Antidepressants & Medical Marijuana: A Review


SSRI’s or Selective Serotonin Reuptake Inhibitors are the most commonly prescribed antidepressant. SSRIs work by directly raising levels of serotonin via binding to SERT(5-HTT) allowing more serotonin to fit between neurons- while also increasing ITGB3 protein activity. In short- SSRIs increase serotonin easing the feeling depression and making you feel “happy” or good.
SSRIs are typically metabolized by P450 as almost all medications but more specifically CYP2D6 which is responsible for an estimated 25% of drug metabolism.


SNRIs or Serotonin–norepinephrine reuptake inhibitors aremonoamine reuptake inhibitors; they inhibit the reuptake of serotonin and norepinephrine which are neurotransmitters critical for
regulating one’s mood. SNRIs are typically second line anti-depressants should patients not find relief while using SSRIs. Metabolism for SNRIs varies but is often done by 2D6/3A4 primarily.


Tricyclics exert their antidepressant effect by inhibiting nerve cells from reabsorbing serotonin and norepinephrine, which allows more of these substances to be available for use in the brain. These are usually metabolized by 2C19/2D6.


Monoanime Oxidase Inhibitors are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as powerful anti-depressants, as well as effective therapeutic agents for panic disorder and social phobia. MAOIs are not as commonly used but are still important to know.


MMJ or Medical Marijuana (Or Marijuana) is legal in 29-states in the U.S., and has been studied for various medicinal properties since the early 1600’s, with a Mental Handbook detailing it as a possible treatment for depression. (The Anatomy of Melancholy, Robert Burton). Since then it has been studied for ost availablecondition you can think of with fantastic efficacy results in addressing Epilepsy, Chronic/Neuropathic Pain, MS, etc.

MMJ is made up of several components the two most traditionally sought after/studied being THC & CBD- THC having the psychoactive, or inebriating effect often sought after while also encouraging appetite, assisting with inflammation, and more. CBD is non-psychoactive, having no inebriating effect and is highly studied for conditions mentioned above.

MMJ has been found to be an atypical potent inhibitor of several isoenzymes including CYP2D6, 3A4- and also has been found in appropriate dosages to work directly on 5-HT1A, TRPV1, and several other receptors.


Being MMJ is a potent CYP2D6 Inhibitor and works on 5-HT1A, and SSRIs are metabolized by CYP2D6 primarily, and work on 5-HTT- things can get complicated for TWO main reasons.
1.) Inhibiting 2D6 can increase plasma concentrations leading to varying adverse side effects depending on SSRI Prescribed
2.) Increasing serotonin can in rare cases lead to "Serotonin Syndrome" characterized most often by confusion, agitation, hyperthermia, myoclonus, and hyperreflexia.


In Dr. Ranga Chelva Krishna’s experience with SSRIs/SNRIs/TCIs and MMJ over a large patient population, significant adverse effects are NOT noted in any form or fashion.

Patients are carefully titrated to effective dosages for given conditions on a regimented, monthly basis adjusted per case.

Blood results were taken prior to starting the program, 1 month-after, 3 months-after, and 6-months after.

No negative changes noted, and patients reported no change in behavior, sleep, agitation, etc.

All patients reflexes/ROM/etc remained consistent with condition and prior noted levels. HOWEVER, it should be noted that outside parties HAVE reported more significant effects, including a
patient on Amitriptyline 25mg who combined with an unspecified dosage of marijuana did present with tachycardia. We believe this due to be CBD being an up regulator(Enhancing effects of metabolism) of 2C9 which is the main metabolizer of Amitriptyline converting it to its metabolite Nortriptyline. One of Nortriptyline’s main listed side-effects is tachycardia. With such, due to the up regulation the Amitriptyline was hyper metabolized, leading to presentation of this side effect.

More information can be found at

Personal Titration Format

For those interested in a titration format:

Sublingual dosing of 15 MG/DAILY separated into 3 dosing periods Breakfast/Lunch/Dinner. (Can take as two doses if preferred.) Monitor for efficacy as well as adverse effects for 7-days. If reporting & improvement, titrate dosage up to 20MG/DAILY, and monitor for efficacy/adverse effects for 7-days.

Continue this dosing schedule moving up to a maximum of 50MG/DAILY. If patient opts for capsules/edibles/vape, then further adjustment is necessary.

Please NOTE: Anything discussed is purely based on Dr. Ranga Krishna’s experience with CBD/MMJ & Antidepressants and is not in any shape/form a guarantee or an official medical recommendation. Every case is different, and it is always encouraged you seek advice from your primary doctor or another specialist who is aware of your history before proceeding. Dr. Ranga Chelva Krishna is a board certified Neurologist & Pain Specialist with focuses in Epilepsy, Stroke, TBI and Medical Marijuana. Dr. Ranga Chelva Krishna is also a licensed NY MMJ program prescriber since initiation in 2015.


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