There has been a lot of news recently about Sam Bankman, the onetime billionaire turned supervillain. At its peak, his company FTX had an in-house performance coach and psychiatrist named George K. Lerner. It’s unclear how many FTX employees Dr. Lerner treated but he did admit to treating some for ADHD and stated “the rate of ADHD at FTX was in line with most tech companies” whatever that means. I’m not here to debate the practices of the good doctor, but Bankman was known to talk publicly about experimenting with focus-enhancing medications. The main medications he allegedly used to become limitless were stimulants such as Adderall and the more interesting one to me and the topic of this week’s video the selegiline patch.

We are going to discuss selegiline in depth and try to understand why a medication primarily used to treat Parkinson’s may be useful for enhancing focus, creativity, and productivity in the fast-paced world of cryptocurrency. 

What is Selegiline?

Although many may not have heard of this medication, it’s actually a very old concept in psychiatry. A common “pimping” question in psychiatry residency is what was the first antidepressant medication? Most residents will say it was the tricyclic antidepressants which isn’t a bad guess but it’s not correct. The correct answer is the monoamine oxidase inhibitors (MAOIs) specifically iproniazid a failed treatment for tuberculosis. In 1952 researcher noted that patients receiving this medication became unusually happy, this was shocking considering the medication did nothing for their tuberculosis.

Transdermal selegiline is a tissue selective MAOI (MAO-A and MAO-B inhibitor in the brain) and a relatively selective MAO-B inhibitor in the gut. This is an important point, and I will explain more about it as we move through this topic. 

How Do MAOIs Work?

We are speaking about the transdermal selegiline patch here but there is also an oral version that is not approved for major depressive disorder and is a selective MAO-B inhibitor. 

The transdermal patch acts in the brain as an irreversible inhibitor of both MAO-A and MAO-B which are enzymes responsible for breaking down norepinephrine, serotonin, and dopamine which in turn will boost the noradrenergic, serotonergic, and dopaminergic neurotransmission. 

In lay terms this medication increases the availability of all three major neurotransmitters so that more serotonin, norepinephrine, and dopamine is available to act on post synaptic receptors affecting changes in cells and circuits involved in depression. 

FDA Approvals for Selegiline

This is a little complicated because news outlets have stated the medication is only used for Parkinson’s disease which is true if we are talking about the oral tablets. The transdermal patch is FDA approved for major depressive disorder. 

Off label use includes the treatment of treatment resistant depression, panic disorder, social anxiety (which MAOIs are usually superior at treating), treatment resistant anxiety, and Alzheimer’s disease. 

How to Dose Selegiline

The transdermal patch comes in various doses: 

• 6 mg/24 hours
• 9 mg/24 hours
• 12 mg/24 hours 

The initial dose for depression is 6 mg/24 hours and it can be increased by 3 mg/24 hours every 2 weeks to a maximum dose of 12 mg/24 hours. Dietary modification to restrict tyramine from food sources is not required for the 6 mg/24hr patch but at higher doses the same food restrictions are required as other oral MAOIs such as phenelzine. This will be important for our next discussion on side effects. 

Side Effects of Selegiline

Before starting the medication, the patient should be aware of the potential for increased blood pressure. 

Notable Side effects include 

• Skin reactions at the site of application (the location of the patch should be rotated daily) 
• Headaches
• Dry mouth 
• Diarrhea
• Insomnia
• Sedation
• Possible weight gain 

Serious side effects include: 

• Hypertensive Crisis 
• Seizure
• Induction of manic episodes in bipolar disorder 

Contraindications when combined with:

• Meperidine
• Another MAOI 
• SSRIs, SNRIs, TCAs, tramadol 
• Dextromethorphan
• St. John’s wort 
• Methadone
• History of Pheochromocytoma 
• Elective surgery 
• Proven allergy to selegiline 

The Dreaded Tyramine Reaction 

I believe that MAOIs might be the most effective of the antidepressants because of their ability to affect all three major neurotransmitter circuits, but they are rarely used clinically. In most residency training programs, we are not taught to use these medications. The main barrier is the dietary restrictions and risk for hypertensive crisis if the diet is not followed. 

This diet should be started a week or so before staring the medication. It allows the patient time to get accustomed to the dietary recommendations before being on the medication when the stakes are higher. The diet must be followed for 2 weeks after stopping the MAOI as it can take time for the MAO enzymes to regenerate due to irreversible inhibition. 

Tyramine is an amino acid that is found in some foods, and it helps to regulate blood pressure. MAOIs are responsible for breaking this amino acid down so it’s inactive and unable to causes an increase in blood pressure. When you block MAO excess tyramine will be available to affect blood pressure. 

Ingestion of a high tyramine meal is generally considered to be any meal with 40 mg or more in the fasted state. For the low dose transdermal patch 6 mg/24 hours studies show that 200-400 mg of tyramine in the fasted state is required for a hypertensive response. In general, at low doses dietary modification is not required. If the dose is increased to 12 mg/24 hours than 70-100 mg of tyramine is required for a hypertensive response. Although dietary modification may not be required at higher doses, it’s safer to avoid tyramine rich foods once the selegiline dose is increased and to be cautious at lower doses as well. 

Low Tyramine Diet Principles

When a patient is on an MAOI diet they should only eat things that are fresh. This goes for food that are stored as well as the storage process may affect the tyramine content. The patient should avoid foods that are beyond their expiration date and avoid fruits and vegetables that are overly ripe. Some cheeses are allowed in the diet, but all aged cheese should be avoided. The same can be said for meat products, fresh meats are fine, but aged or spoiled meats should be avoided. 

Fermented products need to be avoided when MAOIs are being used. This goes for all fermented products without exception. 

Chinese food and some other eastern foods should be avoided because they contain soy, shrimp paste, tofu, and soy sauces all of which are high in tyramine. 

Fava and other broad beans should be avoided this includes Italian green beans. 

Foods to Avoid

• Matured or aged cheeses (cheddar, and blue examples) 
• Meats: fermented or dry sausages (pepperoni, salami), aged, cured, unrefrigerated, pickled, smoked meats 
• Caviar, dried, pickled, or smoked fish 
• Overripe avocados, fava beans, sauerkraut, fermented soya bean, and soya bean paste 
• Overripe fruits: canned figs, banana peel, orange pulp 
• Beverages: chianti, sherry, liquors, all tap beers, unfiltered beer containing yeast 
• Soy products: soy sauce, tofu 
• Other: miso soup, yeast vitamin supplements, packaged soups 

Foods That are Allowed

• Cheeses: cream cheese, ricotta, fresh cottage cheese, mozzarella, processed cheese slices like American cheese 
• Milk Products: yogurt, sour cream, and ice cream 
• Meat: fresh packaged or processed meat e.g. hot dogs 
• Beverages: coffee, tea, soda, up to a maximum of 2 drinks either 12 oz of canned or bottled beer or 4 oz of red/white wine. 
• Soy products: soy milk 
• Other foods: chocolate in moderation and monosodium glutamate in moderation 

Onset of Action

The therapeutic effect is usually not immediate and still requires 2-4 weeks or longer once an adequate dose is reached. 

Augmentation

For expert psychopharmacologist Only: 

• You may consider a stimulant such as d-amphetamine, or methylphenidate while watching for increased blood pressure, suicidal ideation, and activation of bipolar disorder) 
• Lithium
• Seconded generation dopamine blocking medication 
• Mood stabilizing anticonvulsant 

Advantages to using MAOIs

• May be effective in treatment resistant depression 
• May improve atypical depressive symptoms such as hypersomnia and hyperphagia 
• Lower risk for weight gain and sexual side effects 

Why Would Selegiline Improve Cognitive function?

Selegiline will increase dopamine and more dopamine in the prefrontal cortex theoretically will enhance cognitive function. A lot of the research on MAOIs and cognitive enhancement come from studies in neurodegenerative disorders such as Alzheimer’s disease. While promising as reported in several articles it does not appear that proper randomized controlled trials were ever conducted. If you watch my videos than you should know the risk of assuming that something that should theoretically work will also work clinically. This is the story of many medications in psychiatry. We also cannot extrapolate that to healthy individuals who do not have neurodegenerative disorders.

Selegiline is metabolized to l-amphetamine, and l-methamphetamine which are well known stimulants that may improve symptoms of attention deficit hyperactivity disorder (ADHD). Again, this is theoretical and has never been proven but based on the metabolism of the medication it makes sense that it may enhance cognition in those with ADHD or even healthy individuals. 

People often forget that depression itself is a major reason for cognitive problems. Depression in elderly patients is sometimes referred to as pseudodementia because it can look like the individuals has substantial cognitive deficits in severe cases. It’s possible that the improvement in depressive symptoms is responsible for the enhanced cognitive function. 

Conclusion

I think this is a good discussion because it highlights an often-forgotten class of medication in modern psychiatry that can be utilized for patients who have failed other medication options. Many psychiatrists are untrained or too scared to use these medications clinically. As far as cognitive enhancement and finding that limitless pill, I do not think this is it. While it may theoretically improve cognitive function it’s never been proven in randomized controlled trials. I would say the evidence supporting this idea is weak and may even be dangerous given the risk for hypertensive crisis.