Comments on Dr. Huberman’s Podcast – ADHD Treatment

On Monday, Dr. Andrew Huberman, Ph.D., released his most recent podcast episode covering ADHD medication treatment, focused on Adderall (75% dextroamphetamine/25% amphetamine salts), stimulants, and modafinil. I’m grateful patients, and the general public has such a fantastic resource. In my book, his podcast is a must-listen. Some of my favorite episodes have been his various episodes covering sleep, ADHD, water, and alcohol. I’m also envious that he’s had the chance to speak with Dr. Satchin Panda, Ph.D., and Dr. Peter Attia, M.D., in successive weeks. I’ve been a big fan of their work for years. 

Dr. Huberman must be a fantastic professor of Neurobiology and Opthalmology. He does an excellent job of explaining things in language his audience can understand. That is not easy to do, especially with these subject matters. He’s also tremendously well-prepared for his podcasts. I use the Overcast app when consuming podcasts, which allows you to listen to podcasts at 3x+ speed. The + is where it removes silences and longer pauses between words. Dr. Huberman has very few of those pauses, which speaks to how well-prepared he is.

My comments here are simply from the viewpoint of a physician and psychiatrist specializing in treating ADHD and having had ADHD since I was a child. Working with and educating patients with ADHD is my primary professional passion. I also understand there are time constraints, and there’s only so much you can cover in roughly 2 hours without breaking the subject down into multiple episodes. Nevertheless, I hope the following comments are helpful for some folks out there.

These are just a few key takeaways from the podcast that I can’t emphasize enough:

• The level of impairment from these symptoms in patients with ADHD is significantly higher than population norms. So it’s not uncommon to have a symptom or even a few but still not meet the diagnostic criteria for ADHD.
• Early treatment of ADHD significantly improves outcomes in life. Patients with untreated ADHD often develop co-morbid psychiatric conditions, such as anxiety, depression, and substance use. Therefore, early treatment of ADHD can lead to considerably better life outcomes.
• There is no blood test or genetic test that can identify which medication will be most effective and compatible for a patient. 
• There is no average dose or way of predicting what dose will work best for a patient.
• The best treatment of ADHD looks beyond just medications.

Ritalin (methylphenidate):

• I really wish the Ritalin (methylphenidate), more technically known as methylphenidate (MPH) family, was described as the second-best set of treatments for ADHD. This family of medications includes many different medications, which have been life-changing for patients with ADHD who cannot tolerate or find adequate benefit from Adderall, more technically known as the amphetamine (AMP) family.

Amphetamine family:

• Regarding the differences between levoamphetamine and dextroamphetamine, it’s important to include the increased wakefulness from the levoamphetamine molecule and the increased appetite suppression from the dextroamphetamine molecule. The dextroamphetamine molecule is primarily where the cognitive benefits come from and, interestingly enough, has a longer half-life than the levoamphetamine molecule.
• In addition to being more powerful molecules, the other significant advantage of the AMP family is their susceptibility to acidic environments. I encourage most patients treated with this medication type to take supplement-size doses of Vitamin C in the evening or at night to help clear the residual medication from their systems. On that note, I would not recommend taking Athletic Greens in the morning when on an AMP-based medicine, as Vitamin C intake above 200-250 mg can increase the clearance of the medicine.

Desoxyn (methamphetamine):

• I appreciate Dr. Huberman highlighting the distinction that methamphetamine is neurotoxic due to the additional methyl group, while the far more commonly prescribed AMP family-based medications, such as Adderall, Vyvanse, etc., are not.
• When comparing Desoxyn (methamphetamine) and illicit street methamphetamine, there is a significant difference in dosing equivalents (illicit methamphetamine dosing tends to start at 4-5x higher). There is a small subset of patients with ADHD who clearly do better with Desoxyn (methamphetamine). Finding a pharmacy that can even order the medication is the biggest hurdle in prescribing this medication. For example, I called a CVS pharmacy on behalf of a patient this last month, and Desoxyn (methamphetamine) wasn’t even a listed medication in their system.

Vyvanse (lisdexamfetamine):

• As Dr. Huberman noted, Vyvanse (lisdexamfetamine) is a prodrug. “lis” is short for lysine (an essential amino acid) attached to a dextroamphetamine molecule. 
• Vyvanse (lisdexamfetamine) is activated by enzymatic hydrolysis via red blood cells. This does not occur in the GI tract.
• Roughly 7/10ths of the molecular weight of Vyvanse (lisdexamfetamine) is due to the lysine amino acid, with the other 3/10ths being dextroamphetamine. I believe I heard Dr. Huberman state that only about 1/10th or 10% of lisdexamfetamine is activated to dextroamphetamine.

Stimulant treatment:

• I would say very few patients being treated with stimulants for ADHD end up with dose decreases over time. From what I’ve seen in clinical practice, this would describe less than 10% of patients. Once the initial phase of treatment optimization is completed, it’s essential to have a solid justification for any subsequent dose increases. These could be tied to life changes that come with increased responsibilities, like advancing to the next academic level, earning a promotion, or transitioning into parenthood. However, a lack of sufficient sleep (which can present as worsening symptoms) should not be the impetus for a dose increase.
• The patients experiencing the most significant withdrawal effects from these medications are those with more substantial sleep deficits. Many patients with ADHD will intentionally not take their medications for a day, weekend, vacation, break from school, etc., and not experience any withdrawal effects. As a personal anecdote, I did not take my medication this year on Mother’s Day. We had a brunch scheduled for my wife, and I wasn’t sure if the prix fixe menu might have included a champagne toast. I did not want to risk even the potential of consuming alcohol in such close proximity to taking a stimulant medication.

guanfacine as Intuniv (guanfacine ER) or Tenex (guanfacine):

• guanfacine can be sedating, and obviously, alcohol can be as well.
• Taking both together increases the chance and degree of sedation; however, I have never heard of “even small amounts of alcohol can have severe consequences including death when combined with guanfacine.” I would certainly love to hear more or receive further information. This is not mentioned anywhere when thoroughly reviewing resources like Pubmed, DrugBank, Tenex (guanfacine), and Intuniv (guanfacine ER) prescribing information sheets. 
• I would think an interaction of that level would merit an FDA Black Box Warning, yet guanfacine does not have any such warnings.
• It’s worth adding guanfacine has had a pilot study demonstrating moderately good evidence as a potential treatment for Alcohol Use Disorder. The pilot study recommended further examination of guanfacine’s clinical efficacy in individuals; a clinical trial is ongoing. If researchers had concerns over the combination of guanfacine with even low doses of alcohol, it would be inconceivable for researchers to risk even a trial dose of guanfacine in patients suffering from alcohol use disorder.
• I would estimate that roughly half of the patients with Adult ADHD would benefit from adjunctive treatment with guanfacine, especially in the Intuniv (guanfacine ER) form. This medication tends to help with the other symptom clusters of ADHD, which are often glossed over, such as impulsivity, hyperactivity, mood regulation, and anxiety regulation. This includes patients diagnosed with Attention-Deficit Hyperactivity Disorder, Predominantly Inattentive Type. As the word predominantly indicates, most patients with Inattentive ADHD will still have lesser degrees of impulsive and hyperactive symptoms as compared to patients diagnosed with the Combined Type or especially the Hyperactive Type.

Non-stimulants:

• Beyond guanfacine, available as Intuniv (guanfacine ER) or Tenex (guanfacine), there are other non-stimulant medications for ADHD which can be effective. The most notable example of an effective, tolerable option is Qelbree (viloxazine ER). Strattera (atomoxetine) is also an option; however, this medication tends to have significant limitations in tolerability and effectiveness.

Eugeroic or Sleep-Wake Promoting medications:

• Provigil (modafinil) and Nuvigil (armodafinil) are considered eugeroic stimulants or wakefulness-promoting medications.
• From what I have seen in clinical practice, these medications are rarely (<5% of patients, by my estimate) the best treatments for patients with ADHD.
• Their cost is actually very affordable these days. Even without insurance coverage, a monthly supply could be as little as $5-70 via a medication savings card, such as GoodRx.

Brand vs. Generic stimulant medications:

• Unfortunately, the literature doesn’t cover this well, but there are significant differences between various generic formulations. This effect is magnified when you factor in the effect size of these medications.
• Let’s face it, store brand diet cola is not the same thing as Diet Coke. They’ve spent millions of dollars (if not more) to attempt to replicate the consistency and taste without perfection. 
• The FDA has even rescinded approval of certain generic stimulant medications. The best example that comes to mind is Mallincrodt’s formulation of Concerta (methylphenidate SR).
• It is customary in my practice to ask patients how they are doing with their medication. If applicable, we ask which generic they are taking and which generics they have done best with. We keep notes on which generics work best for patients individually and have a ranking of the different generic stimulant preparations.
• One particular patient example comes to mind. About a year ago, I was meeting with a patient for a follow-up appointment. We compared where his objective symptoms were via clinically validated scales at that June appointment vs. the prior a few months earlier. His symptoms of ADHD increased across the board. We reviewed everything relevant medically and related to his life, such as if there were any changes in his health, any added stress in life, work, etc., any changes in his diet, how he was taking his medication, and his overall sleep, among other things. Nothing had changed. So then I asked, “Do your pills look any different?” “Well, now that you mention it, they have been giving me a different version over the last 2 months.” The medicine was then prescribed in a way to ensure that he no longer received that generic formulation of his medication
• I’ll add that the Vyvanse (lisdexamfetamine) patent expires on August 24, 2023. I will definitely be working closely with my patients to see how they respond to various generic formulations as those start to become available in the fall of 2023 and as some insurance plans will no longer cover the brand version of Vyvanse (lisdexamfetamine) on their 2024+ formularies.

Dr. Huberman, thank you for all that you do for science, neuroscience, and educating the public on subject matters of great importance that are also near and dear to my heart.