medication but did not warrant discontinuation of the drugs
It is important to find the minimal effective dosage for ADHD medication
Individuals taking ADHD medication should engage in healthy lifestyle practices to support cardiovascular health, such as avoiding smoking, regular exercise, etc
  • Alcohol consumption, even in moderation, is best avoided when taking ADHD medication
  • Combining alcohol with ADHD medication can have detrimental effects on the brain and body
Benzodiazepines and similar drugs should be avoided unless prescribed by a physician
Always consult a physician for personalized advice regarding ADHD medication and potential interactions
Few studies have examined the long-term effects of drugs like Adderall, Ritalin, and Vivance on the hormone systems of the body
Chronic elevation of the sympathetic nervous system, caused by these drugs, can increase cortisol levels, which is a stress hormone
Cortisol has positive roles in the body, including enhancing focus, activating the immune system, and setting the mood
The timing of cortisol release is crucial, with higher levels in the early part of the day and tapering off towards the end
  • Late-day elevations in cortisol are associated with depressive symptoms
These drugs can disrupt the endocrine system by affecting other hormones such as thyroid hormone, testosterone, and estrogen
Chronically elevated cortisol levels can reduce testosterone production and affect libido, muscle, bone mass, and other aspects of testosterone-related biology
Chronic elevation of cortisol may suppress ovulation in women, but no studies show that taking ADHD medication leads to irregular ovulatory cycles or cessation of menstruation
There is no evidence that ADHD medication leads to lower overall testosterone levels
The effects of these drugs on hormones should be considered in the context of individual responses and feedback between hormones and productivity
Prolonged stress is generally unfavorable for the immune and hormone systems
The treatment of ADHD with these drugs should not come at the expense of other critical biological systems
Properly treated ADHD patients have a reduced risk of forming addictions to other substances
Tapering off ADHD medications can result in withdrawal effects and changes in brain systems
  • Withdrawal effects can include a foggy brain, inability to focus, and depressed mood
  • It’s unclear whether these symptoms are due to withdrawal or changes in brain activation
Psychosis can be induced by amphetamines and methylphenidate
  • Predisposition to psychosis and family history increase the likelihood of experiencing psychotic episodes
  • Stopping methylphenidate often ceases psychotic episodes, but with amphetamines like Adderall, episodes may persist even after discontinuation
Methamphetamine is highly detrimental, causing various health issues and neurotoxicity
  • Methamphetamine can induce psychosis in individuals with or without a predisposition
  • Prescription methamphetamine has very limited clinical use
ADHD drugs with amphetamine, like Adderall, have a higher likelihood of inducing psychosis in individuals with a predisposition
Methylphenidate (Ritalin) has a lower potential for inducing psychosis compared to amphetamines
Vyvanse (long-release dextroamphetamine) is associated with fewer psychotic episodes and less abuse potential
The kinetics of dopamine release plays a significant role in addiction and psychotic episodes
Methamphetamine’s fast and intense dopamine release makes it highly addictive and prone to induce psychosis
  • The duration of dopamine increases affects abuse potential and the risk of psychotic episodes
Vyvanse’s extended-release dopamine and norepinephrine reduce abuse potential and the likelihood of psychotic episodes
People without ADHD who take ADHD medications experience significant increases in dopamine and euphoria
Recreational or off-prescription use of ADHD medications can lead to a higher risk of addiction and psychotic episodes
Children and adults with ADHD who are prescribed these medications are at lower risk for addiction and other related issues
Caution is advised against using these medications without a prescription for ADHD
Psychiatrists often start with low dosages and adjust based on individual response and sensitivity
Repeated use of the medication by individuals with ADHD leads to lesser peaks in dopamine over time
Homeostatic plasticity and habituation occur, where the brain normalizes its response to the medication
The initial response to the drug is different from the response when taking the drug repeatedly
The long-term effects of chronic use of ADHD medications need more attention and discussion
Original clinical literature suggested that ADHD medications should not be taken every day
  • Some medications were designed to be taken during the school week with weekends off or during the school year with vacations in the summer
Sociological and financial factors have influenced the pattern of intake for ADHD medications
Different biological and neuroplastic responses occur when taking medication intermittently versus daily over a long period
Long-term effects of ADHD medications have been studied primarily for methylphenidate (Ritalin)
Studies on Adderall and Vyvanse, as well as other medications, are limited but exist
Most studies on long-term effects focus on adults who were treated with methylphenidate as children
Fewer studies directly address the long-term effects of newer medications like Adderall and Vyvanse
Studies have shown improvements in executive function in individuals who have taken ADHD medications for months to years
Non-amphetamine compounds are now being used more frequently to treat ADHD in both children and adults
Modafinil (commercial name Provigil) and Armodafinil (brand name Nuvigil) are non-amphetamine treatments for ADHD
Modafinil was released first, while Armodafinil is the second generation of these drugs
Modafinil tends to be expensive, with prices as high as $25 per pill or over $1,000 per month, making it prohibitive for some individuals
Experts report no major differences between Modafinil and Armodafinil, but consumer experiences and preferences vary
Some people believe that brand-name versions of drugs work better for them, but concrete evidence supporting this claim is lacking
Modafinil and Armodafinil are prescribed for various conditions causing daytime sleepiness, such as narcolepsy, post-surgery anesthesia, dementia-related sleepiness, traumatic head injury, and stroke recovery
  • The use of these drugs should be carried out under the supervision of a certified physician
Huberman’s personal experience with armodafinil indicates that it relieved daytime sleepiness and increased alertness for 4-6 hours
  • The heightened state of attention induced by armodafinil was uncomfortable and took several hours to subside
  • Huberman’s preference is to be in a state of alertness and calmness for learning rather than a highly aroused state induced by armodafinil
Modafinil and Armodafinil can have side effects such as decreased appetite, runny nose, headaches, and skin rashes (rare cases of Stevens-Johnson syndrome)
  • The potential risk of Stevens-Johnson syndrome has been associated with Modafinil, but ADHD specialists argue that its frequency is no higher than with other approved drugs
Prescribing Modafinil and Armodafinil for ADHD in children requires caution and consideration of potential risks
Other atypical drugs used for ADHD treatment include Propririn, Wellbutrin, and others
Guanfacine is an alpha 2A agonist initially developed to lower blood pressure
  • It is a non-stimulant medication used to treat ADHD by targeting the noradrenergic system, specifically increasing norepinephrine
Unlike other ADHD medications that increase both dopamine and norepinephrine, Guanfacine only affects norepinephrine
Guanfacine activates pathways that dampen down the sympathetic nervous system, resulting in a calming effect
  • It is not frequently prescribed as it either has no effect on ADHD symptoms or causes drowsiness
  • However, approximately 5-10% of individuals, including children, experience significant relief from ADHD symptoms and tolerate Guanficine better than other medications
Guanfacine works by stimulating alpha 2A receptors in the locus coeruleus, a brain region involved in releasing norepinephrine
Activation of prefrontal cortical networks by Guanfacine improves executive function and enhances the coordination between locus coeruleus neurons and the prefrontal cortex
Guanfacine is primarily used in children aged 6-17 for the treatment of ADHD, to improve attention, reduce impulsivity and hyperactivity
It may be prescribed alongside other ADHD medications to counteract side effects or enhance treatment efficacy
The use of drug combinations raises concerns about polypharmacology, but for some individuals, Guanfacine provides significant relief when standard ADHD medications are ineffective
Guanfacine lowers blood pressure and overall sympathetic arousal, which necessitates caution when considering alcohol consumption
  • Even small amounts of alcohol can have severe consequences, including death when combined with Guanfacine
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Brain alterations in children/adolescents with ADHD revisited: A neuroimaging meta-analysis of 96 structural and functional studies (Neuroscience & Biobehavioral Reviews)
Impulsivity, Compulsivity, and Top-Down Cognitive Control (Neuron)
Dopaminergic System Dysfunction in Recreational Dexamphetamine Users (Neuropsychopharmacology)
Modafinil enhances alerting-related brain activity in attention networks (Psychopharmacology)
Association of Intrinsic Brain Architecture With Changes in Attentional and Mood Symptoms During Development (JAMA Psychiatry)
Cognitive enhancement effects of stimulants: a randomized controlled trial testing methylphenidate, modafinil, and caffeine (Psychopharmacology)
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