Migraine treatments

Migraine treatments discusses, compares, and contrasts all of the new abortive and preventive migraine treatments as they become available, as well as older treatments. It discusses new medications, as well as neuromodulatory devices.

Last updated on October 21st, 2020 at 09:54 am




Aimovig vs. Ajovy, Aimovig vs. Emgality, Aimovig vs Vyepti, Ajovy vs. Emgality, Emgality vs. Vyepti, Ajovy vs. Vyepti. So many questions. so many answers. Let’s discuss them all. So it finally happened! The 1st migraine specific preventive medications FINALLY became available with the CGRP (calcitonin gene related peptide) monoclonal antibody (CGRP mAb) antagonists which first came to market in 2018. Prior to 2018, all of the migraine preventive medication options had been “adopted” from other specialties. For example, the 3 main categories of preventive medicines prior to 2018 were select evidence-based options within the anticonvulsant (antiseizure), antidepressant/antianxiety, and antihypertensive (blood pressure) medicine categories. These conventional migraine preventive treatments are certainly still used, can be very effective, and are discussed in much greater detail here. Migraine preventive therapies also include nutraceuticals and natural treatments, and neuromodulatory devices. This blog article will discuss and compare the 4 new options of CGRP mAb medications; Aimovig (Erenumab), Ajovy (Fremanezumab), Emgality (Galcanezumab), and Vyepti (Eptinezumab).

CGRP plays a strong role in neurogenic inflammation in the nervous system and is involved in the transmission of pain. It is also a potent vasodilator (dilates blood vessels), and increases overexcitability of neurons, both factors of which increase the intensity of migraine pain. CGRP has been studied since the early 1980s when it was discovered. It was found throughout the trigeminovascular system and trigeminal cranial nerves which transmit pain, so a role in migraine was suspected. The trigeminal nerves and their associated electrical circuitry throughout the brain, brainstem, and arteries in the brain is called the trigeminovascular system. This system is the basis and “on switch” for migraine. In the early 1990s it was shown that CGRP was released by the trigeminal nerves and levels increased during an acute migraine attack. In 2004, a CGRP antagonist (blocks the binding of CGRP to its receptor) was shown to abort an acute migraine attack, and decrease CGRP levels. Subsequent studies including preventive migraine studies done since 2014 with a CGRP antibody to block the effects of CGRP eventually led to 3 FDA approved CGRP mAbs in 2018, and a 4th CGRP mAb FDA approved in 2020.


How are the CGRP mAbs made and what is the science behind them?

The CGRP mAbs are considered biologic drugs because they are made by the cells of living organisms. This is in contrast to conventional medications made by chemical synthesis. The 4 CGRP mAbs are all classified as “humanized” monoclonal antibodies. Humanized CGRP mAbs are made in a laboratory by combining part of a human antibody with a small part of a non-human (such as hamster or yeast) monoclonal antibody by a process called recombinant DNA technology. The non-human part of the antibody binds to the target antigen (in this case, either the CGRP ligand (protein) or CGRP receptor), and the human part makes it less likely to be seen as a “foreign antigen” destroyed by our immune system. To explain further, these humanized CGRP mAbs are produced and cloned repeatedly in non-human immune system living cells (hamster ovarian cells or yeast cells), ensuring that they are all of identical genetic material (monoclonal), and their protein structure is modified to increase their similarity to antibody structures produced naturally in humans.

As a review, antibodies are proteins made by living organism cells which bind unique parts of other proteins that are recognized as a “foreign” to that biologic system. For example, when your body is exposed to a virus or bacteria by infection or immunization, your body makes specific antibodies against that microbe to destroy it. If your body encounters that microbe in the future, it remembers it (immune response), and your antibodies attach to it to neutralize and destroy it.


How do the CGRP mAbs work for migraine?

The CGRP mAbs target either the CGRP receptor and block it (antagonist) to prevent the CGRP ligand (protein) from binding, or they target the CGRP ligand itself and prevent it from binding (sticking) to the CGRP receptor. Clinically, some patients tend to respond better to the CGRP receptor blockade, whereas others tend to do better with binding the CGRP ligand itself. There is not really any data on this in terms of who may respond to which type of CGRP mAb target, but I’m sure it will be studied further eventually. In general, the CGRP mAbs tend to all be quite effective. However, the point is if one type of CGRP mAb doesn’t work, it doesn’t mean the others won’t work either. I have seen many patients who did not respond to one type of CGRP mAb, but responded dramatically well to another. So, if you do not respond to one type of CGRP mAb target (such as the CGRP receptor), it may be worth trying another type of CGRP mAb target (such as the CGRP ligand). The bottom-line is don’t lose hope if one type doesn’t work well for you!

The CGRP mAbs are administered by injection or infusion because oral absorption is poor and degradation in the gastrointestinal system would inactivate the antibodies before they would even be able to enter the circulatory system. They are systemically absorbed by transport through the lymphatic system and into the blood. Metabolism occurs in the reticuloendothelial system, not the liver or kidneys.


How effective are the CGRP mAbs?

All 4 of the CGRP mAbs have shown excellent tolerability, safety, and superior effectiveness in migraine prevention when compared to placebo. Compared to oral preventive therapies which have been the mainstay for decades (discussed here), the CGRP mAbs work much faster and do not require a slow dose titration, as is done with most oral preventives. They are sometimes seen to be effective in just a few days, often within a month, and the data suggests that the longer a patient is on a CGRP mAb, the more effective it is. I typically recommend a minimum of at least 3 months, and if receiving some benefit at that point, at least 6 months is suggested.

The majority of CGRP mAb studies had at least 50% (half) of patients who were 50% responders (migraine days cut in half), which is great! In general, the CGRP mAbs provide an overall average net reduction of around 2 migraine days per month for episodic migraine and 4-6 days for chronic migraine. With that said, this number can be much higher depending on the patient and migraine characteristics being studied, such as baseline migraine frequency.

There are a group of patients that we see called “super responders” because they improve dramatically to having greater than 75% decrease in migraine days, and sometimes even no migraines. In the CGRP mAb studies, about 1/3rd of patients were “super responders”, with many them obtaining 100% reduction in migraine days. Although this is wonderful to see when it happens, it should not be the expectation or goal (nor should this be the goal with any preventive migraine treatment).


What are the CGRP mAb side effects and are they safe in pregnancy and breastfeeding?

Side effects are minimal, and very similar to placebo in most of the studies, which is great compared to the frequent side effects seen with most of the oral preventive pills we often use. The most common side effects are listed in the table below, but mild injection site reactions tend to be the most common reported side effect among the 3 subcutaneous self-injection CGRP mAbs. Cumulative data show no immunological (they do not suppress or alter the immune system because they do not have a target within the immune system), cardiovascular, or neurological safety concerns of significance. CGRP is suspected to play a possible role in regulating uteroplacental blood flow, myometrial and uterine relaxation, and in maintaining normal gestational blood pressure. Since the mAbs have a long half-life and can last in the system for 5 months, it is recommended to stop it about 6 months prior to pregnancy planning. The CGRP mAbs are also not recommended to use during breast-feeding since we do not have enough safety data at this time.


Can I use a CGRP mAb with Botox injections or with the gepants (Nurtec, Ubrelvy)?

Insurance companies often present various hurdles to using preferred treatment options (the bane of my existence). One common issue for patients with chronic migraine who are receiving Botox injections is that most insurance companies will now make the patient choose between Botox or the CGRP mAb. There is of course no good scientific basis for this, other than the company doesn’t want to pay for both. In fact, there is evidence that using Botox with the CGRP mAbs works better together than with either individually. An abstract presented at the American Headache Society Annual Scientific meeting in June 2020 showed that in patients with chronic migraine and a baseline frequency of 25.7 days per month, the frequency dropped to 14.8 days with Botox, and 9.1 days with Botox plus a CGRP mAb.

A similar insurance battle often ensues when trying to use the large molecule preventive CGRP mAbs with the small molecule abortive gepant medications (Nurtec, Ubrelvy), which also work by a CGRP mechanism. Insurance companies will often not allow these to be used together, but again, no good scientific basis. Actually, there is some limited evidence showing that these medications can work synergistically together, which would make sense when taking their mechanisms of action into account. Specifically, there was a publication of data from only a 2-patient cohort showing that the use of these acute and preventive CGRP migraine therapies together can be successful and safe. These two patients had been using rimegepant (Nurtec) in a long-term safety study and had added erenumab (Aimovig). The combination of both successfully aborted 100% of their acute migraine attacks. Certainly we need need larger studies to confirm the suspicion that they likely work together synergistically.

The bottom line is that the CGRP mAbs as a class are all very effective for the majority of patients. Ultimately, the one prescribed will often depend on insurance formulary preferences, but there are no “bad options” among them!


Clinical comparisons of the CGRP mAbs

There are currently 4 CGRP mAbs available, and each is detailed and compared below in order of FDA approval and becoming available for use. There are some characteristics for each one which can be used to fine tune selection based on specific patient clinical perspectives.


Aimovig (Erenumab)

Aimovig was the first of the CGRP mAbs to come on the scene. It is made by Amgen and was FDA approved for migraine prevention 5/17/18. The antibody is produced by recombinant DNA technology in Chinese hamster ovary cells. It is the only one thus far which targets the CGRP receptor rather that the CGRP ligand (protein) itself. Therefore, it binds to the receptor, blocking the ability of the CGRP ligand to bind to the receptor and activate the migraine. It is dosed by either a 70 mg or 140 mg once monthly subcutaneous autoinjector. Since Aimovig came out first, we have longer term data available for it. At close to 5 years on the 140 mg dose, 77% of patients had a 50% reduction in monthly migraine days, 56% of patients had a 75% reduction in monthly migraine days, and 33% of patients had a 100% reduction in monthly migraine days. The dose can be administered to the abdomen, arm, buttocks, or thigh areas.

In post-marketing observations, there have been some reports of hypersensitivity reactions (rash, allergic reactions, itching) in which most were not serious and occurred within hours of administration, and up to 1 week after. Constipation was noted in the studies to occur in a very small percentage (1% for 70 mg, 3% for 140 mg). In post-marketing observations, there have been further reports of constipation with serious complications as well. Constipation occurs after the first dose in the majority of patients who will have this side effect (keep in mind the vast majority do not). Regardless, if you already have problems with constipation, I typically suggest trying one of the other CGRP mAbs (although it doesn’t mean it still can’t be tried). Post-marketing observations have also shown some worsening of pre-existing hypertension or development of hypertension. This observation was most frequently reported within 7 days of administration. Most of these patients already had pre-existing hypertension, or risk factors for developing it.


Ajovy (Fremanezumab)

Ajovy was the 2nd of the CGRP mAbs to come along. It is made by Teva and was FDA approved for migraine prevention 9/14/18. It is produced by recombinant DNA technology in Chinese hamster ovary cells. It targets the CGRP ligand, rather than the CGRP receptor. It binds to the CGRP ligand, interfering with its ability to bind to the CGRP receptor and activate the migraine. It is dosed by either a 225 mg once monthly or 675 mg once quarterly autoinjector or syringe. The dose can be administered to the abdomen, arm, buttocks, or thigh areas. There have been some reports of hypersensitivity reactions (rash, allergic reactions, itching) as well, typically mild to moderate and occurred hours to 1 month after administration. Ajovy has the least potential for constipation, so if that is an ongoing significant issue for a patient, then I typically suggest trying Ajovy first. Ajovy also has the longest half-life, so if the patient tends to wear off early towards the end of the month, it may help to extend relief closer to the next monthly injection.

Of note, in the Ajovy chronic migraine studies, all patients receiving medication were given a loading dose of 675 mg for dose 1 followed by the standard 225 mg each subsequent month. However, this is not how it is normally dosed clinically for patients doing monthly treatments of 225 mg (no loading dose). Therefore, this initial loading dose could have potentially influenced some of the subsequent data.


Emgality (Galcanezumab)

Emgality was the 3rd of the CGRP mAbs to come along. It is made by Eli Lilly and was FDA approved for migraine prevention 9/26/18. Notably, it is the only one which also has FDA approval for prevention of episodic cluster headache, which was received on 6/4/19. It is produced by recombinant DNA technology in Chinese hamster ovary cells. It targets the CGRP ligand, rather than the CGRP receptor. Thus, it binds to the CGRP ligand, interfering with its ability to bind to the CGRP receptor and activate the migraine. It is dosed by a 240 mg subcutaneous autoinjector for the 1st month only, followed by a 120 mg once monthly injection thereafter. The higher initial loading dose allows for obtaining a rapid steady state concentration level in the blood compared to Aimovig and Ajovy. The dose can be administered to the abdomen, arm, buttocks, or thigh areas. There have been some reports of hypersensitivity reactions (rash, allergic reactions, itching) as well.


Vyepti (Eptinezumab)

Vyepti was the 4th and most recent of the CGRP mAbs to become available. It is made by Lundbeck and was FDA approved for migraine prevention 2/21/20. The antibody is produced in Pichia pastoris yeast cells by recombinant DNA technology. It targets the CGRP ligand, rather than the CGRP receptor. It binds very strongly to the CGRP ligand, interfering with its ability to bind to the CGRP receptor and activate the migraine. It comes in 100 mg and 300 mg doses and is dosed once quarterly (every 3 months) by a quick 30-minute infusion. The 100 mg dose is the recommended starting dose which can be titrated as needed to the higher dose later.

This is the only intravenous (IV) option available. Since it is administered IV, it is 100% bioavailable compared to the bioavailability of the other subcutaneous injections of 50-82%. It also reaches Cmax (maximum concentration) in about 30 minutes compared to 5-7 days of the other subcutaneous injections. Therefore, not surprisingly Vyepti showed treatment benefit in the first 7 days, often as early as 1 day post treatment, and showed continued effect through week 4, which is great since many patients on the once monthly self-injection CGRP mAbs often report a wearing off effect as they are approaching their next due injection.

This is certainly a good first line consideration, but also a good option for patients who do not like the thought of giving themselves a once monthly shot, have injection site reactions, or have failed the other CGRP mAbs options. Studies have shown some impressive highlights compared to other mAbs. In both the chronic and episodic migraine studies, almost 31% of patients had 75% or more reduction in migraine days in the 1st month alone. In the chronic migraine studies, about 27% of patients had a 75% or more reduction in migraine days over the first 3 months with 100 mg. After the 2nd dose (months 4-6), this increased to over 39% of patients! In the episodic migraine studies, over 22% of patients had a 75% or more reduction in migraine days over the first 3 months with 100 mg. After the 2nd dose (months 4-6), this increased to over 33.5% of patients.


Data comparisons of the CGRP mAbs

The comprehensive table which follows compares all available data between the 4 CGRP mAbs, as I have compiled from a combination of published studies, scientific posters, and supplemental data provided from medical science liaisons from each company. I have highlighted some of the data throughout the table when it is a unique aspect or superior response in that category. All 4 CGRP mAbs have variable highlights that makes them stand out from the others in various categories, but overall they are all very effective options as a medication class. It is important to realize that the data compiled in the table should not be considered as a direct head to head comparison between the medications, and not all data points were looked at for each drug. For each CGRP mAb, there were variations and differences in many trial aspects such as the study designs, how responder rates were calculated, statistical analysis used, trial endpoints, some responses were based on open label portions of trials (in which patients typically report a higher response rate when they know they are receiving the drug and not placebo), varying definitions such as “headache of at least moderate severity”, what defined a “headache” or “migraine day”, preventive medications being used simultaneously, and baseline migraine frequencies included in the studies. The extent of reduction in migraine days can be influenced by the patient’s baseline migraine frequency in both the episodic and chronic migraine studies (high frequency vs lower frequency). For example, some studies included patients with a much higher baseline migraine frequency, and thus the extent of their migraine day reduction may not be as great as a group studied with a lower baseline frequency to start with.


  Aimovig (Erenumab) Ajovy (Fremanezumab) Emgality (Galcanezumab) Vyepti (Eptinezumab)
Dosing 70 mg or 140 mg once monthly by subcutaneous autoinjector 225 mg once monthly or 675 mg once quarterly by autoinjector or syringe 240 mg subcutaneous autoinjector for 1st month followed by 120 mg monthly 100 mg or 300 mg quarterly by 30-minute intravenous (IV) infusion
Target CGRP receptor CGRP ligand CGRP ligand CGRP ligand
Half-life 28 days 31 days 27 days 27 days
Median Peak Serum Concentration 6 days 5-7 days 5 days 30 minutes (after infusion)
Steady State 3 months 168 days (6 months) After the 240 mg loading dose After 1st dose
Bioavailability 82% 54-57% N/A 100%
Episodic migraine: Reduction in mean monthly migraine days in month 1 70 mg: -2.32 days

140 mg: -2.72 days Placebo: -0.9 days

675 mg quarterly: -3.3 days

225 mg monthly: -3.5 days

Placebo: -1.7 days

Episodic migraine: Reduction in mean monthly migraine days in months 1-3 N/A 675 mg quarterly: -3.7 days

225 mg monthly: -3.4 days

Placebo: -2.2 days


*Months 1-3 in long term extension study (open label):

675 mg quarterly: -4.7 days

225 mg monthly: -4.8 days

120 mg monthly: -4.1 days

Placebo: -2.1 days

100 mg: -3.9 days

300 mg: -4.3 days

Placebo: -3.2 days

Episodic migraine: Reduction in mean monthly migraine days in months 4-6 70 mg: -3.2 +/- 0.2 days

140 mg: -3.7 +/- 0.2 days

Placebo: -1.8 +/- 0.2 days

N/A 120 mg monthly: -5 days

Placebo: -3 days

100 mg: -4.5 days

300 mg: -4.8 days

Placebo: -3.8 days

Episodic migraine: Reduction in mean monthly migraine days in months 1-6 N/A 675 mg quarterly: -5 days

225 mg monthly: -4.9 days


*months 1-3 placebo, months 4-6 open label

120 mg: -4.3-4.7 days

Placebo: -2.3-2.8 days

Episodic migraine: Reduction in mean monthly migraine days in months 1-12 70 mg: -4.22 +/- 0.22 days

140 mg: -4.64 +/- 0.19 days

Placebo: -1.8 days

675 mg quarterly: -5.2 days

225 mg monthly: -5.1 days


*months 1-3 placebo, months 4-12 open label

120 mg: -5.13 days


*12 month safety study with no placebo

100 mg: -4.6 days

300 mg: -5.2 days

Placebo: -4 days


*Reported as months 7-12

Episodic migraine:

50% or more reduction in migraine days in month 1

70 mg: 32.7%

140 mg: 35.5% Placebo: 15.5%

675 mg quarterly: 44%

225 mg monthly: 47% Placebo: 25%


120 mg: 50.8%

Placebo: 23.7%

100 mg: 59.3%

300 mg: 56.3%

Placebo: 40.5%

Episodic migraine:

50% or more reduction in migraine days in months 1-3

70 mg: 41.3%

140 mg: 48.1% Placebo: 26.3%

675 mg quarterly: 44.4%

225 mg monthly: 47.7% Placebo: 27.9%


*At month 3 alone (not averaged over months 1-3):

675 mg quarterly: 49%

225 mg monthly: 51% Placebo: 37%


*At month 3 in long term extension study (open label):

675 mg quarterly: 59%

225 mg monthly: 61%

120 mg: 55%

Placebo: 32%


*At month 2 alone:

120 mg: 54.1%

Placebo: 34.5%


*At month 3 alone:

120 mg: 57.7%

Placebo: 37.9%



100 mg: 49.8%

300 mg: 56.3%

Placebo: 37.4%

Episodic migraine:

50% or more reduction in migraine days in months 4-6

70 mg: 43%

140 mg: 50%

Placebo: 26.6%

N/A 120 mg: 67%

Placebo: 43%


*At month 4 alone:

120 mg: 65.2%

Placebo: 41.9%


*At month 5 alone:

120 mg: 68.6%

Placebo: 43.7%


*At month 6 alone:

120 mg: 66%

Placebo: 44.8%

100 mg: 62%

300 mg: 65.3%

Placebo: 51.4%

Episodic migraine:

50% or more reduction in migraine days in months 1-6

N/A 675 mg quarterly: 65%

225 mg monthly: 60%


*months 1-3 placebo, months 4-6 open label, data is at month 6

120 mg: 59.3-62.3% days

Placebo: 36-38.6%

Episodic migraine:

50% or more reduction in migraine days in months 1-12

70 mg: 61%

140 mg: 64.9% Placebo: N/A

675 mg quarterly: 66%

225 mg monthly: 68%


*months 1-3 placebo, months 4-12 open label, data is at month 12

N/A 100 mg: 64.7%

300 mg: 69.4%

Placebo: 55.9%


*Reported as months 7-12

Episodic migraine:

75% or more reduction in migraine days in month 1

N/A 675 mg quarterly: 20%

225 mg monthly: 22% Placebo: 10%


120 mg: 25.7%

Placebo: 6.5%


100 mg: 30.8%

300 mg: 31.5%

Placebo: 20.3%

Episodic migraine:

75% or more reduction in migraine days in months 1-3

N/A 675 mg quarterly: 18.4%

225 mg monthly: 18.5% Placebo: 9.7%


*At month 3 alone (not averaged over months 1-3):

675 mg quarterly: 30%

225 mg monthly: 29% Placebo: 10%

120 mg: 30%

Placebo: 14%


*At month 2 alone:

120 mg: 31.2%

Placebo: 11%


*At month 3 alone:

120 mg: 34.2%

Placebo: 12.8%

100 mg: 22.2%

300 mg: 29.7%

Placebo: 16.2%

Episodic migraine:

75% or more reduction in migraine days in months 4-6

70 mg: 20.8%

140 mg: 22%

Placebo: 7.9%

N/A 120 mg: 42%

Placebo: 24%


*At month 4 alone:

120 mg: 41.6%

Placebo: 15.2%


*At month 5 alone:

120 mg: 41.4%

Placebo: 15.5%


*At month 6 alone:

120 mg: 43.9%

Placebo: 15.8%

100 mg: 33.5%

300 mg: 40.1%

Placebo: 24.8%

Episodic migraine:

75% or more reduction in migraine days in months 1-6

N/A 675 mg quarterly: 39%

225 mg monthly: 37%


*months 1-3 placebo, months 4-6 open label, data is at month 6

120 mg: 33.5-38.8%

Placebo: 17.8%-19.3%


Episodic migraine:

75% or more reduction in migraine days in months 1-12

70 mg: 38.5%

140 mg: 40.8% Placebo: N/A

675 mg quarterly: 42%

225 mg monthly: 45%


*months 1-3 placebo, months 4-12 open label, data is at month 12

N/A 100 mg: 41.2%

300 mg: 47.7%

Placebo: 32%


*Reported as months 7-12

Episodic migraine:

100% reduction in migraine days in month 1

N/A 675 mg quarterly: 5%

225 mg monthly: 8% Placebo: 2%


120 mg: 8.8%

Placebo: 2.2%


100 mg: 8.6%

300 mg: 14.9%

Placebo: 5.9%

Episodic migraine:

100% reduction in migraine days in months 1-3

N/A 675 mg quarterly: 0.7%

225 mg monthly: 2.4% Placebo: 0%


120 mg: 11%

Placebo: 4%


*At month 2 alone:

120 mg: 11.8%

Placebo: 3.7%


*At month 3 alone:

120 mg: 12.2%

Placebo: 7.3%

100 mg: 11.4%

300 mg: 16.8%

Placebo: 9.1%

Episodic migraine:

100% reduction in migraine days in months 4-6

70 mg: 3.2%

140 mg: 5%

Placebo: 2.8%

N/A 120 mg: 17%

Placebo: 9%


*At month 4 alone:

120 mg: 16.3%

Placebo: 8.5%


*At month 5 alone:

120 mg: 17.6%

Placebo: 8.7%


*At month 6 alone:

120 mg: 16.5%

Placebo: 9.5%

100 mg: 19.8%

300 mg: 24.5%

Placebo: 14.3%

Episodic migraine:

100% reduction in migraine days in months 1-6

N/A 675 mg quarterly: 18%

225 mg monthly: 20%


*months 1-3 placebo, months 4-6 open label, data is at month 6

120 mg: 11.5-15.6%

Placebo: 5.7-6.2%


Episodic migraine:

100% reduction in migraine days in months 1-12

70 mg: 19.8%

140 mg: 21.2% Placebo: N/A

675 mg quarterly: 17%

225 mg monthly: 21%


*months 1-3 placebo, months 4-12 open label, data is at month 12

N/A 100 mg: 26.8%

300 mg: 30.6%

Placebo: 20.5%


*Reported as months 7-12

Chronic migraine: Reduction in mean monthly migraine days in month 1 70 mg: -5 +/- 0.42 days

140 mg: -5.1 +/- 0.42 days

Placebo: -2.7 +/- 0.34 days

675 mg quarterly: -4.8 days

225 mg monthly: -4.7 days

Placebo: -2.7 days

120 mg: -4.06

Placebo: -1.78


Chronic migraine: Reduction in mean monthly migraine days in months 1-3 70 mg: -6.6 +/- 0.4 days

140 mg: -6.6 +/- 0.4 days

Placebo: -4.2 +/- 0.4 days

675 mg quarterly: -5 days

225 mg monthly: -4.9 days

Placebo: -3.2 days


*Months 1-3 in long term extension study (open label):

675 mg quarterly: -6 days

225 mg monthly: -6.7 days

120 mg: -4.8 days

Placebo -2.7 days


*At month 2 alone:

120 mg: -5.01

Placebo: -3.04


*At month 3 alone:

120 mg: -5.41

Placebo: -3.39

100 mg: -7.7 days

300 mg: -8.2 days

Placebo: -5.6 days

Chronic migraine: Reduction in mean monthly migraine days in months 4-6 N/A N/A N/A 100 mg: -8.2 days

300 mg: -8.8 days

Placebo: -6.2 days

Chronic migraine: Reduction in mean monthly migraine days in months 1-6 N/A 675 mg quarterly: -6.5 days

225 mg monthly: -7.6 days


*months 1-3 placebo, months 4-6 open label

Chronic migraine: Reduction in mean monthly migraine days in months 1-12 70 mg: -8.5 days

140 mg: -10.5 days

Combined 70 mg and 140 mg: -9.3 days

Placebo: N/A

675 mg quarterly: -7.2 days

225 mg monthly: -8 days


*months 1-3 placebo, months 4-12 open label

120 mg: -7.21


*12 month safety study with no placebo

Chronic migraine:

50% or more reduction in migraine days in month 1

70 mg: 23.9%

140 mg: 28.3% Placebo: 11.4%

675 mg quarterly: 33%

225 mg monthly: 36%

Placebo: 19%

120 mg: 26.4%

Placebo 11%


100 mg: 54.5%

300 mg: 60.6%

Placebo: 36.1%

Chronic migraine:

50% or more reduction in migraine days in months 1-3

70 mg: 40%

140 mg: 41%

Placebo: 23%

675 mg quarterly: 30.7%

225 mg monthly: 33.3%

Placebo: 19.9%


*At month 3 alone (not averaged over months 1-3):

675 mg quarterly: 37%

225 mg monthly: 39% Placebo: 25%


*At month 3 in long term extension study (open label):

675 mg quarterly: 42%

225 mg monthly: 48%

120 mg: 27.6%

Placebo 15.4%


*At month 2 alone:

120 mg: 30.7%

Placebo: 17.7%


*At month 3 alone:

120 mg: 35.2%

Placebo: 24.7%


100 mg: 57.6%

300 mg: 61.4%

Placebo: 39.3%

Chronic migraine:

50% or more reduction in migraine days in months 4-6




100 mg: 61%

300 mg: 64%

Placebo: 44%

Chronic migraine:

50% or more reduction in migraine days in months 1-6

N/A 675 mg quarterly: 44%

225 mg monthly: 54%


*months 1-3 placebo, months 4-6 open label, data is at month 6

N/A, however:


*At month 6 in open label extension trial:

120 mg: 44.5%

Chronic migraine:

50% or more reduction in migraine days in months 1-12

70 mg: 53.3%

140 mg: 67.3%

Combined 70 mg and 140 mg: 59%

Placebo: N/A

675 mg quarterly: 53%

225 mg monthly: 57%


*months 1-3 placebo, months 4-12 open label, data is at month 12

N/A, however:


*At month 9 in open label extension trial:

120 mg: 53.9%


*At month 12 in open label extension trial:

120 mg: 56.9%

Chronic migraine:

75% or more reduction in migraine days in month 1

N/A Month 1 in long term extension study (open label):

675 mg quarterly: 21%

225 mg monthly: 21%

N/A 100 mg: 30.9%

300 mg: 36.9%

Placebo: 15.6%

Chronic migraine:

75% or more reduction in migraine days in months 1-3

70 mg: 17%

140 mg: 20.9% Placebo: 7.8%

675 mg quarterly: 9.6%

225 mg monthly: 12.3%

Placebo: 5.4%


*At month 3 in long term extension study (open label):

675 mg quarterly: 20%

225 mg monthly: 24%

120 mg: 7%

Placebo 4.5%


100 mg: 26.7%

300 mg: 33.1%

Placebo: 15%

Chronic migraine:

75% or more reduction in migraine days in months 4-6

N/A N/A N/A 100 mg: 39.3%

300 mg: 43.1%

Placebo: 23.8%

Chronic migraine:

75% or more reduction in migraine days in months 1-6

N/A 675 mg quarterly: 28%

225 mg monthly: 24%


*months 1-3 placebo, months 4-6 open label, data is at month 6

N/A, however:


*At month 6 in open label extension trial:

120 mg: 21.7%

Chronic migraine:

75% or more reduction in migraine days in months 1-12

70 mg: 27.1%

140 mg: 41.8%

Combined 70 mg and 140 mg: 33.2%

Placebo: N/A

675 mg quarterly: 28%

225 mg monthly: 31%


*months 1-3 placebo, months 4-12 open label, data is at month 12

N/A, however:


*At month 9 in open label extension trial:

120 mg: 27.9%


*At month 12 in open label extension trial:

120 mg: 31.1%

Chronic migraine:

100% reduction in migraine days in month 1

N/A Month 1 in long term extension study (open label):

675 mg quarterly: 6%

225 mg monthly: 5%

N/A 100 mg: 7.9%

300 mg: 13.4%

Placebo: 2.7%

Chronic migraine:

100% reduction in migraine days in months 1-3

70 mg: 4.3%

140 mg: 2.7%

Placebo: 0.4%

675 mg quarterly: 5.3%

225 mg monthly: 4.5%

Placebo: 4%


*At month 3 in long term extension study (open label):

675 mg quarterly: 5%

225 mg monthly: 6%

120 mg: 0.7%

Placebo 0.5%


100 mg: 10.8%

300 mg: 15.1%

Placebo: 5.1%

Chronic migraine:

100% reduction in migraine days in months 4-6

N/A N/A N/A 100 mg: 17.8%

300 mg: 20.8%

Placebo: 9.3%

Chronic migraine:

100% reduction in migraine days in months 1-6

N/A 675 mg quarterly: 8%

225 mg monthly: 8%


*months 1-3 placebo, months 4-6 open label, data is at month 6

Chronic migraine:

100% reduction in migraine days in months 1-12

70 mg: 6.1%

140 mg: 12.7%

Combined 70 mg and 140 mg: 8.9%

Placebo: N/A

675 mg quarterly: 9%

225 mg monthly: 10%


*months 1-3 placebo, months 4-12 open label, data is at month 12

Side effects:


70 mg: 3-9.9%

140 mg: 2-11%

Placebo 6-10%

675 mg quarterly: 5-8%

225 mg monthly: <1-8%

Placebo: 4-9%

120 mg: 7.4%

Placebo: 6.5%

100 mg: 6%

300 mg: 8%

Placebo: 6%

Side effects:

Hypersensitivity reactions

70 mg: <1%

140 mg: <1%

Placebo : <1%

675 mg quarterly: <1%

225 mg monthly: <1%

Placebo: <1%

120 mg: 1%

Placebo: 1%

100 mg: 1%

300 mg: 2%

Placebo: 0%

Side effects:


70 mg: 1%

140 mg: 3%

Placebo 1%

675 mg quarterly: <1%

225 mg monthly: <1%

Placebo: <1%

120 mg: 1%

Placebo: <1%

100 mg: <1%

300 mg: <1%

Placebo: <1%

Side effects:

Cramps, muscle spasms

70 mg: <1%

140 mg: 2%

Placebo <1%

675 mg quarterly: <1%

225 mg monthly: <1%

Placebo: <1%

120 mg: <1%

Placebo: <1%

100 mg: <1%

300 mg: <1%

Placebo: <1%

Side effects:

Injection site reactions

70 mg: 6%

140 mg: 5%

Placebo 3%

675 mg quarterly: 18-19%

225 mg monthly: 23%

Placebo: 4%

120 mg: 18%

Placebo: 13%



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Last updated on October 20th, 2020 at 06:49 am




Migraine is a very disruptive disorder to have to deal with. It interferes with patients’ family, work, and social lives. When the burden of migraine becomes excessive on one or more of these life aspects, preventive migraine therapy should be used. In general, if someone is averaging more than 4 migraines per month, preventive treatment should be offered and discussed, although this number is not an absolute. For example, if someone has 1 migraine per month, but it wipes them out for 1 week and they are missing work, there are certainly variations on when preventive medications should be considered, such as this scenario. If the decision to use a preventive migraine medication has been made, there are several important factors to keep in mind in order to optimize treatment success, as discussed below.



Any preventive medication needs an adequate “therapeutic trial”. In short, you need to be patient and give it enough time to work, as well as get to the correct dose. I see patients all the time that tell me their doctor put them on a medication (usually at too low of a dose), and they stopped it after 3 weeks because it “wasn’t doing anything”. Well, it’s not going to do anything that soon, and that is too early to expect any significant improvement. In general, any preventive medication needs 4-6 weeks to begin working, and 2-3 months until full effect is seen (assuming a good dose has been reached). Unfortunately, there is no way to expedite this process. That doesn’t mean the treatment can’t work sooner. However, that is the standard duration of treatment for a medication to have had a fair trial. Finding a migraine preventive is often a trial and error process. If one treatment is not starting to help by at least 8 weeks at a good dose, changing to a different therapy is suggested. However, once an effective treatment is found, the wait is well worth the decline of migraine frequency and severity!



In addition to an adequate trial duration, an adequate trial dose is also necessary. For example, a common first line medication used for migraine prevention is Topiramate (which is also FDA approved for migraine prevention). I often see patients who come in on 25 mg or 50 mg and have been on that dose for a year or more without much benefit. I discuss with them that the goal dose is at least 100 mg total daily dose, so the dose is too low. For example, in the migraine preventive trials, once patients reached 100 mg and had been at that dose specifically for at least 4 weeks, that is when improvement of statistical significance began. So, I typically start 25 mg at bedtime for 1 week. Then each week increase by 25 mg at bedtime until 100 mg is reached, and then I give a 100 mg pill to begin. I tell them if there is no improvement starting after at least 4 weeks from reaching the 100 mg dose specifically, let me know. I usually dose it all at bedtime which can help limit side effect potential (since you’ll be sleeping). However, it is generally meant to be taken as a twice daily medicine (such as 50 mg twice daily), and most patients tolerate that fine too.


With that said, patients can certainly respond to low doses of medications. However, if improvement has been minimal after a month of a lower dose, it is always a good idea to begin titration up to a better dose. The American Headache Society and American Academy of Neurology published guidelines of migraine preventive medications which includes common goal dose targets for some of these preventive medications here.



There are many preventive treatments used, although most of them are considered “off-label” for migraine prevention. This means they are not actually FDA approved for migraine prevention, but there is enough evidence based on research trials or clinical experience to warrant them as a valid option to try. As far as true FDA approved oral (pills by mouth) preventive medications, there are 4 available that have this distinction; Topiramate, Divalproex, Propranolol, and Timolol. There are also a number of natural supplements which have evidence for migraine prevention, and those are detailed and discussed here.


The categories of oral preventive migraine medications all sound bizarre. They consist of anti-seizure (anti-convulsant), anti-depressant/anti-anxiety, and anti-hypertension (blood pressure) medications. It is important for patients to know that the medicine is being used specifically for migraine. I often see patients who say they didn’t start the medicine their doctor prescribed because they got home, Googled it, and they tell me, “I’m not depressed”. I explain the reasoning for the medication and that it is not for depression, but for migraine prevention since there are overlapping electrical pathways between many of these types of disorders. Furthermore, there are select medications within each of these categories that have evidence from trials and clinical experience for migraine prevention, as listed here and here.


It is also important to know that the medications in each of these medication classes are not a “one size fits all” for every medicine within that category. For example, there is no good evidence for migraine prevention in the SSRI (selective serotonin reuptake inhibitors) anti-depressant/anti-anxiety medication category (Fluoxetine, Sertraline, Escitalopram, Citalopram, etc.). However, there is evidence for benefit in some of the SNRIs (serotonin and norepinephrine reuptake inhibitors) such as Venlafaxine XR, Duloxetine, as well as some of the TCAs (tricyclic antidepressants), primarily Amitriptyline and Nortriptyline. Similarly, there are select medications within the anti-seizure/anti-convulsant category which have the best evidence (Topiramate, Divalproex), as well as the anti-hypertension category (Propranolol, Metoprolol, Atenolol, Nadolol, Verapamil).


There are now 4 monoclonal antibody CGRP receptor antagonists which have this FDA approval for migraine prevention also. Three of them are once monthly auto/self-injections (Aimovig, Ajovy, Emgality), and one is a once quarterly (every 3 months) 30 minute IV (intravenous) infusion (Vyepti). In general, these are an option for those with 4 or more migraines per month on average. These medications are all discussed in much greater detail and comparison here.


Neuromodulatory devices that are FDA cleared for migraine prevention are also available and include sTMS (SAVI, SpringTMS, sTMS mini),  eTNS (CEFALY), and nVNS (GAMMACORE), all of which are discussed in much greater detail here. There are also nutraceuticals and supplements which have good evidence for migraine prevention. Yoga, relaxation and wellness therapies are also helpful in migraine prevention.


An exciting development is that there are 2 migraine preventive medications in the new gepant classification which are currently in clinical trials, and showing good evidence of effectiveness. They are both oral pills and include Atogepant and Rimegepant (currently FDA approved for abortive migraine treatment under the name Nurtec ODT). So these will open up another new class of preventive migraine medications engineered purely for migraine treatment!


When choosing a preventive treatment, I like to fine-tune the treatment to “hit as many birds with one stone”. In other words, pick something that will not only help with migraine prevention, but may also help with other medical conditions at the same time. Doing this can allow you to help minimize the number of medications used overall, by using something with benefit for several disorders in addition to the migraine. For example, if someone has depression or anxiety, targeting their migraine preventive medication with an anti-depressant/anti-anxiety category would make sense. If the patient has other chronic musculoskeletal pain issues, fibromyalgia, occipital neuralgia, etc., the SNRIs and the TCAs are good considerations. If the patient has insomnia, Amitriptyline or Nortriptyline are great options. If they have seizures, an anti-seizure medication such as Topiramate or Divalproex would make sense. If they are overweight, Topiramate also causes weight loss. Divalproex is another anti-seizure medicine which is also FDA approved for migraine prevention. However, this should be avoided when possible in young women of child-bearing age given the high risk of congenital birth defects while taking it (and most pregnancies are unplanned).


Here are some treatment considerations to take into account for migraine preventive therapy in addition to the following medical conditions the patient may also have:

-Obese/Overweight: Topiramate, Topiramate ER/XR (extended release), Zonisamide (All can cause weight loss, so also use with caution if patient is extremely thin to limit further weight loss.) If they improve with Topiramate but have side effects, changing to Topiramate ER/XR (extended release) or Zonisamide tend to have similar benefit with less side effects. Would avoid Amitriptyline, Nortriptyline since there is a risk of weight gain for some.

-Underweight/Excessively thin: Amitriptyline, Nortriptyline

-Depression and/or anxiety: Venlafaxine ER, Duloxetine, Amitriptyline, Nortriptyline, Desvenlafaxine

-Mood disorder such as bipolar or psychosis: Divalproex, Topiramate, Carbamazepine

-Anxiety without depression: Venlafaxine ER, Amitriptyline, Duloxetine, Nortriptyline, Desvenlafaxine, Propranolol

-Insomnia: Amitriptyline, Nortriptyline

-Fatigue/Low energy: Venlafaxine ER, Duloxetine (these can be energizing for many, so are best taken in morning)

-Hypertension: Propranolol, Metoprolol, Nadolol, Atenolol, Lisinopril, Candesartan, Verapamil

-Palpitations: Propranolol, Metoprolol, Nadolol, Atenolol

-Chronic musculoskeletal pains, fibromyalgia, neuropathy/nerve pains: Amitriptyline, Duloxetine, Nortriptyline, Gabapentin

-Non-oral route needed or preferred: Once monthly self/auto injections of monoclonal antibody CGRP receptor antagonists (Aimovig, Ajovy, Emgality) or once quarterly 30 minute IV infusion (Yvepti), which are all detailed here. Botox is another non-pill option for those averaging 15 or more headache days per month with at least 8 of those days having any migrainous features (throbbing, nausea, sensitivity to light (photophobia) or sound (phonophobia)) for 3 or more consecutive months (chronic migraine). Neuromodulatory devices that are FDA cleared for migraine prevention are also available and include sTMS (SAVI, SpringTMS, sTMS mini),  eTNS (CEFALY), and nVNS (GAMMACORE), all of which are discussed in much greater detail here.

-Averaging 15 or more headache days per month with at least 8 of those days having any migrainous features (throbbing, nausea, sensitivity to light (photophobia) or sound (phonophobia)) for 3 or more consecutive months (chronic migraine): Botox (Onabotulinumtoxin-A) injections every 3 months according to the PREEMPT chronic migraine treatment protocol. This is the only truly FDA approved medication for prevention of chronic migraine as of 2010. Any of the above listed medications are also options to consider, and most insurances will require failure of at least 2 classes of preventative oral medications before Botox is approved anyway, but this varies by insurance.



Expectations in migraine management are important. If your expectation is that your migraines will stop completely when you use preventive medications, you will be sorely disappointed. Of course it can certainly happen, but that is rare and should never be the expectation or goal. The goal of preventive therapy is a decrease in migraine frequency and/or severity of attacks (optimally both) to some extent to make them more tolerable and less intrusive into life. A general goal is 50% improvement in frequency and/or severity. Some patients can get much more than that, while others get much less (which would signal trials of a different medication class). In general, studies estimate that about 45% of patients on conventional preventive therapy (such as oral medications) receive 50% reduction in monthly migraine days. Thus, 55% will receive less improvement than this. The CGRP mAbs tend to have a higher rate of improvement then conventional treatments as detailed here.



There is no absolute answer of when to stop preventive therapy. It depends on how well one is doing, how long they have been doing well, and how much they want to get rid of treatments. Some people want off as soon as they can, others prefer to stay on for years since they are doing very well with few migraines, and don’t want to “rock the boat”. In general, the goal is to continue preventive therapy until the patient is doing significantly better for at least 3 months, but preferably closer to 6 months or so. I always make sure to tell patients that preventive medicines or treatments are not necessarily meant to be a life-long commitment. Rather, we use these treatments to “reboot” and “reset” the brain’s electrical system to have less frequent and/or severe migraines, and then try to sneak away off the medications once they are consistently doing better.

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Last updated on October 22nd, 2020 at 12:01 am





Cefaly vs. Nerivio, Nerivio vs. GammaCore, Cefaly vs. GammaCore, Nerivio vs. SpringTMS, Cefaly vs. SpringTMS, GammaCore vs. SpringTMS. These are common questions that patients have about migraine neuromodulation devices. Many patients do not respond to conventional migraine abortive medications, they do not tolerate them, do not like taking medications, or they cannot take them due to medical contraindications. These standard migraine abortive options are discussed here. Luckily, there have been several neuromodulatory devices for the treatment of migraine which have entered the market over the last few years. These non-invasive neuromodulation devices open up new migraine treatment options for those in these sensitive and difficult patient populations, including pregnancy as well. These also avoid the complications of medication overuse headache (rebound headache) that is often an issue with using too much abortive migraine medication, as discussed in greater detail here.

But do they really work? Is one better than the other? Do they hurt? Are they used for abortive or preventive treatment? Are they expensive? Does insurance cover them? How do they compare, and is one best for you? This blog will address all of these questions.

These devices include Single-Pulse Transcranial Magnetic Stimulation (sTMS) (SAVI, SpringTMS, sTMS mini), external trigeminal nerve stimulation (eTNS) (Cefaly), noninvasive Vagus Nerve Stimulation (nVNS) (GammaCore), and the most recent, wireless remote electrical neuromodulation (REN) (Nerivio). We’ll discuss these devices in the order in which they became available and FDA cleared. The table further down is a summary of comparison data between devices gathered from published studies and directly from the companies as well. It’s important to keep in mind that the data in this table are not from head to head studies between devices. Each of these devices had separate study designs (which were quite varied), and the results of those studies is what is reflected here, certainly not a direct comparison between devices. All devices require a prescription from your doctor. Pricing and intermittent promotional specials can be found on each device’s website and some of these are discussed below. Sometimes the long-term costs equal out or can even be less than the cumulative cost of many medications and treatments used abortively and preventively.



The first device which was FDA cleared was the Single-Pulse Transcranial Magnetic Stimulation (sTMS), made by the company eNeura. It was initially FDA cleared for the acute treatment of episodic migraine with aura in adults in December 2013. It then received FDA clearance for both acute and preventive treatment of migraine in adults in 2017. This clearance was then expanded to the acute and preventive treatment of migraine in children 12 years of age and older in February 2019. Prior models included the Spring TMS and sTMS mini. The newest model, SAVI, is currently the only FDA cleared device for both the acute and preventive treatment of migraine in adults and children 12 years of age or older. Since the device is used acutely and preventively, the FDA approved it for a maximum of 17 pulses per day.

The user holds the device against the back of the head, and presses a button to release a very short magnetic pulse at the onset of aura or a migraine attack with or without aura. The magnetic pulse delivers a fluctuating magnetic field which induces a mild electric current through the skull and onto the surface of the occipital cortex (visual cortex) of the back part of the brain. This modifies the electrical excitability and hyperactivity of the cortical neurons to block or prevent the onset of a migraine from evolving to a full-blown migraine. The device stops cortical spreading depression, which is suspected to be the basis of migraine aura in the occipital cortex. It is also suspected to interfere with thalamocortical pain pathways that are normally activated during a migraine. The company offers a 90-day money back guarantee, and it is typically rented in 3-month increments.

The most common side effects were mild and brief light-headedness/dizziness, tingling over the back of the head where treatment is performed, brief tinnitus (ringing in ears), nausea, and muscle spasm. You should not use this device if you have a cardiac pacemaker, vagus stimulator (VNS) or other implanted neurostimulator, implanted cardioverter defibrillator (ICD) or any implanted medical device that stimulates the body or uses any signal from the body. It is also suggested that patients with implants affected by a magnetic field should not use this device. Examples of such implants include aneurysm clips or coils, cochlear implants, cerebral spinal fluid shunts, bullets or pellets lodged in the head or upper body, metal plates, screws, staples or sutures in skull, neck, shoulders, arms or hands, and facial tattoos with metallic ink. Dental implants, fillings or other dental appliances are okay to use the device.

Acute migraine treatment consists of 3 sequential pulses (early) at the onset of a migraine (aura or pain). Then wait 15 minutes. If needed, treat with an additional 3 pulses. Then wait another 15 minutes. If needed, treat with an additional 3 pulses. Studies reported that 39% of patients were pain free at 2 hours.

Prevention treatment consists of 4 pulses twice daily. This is performed by giving 2 consecutive pulses, waiting 15 minutes, and then repeating 2 consecutive pulses. Studies reported that 46% of patients had a greater than 50% reduction in monthly headache days and averaged approximately 3 less migraine days per month.

Unfortunately, eNeura filed for Chapter 7 bankruptcy on 8/7/20, so it is unclear what exactly the future holds for these sTMS devices.



Cefaly was the next neuromodulation migraine treatment device that became available, and is an external trigeminal nerve stimulation (eTNS) device (similar to a TENS unit mechanism). It is made by Cefaly Technology. It works by neurostimulation of the trigeminal nerve branches in the forehead. It was FDA cleared for the prophylactic (preventive) treatment of migraine in adults in March 2014, and acute treatment of episodic migraines in adults in November 2017. The Cefaly Dual device is the most recent model, and has settings for both acute and preventive migraine treatment. The company offers a 60-day money-back guarantee. As of 10/13/20, the Cefaly Dual neuromodulation device became the first FDA-approved trigeminal nerve stimulator for migraine treatment available without a prescription and can now be purchased over-the-counter. The Cefaly Dual kit includes the Cefaly device, 1 electrode (good for 20 uses), power adapter, charging cable, and storage case. It normally retails for $499. Three packs of electrodes are $25, or by a cost-saving subscription service.

Cefaly treatment is often described as a mild buzzing and pressure sensation. It should be avoided in patients with implanted metallic or electronic devices in the head, or who have a cardiac pacemaker or implanted or wearable defibrillator.

Acute migraine treatment consists of a 1-hour session. It may be repeated for a second 60-minute session if the migraine pain is not relieved within two hours, or if another migraine attack occurs. Studies reported that at 1 hour, 32% were pain free and 79% had significant pain relief. At 2 hours, 17% were pain free and 65% significant pain relief.

Migraine prevention consists of a nightly 20-minute session. Studies reported a 29.7% decrease in migraine attacks, and 38.1% of patients received at least 50% decrease in migraine attacks.



Noninvasive Vagal Nerve Stimulation (nVNS) is made possible by a hand-held device called GammaCore, from the company ElectroCore. The most recent model is called GammaCore Sapphire. It was initially FDA cleared for the acute treatment of episodic cluster headache in adults in April 2017, followed by the acute treatment of migraine in January 2018, cluster headache prevention in November 2018, and migraine prevention in March 2020. It was the first and remains the only therapy which is FDA-cleared for the prevention of cluster headache This device is placed over the vagus nerve on the side of the neck, just below the angle of the jaw where the pulse of the carotid is felt in the neck. It is suspected that the device works by suppressing cortical spreading depression (a central process in migraine and aura formation), and blocking and modulating the thalamocortical, trigeminovascular and trigeminocervical pain pathways that are normally activated during a migraine.

Acute migraine treatment consists of 2 two-minute stimulations. If the pain remains 20 minutes after the start of the initial treatment, 2 more two-minute stimulations are given. Two more two-minute stimulations may be applied if the pain remains 2 hours after the start of the initial treatment. Studies showed significant pain relief in as soon as 30 minutes, and reported that at 1 hour, 21% were pain free and 35.8% had significant pain relief. At 2 hours, 30.4% were pain free and 40.8% significant pain relief. GammaCore reduced pain intensity over 3x greater than sham (fake device) at 60 minutes and over 6x greater at 120 minutes, and reduced the need for other rescue medications.

Preventive migraine treatment is done by giving 3 treatments daily (morning, mid-day, and night) consisting of two consecutive 2-minute stimulations. Studies showed a 29% reduction in migraine days per month when used preventively, although this number was even higher in those with aura at a 35.8% decrease. Overall, 33.6% of patients received at least a 50% decrease in migraine frequency.

Acute cluster headache treatment is done by giving 3 two-minute stimulations. After completing the 3rd stimulation, the user waits 3 minutes. If pain remains, 3 more two-minute stimulations can be applied. You may treat up to 4 attacks (8 treatments) for a total of 24 stimulations per day. Significantly more episodic cluster attacks treated with GammaCore were pain-free at 15 minutes vs those treated with sham   (47.5% vs 6.2%). Combined study data showed that significantly more (over 2-4x greater response) episodic cluster headache patients responded (no pain or mild pain) to GammaCore at 15 minutes for 50% or more of all treated attacks vs those receiving sham (34.2-64.3% vs 14.9-15.4%). At 15 minutes, there were also significant reductions in pain duration and intensity with GammaCore compared to sham.

Preventative cluster treatment is done by giving 2 treatments (morning and night) consisting of 3 two-minute stimulations. Weekly attack frequency decreased by 40% from baseline when GammaCore was added to standard of care therapy. There was a 57% decrease in the frequency of acute medication use when GammaCore was added.

GammaCore treatment is often described as a deep vibration. GammaCore should not be used with an active implantable medical device, such as a pacemaker, hearing aid implant, or any implanted electronic device. It should be avoided in patients who have a metallic device such as a stent, bone plate, or bone screw implanted at or near their neck, are using another device at the same time (e.g., TENS Unit, muscle stimulator) or any portable electronic device (e.g., mobile phone).



The Nerivio device is made by the company Theranica. It is a wireless remote electrical neuromodulation (REN) device wearable for the acute treatment of migraine applied to the upper-arm. It was FDA-cleared for the acute treatment of migraine in adults in May 2019. Each device provides 12 treatments. When the device is used up, it is recycled and a new refill device is sent. It is the most economical option on the market. Costs can often be similar to monthly triptan prescription costs. The device works through an app downloaded on your smartphone which controls the strength and treatments. The device itself is an arm band that easily straps around the upper arm, and was recognized in TIME Magazine’s annual list of the 100 Best Inventions in 2019. In October 2020, Nerivio became the first neuromodulation device to receive a pharmacy/medical benefit.  is available for $10 on the initial prescription for anyone with any form of medical or pharmaceutical insurance, including government insured patients such as Medicare and Medicaid! Commercially insured patients may have their Co-pay reduced to $0 on future refills, while government insured patients will pay $99 for refills. No patient ever pays more than $99 for a refill, and most will hopefully pay $0 on refills.

It delivers electronic pulses into the skin to generate a proprietary “Conditioned Pain Modulation” response which helps to abort the effects of a migraine in patients with or without aura. Nerivio stimulates specific sensory nerves of the upper arm which normally sense pain. The stimulation from the device is not strong enough to actually trigger pain for the user, but the signal still travels to the brainstem, as it normally would. From here, it interferes and blocks the ongoing activated electrical circuitry of the migraine, and helps to abort it. Many think this is basically a TENS unit, but it is not. It has a proprietary stimulation signal which targets specific pain transmitting nerve fibers that disrupts the electrical activity of a migraine centrally from a remote location peripherally (on the arm).

The device is applied within 60 minutes (preferably at onset) of a migraine headache or migraine aura and stimulation is performed for 45 minutes. It is described as a vibrating sensation. Studies showed that 66.7% of patients had significant pain relief at 2 hours, and 37.4% of patients achieved complete pain relief at 2 hours. Furthermore, 89.7% of patients studied avoided having to take other abortive medications when treating with Nerivio.

Side effects may include a temporary sensation of warmth, local tingling, numbness in the arm, pain in the arm, or redness of the skin, although 96.4% of patients studied did not report any device related adverse events. It is recommended to avoid in congestive heart failure, severe cardiac or cerebrovascular disease and uncontrolled epilepsy. It should not be used with certain medical devices such as a pacemaker or hearing aid implant. Using Nerivio with other implantable medical devices could potentially cause electric shock, electrical interference, or other injury. So it should not be used near any metallic implants.


  sTMS Cefaly GammaCore Nerivio
Acute Migraine Yes Yes Yes Yes
Preventive Migraine Yes Yes Yes No
Acute Cluster No No Yes No
Preventive Cluster No No Yes No
1-hour migraine pain free N/A 32% (13% sham) 21% (sham 10%) N/A
1-hour migraine pain relief N/A 79% (39% sham) 35.8% (sham 24.4%) N/A
2-hour migraine pain free 39% (sham 22%) 17% (sham 7%) 30.4% (sham 19.7%) 37.4% (18.4% sham)
2-hour migraine pain relief N/A 65% (sham 52%) 40.8% (sham 27.6%) 66.7% (38.8% sham)
Migraine preventive relief 46% had > 50% decrease in monthly HA days (20% “statistically derived” placebo) and averaged 3 less migraine days/month 29.7% decrease (sham 4.9%)

38.1% received at least 50% decrease in migraines (sham 12.12%)

29% decrease (sham 18%)

35.8% decrease in patients with aura

33.6% received at least 50% decrease in migraines (sham 23.4%)



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Last updated on October 24th, 2020 at 01:10 am




Medical marijuana (medical cannabis) for treatment of migraine, headache, pain, and chronic pain has become an increasingly hot topic of interest. As states continue to legalize the use of medical marijuana, there are increasing discussions and questions about its medical uses. What are the best medical marijuana strains for migraine, headache, and pain? Is medical marijuana helpful for migraine, chronic migraine, headache, pain, and chronic pain? How is medical marijuana used and dosed? Is medical marijuana legal to use? What are the side effects of medical marijuana? How do you get medical marijuana? How does marijuana differ from CBD (cannabidiol)? Patients ask about this type of treatment and many of these questions all the time, so this blog is to provide a comprehensive overview to answer all of these questions and much more. Reading the whole blog will give you a comprehensive, yet condensed detailed education of its history and everything you need to know about it, with an additional focus in the treatment of migraine and pain. Alternatively, you can skip down to find the specific topic that you are looking for information on.

When many people hear the term “medical marijuana”, they think of a street drug with no true medicinal qualities, used only for recreation and abuse. Their mind immediately activates the visual hippie imagery of the 1967 Summer of Love and 1969 Woodstock festival. However, this is an outdated view in the scientific research community. The term “marijuana” (sometimes spelled marihuana) is a loaded term with many negative connotations including old political and racial associations, and is associated with the plant being used recreationally as a drug of abuse. Cannabis is the scientific name of the plant and is the preferred terminology.

It is best to think of cannabis, as a broad class of medication. Within this medication class there are many types of cultivars (strains, breeds), or more accurately, chemovars (chemotypes). “Cultivar” is short for “cultivated variety”, while “chemovar” refers to “chemical variety”. The older cultivar classification system (Sativa, Indica, Ruderalis) has evolved to the more current, scientific, and simplified chemovar classification system. These systems are discussed in more detail further down under the treatment section.

Each chemovar has standardized reproducible compositions of cannabinoids and terpenes, which are the phytochemicals in cannabis that make up most of the medicinal qualities. The CBD and THC (tetrahydrocannabinol) cannabinoids and terpenes are discussed further down, and are also discussed in great detail here. Similar to a medication, there will be some variation in benefits, responses, effectiveness, and side effects between patients for each chemovar. Also similar to a medication, there are common characteristics attributed to each chemovar that the majority of users will experience.

For comparison of this concept, antidepressants are a broad class of medication. Within this medication class there are many types of drugs. Each drug has standardized reproducible compositions of neurotransmitter targets. Similarly, there will be some variation in benefits, responses, effectiveness, and side effects between patients for each drug, and a set of common characteristics attributed to each drug that the majority of users will experience.



To understand the current legal status of cannabis, it is important to know the history of cannabis, detailed here. The use of cannabis for medicinal purposes dates back to ancient times, with a Western/Central Asian botanical origin. Medicinal uses have been documented to 4000 BC or more. Chinese physicians were using it for joint pains and analgesia in childbirth 5000 years ago. Fast forward to 1839 when Dr. William Brooke O’Shaughnessy introduced the Western world to the medicinal uses of Cannabis indica, or “Indian hemp”, after he spent a professorship in Calcutta, India and learned of its uses while there. He advocated for its use in analgesia and muscle relaxation.

Throughout the 1800s into the 1900s, it was being recommended by many prominent physicians of those times for numerous diseases, particularly pain, headache, chronic daily headache, migraine, and chronic migraine, and was being used both acutely and preventatively.

In 1890, Sir John Reynolds, President of the British Medical Association, and Physician to the Royal household, wrote a paper in Lancet on his 30 years of experience prescribing cannabis for variety of ailments, particularly migraine and neuralgia.

In 1915, the “Father of modern medicine”, Sir William Osler, was recommending cannabis for migraine treatment in his historic medical textbook of those times, The Principles and Practice of Medicine. He went on to suggest that when treating migraine, “Cannabis indica is probably the most satisfactory remedy. Seguin recommends a prolonged course.” Dr. E.C. Seguin whom he referenced was a well-known neurologist and was the President of the NY Neurological Society. He was a vocal proponent of cannabis for migraine.

Cannabis-based preparations had been listed in the US Dispensatory in 1845. In North America, some pharmaceutical companies including Bristol-Meyers Squib, Parke-Davis, and Eli Lilly were producing cannabis-based preparations, as was Burroughs-Wellcome & Co. in England.

In the 1930s, Harry Anslinger was leading the Federal Bureau of Narcotics, which was essentially the early DEA. He began a campaign against cannabis, attempting to associate psychosis, mental deterioration, addiction, and violent crimes to cannabis use. He claimed cannabis was a drug of abuse used by minority and low-income communities. Instead of using the term cannabis when he was pushing his prohibition bill in front of congress in 1937, he purposely would use the term “marijuana,” subtly trying to convey a racial connection since it was commonly associated with recreational use among poor Mexican immigrants who would bring it from Mexico to the USA at that time. He reportedly chose his terminology wisely to fit this agenda and distance the plant from the more scientific term cannabis along with its growing uses for medicinal and industrial purposes. Furthermore, marijuana has a general connotation of being used as an intoxicant and recreationally, whereas cannabis has more of a scientific association. For all of these reasons, cannabis should really be the preferred terminology over marijuana.

The Marihuana Tax Act of 1937 was passed, attributing large fines and prison time to anyone involved with cannabis. Some historians also discuss influence on this law from prominent businessmen such as Andrew Mellon and the DuPont family since the hemp industry was gaining traction in industrial uses, posing a threat to synthetic and other more common competitor products, but that is a whole different discussion. The AMA (American Medical Association) strongly opposed this law.

In 1938, Dr. Robert Walton argued against the new Marihuana Tax Act and published a comprehensive review of cannabis, referencing 12 experts on its effectiveness for migraine.

In 1941 cannabis preparations were taken off the US Pharmacopoeia and National Formulary.

In 1942, Dr. Fishbein, the Editor of JAMA (Journal of the American Medical Association), published his recommendations for oral preparations of cannabis over ergotamine for menstrual migraine. Other physicians also published supporting evidence for cannabis in migraine treatment.

Then the 1960s hit, where there was a resurgence of recreational marijuana use. This left a lasting and ongoing negative stigma of cannabis. Again, cue the visual hippie imagery of the 1967 Summer of Love and 1969 Woodstock festival. Unfortunately, many people who are not aware of cannabis history have been stuck in this mindset since…

The final nail in the coffin for legal cannabis use came with the Controlled Substances Act of 1970. This is what changed cannabis to its schedule 1 drug illegal status, of which it has remained since that time. The Assistant Secretary of Health, Dr. Roger O. Egeberg, stated his reason as follows, “Since there is still a considerable void in our knowledge of the plant and effects of the active drug contained in it, our recommendation is that marijuana be retained within schedule 1 at least until the completion of certain studies now underway to resolve the issue.”

Well, we are well past those studies Dr. Egeberg mentioned, and extensively more have been completed since then, yet cannabis remains federally illegal, despite all the evidence and vast amount of knowledge that we have gained from research. Thus, it is only a matter of time until the tide finally turns completely, and cannabis is rescheduled from Schedule 1 in my opinion.

So, cannabis has been a schedule 1 drug since 1970. Schedule 1 drugs also include heroin, lysergic acid diethylamide (LSD), and 3,4-methylenedioxymethamphetamine (Ecstasy). According to the United States Drug Enforcement Agency (DEA), Schedule I drugs have a high potential for abuse, and have no accepted medical treatment use. If you are saying to yourself, that cannabis doesn’t seem like it fits into this category, you are certainly part of the majority opinion, which has shifted over the years. The DEA has continued to claim that cannabis has “no accepted medicinal use”, a statement which has no evidence to support it, but rather more evidence exists that disprove that claim.

Interestingly, despite this claim of no medicinal benefit, the US Government’s Department of Health and Human Services was awarded a patent (US Patent #6,630,507) for “cannabinoids as antioxidants and neuroprotectants” in 2003. Furthermore, the FDA has approved 3 synthetic versions of cannabinoids for medicinal purposes. Two are synthetic forms of THC (Dronabinol (Marinol), Nabilone (Cesamet)), and one is a purified form of CBD (Epidiolex). So, these statements and facts are clear contradictions to one another…

The schedule 1 classification has been a huge barrier preventing US federal funding for research and the legal ability to even proceed with research, although this has loosened up in recent years. This has historically been the primary hurdle in conducting medical research needed to obtain the evidence-based medicine in support of cannabis in the US. Meanwhile, many other countries such as Israel and Canada have been researching for years and have federal cannabis programs. For example, the Canadian equivalent to the US FDA is Health Canada. They have maintained a successful federal cannabis program for years. Despite this schedule 1 hurdle in the US, there has been accumulating evidence for various therapeutic benefits of cannabis, especially in the treatment of pain disorders.

In 1976, the FDA began an Investigational New Drug Program, after a glaucoma patient sued the government on grounds that cannabis was helping him, and won. This program closed in 1992, and 13 patients in the program at the time of closure were allowed to continue. Most recently, there were still 2 remaining who still receive monthly government supplied cannabis; one for multiple hereditary exostoses (painful bone tumor disorder), and the other for glaucoma. Access to this government supplied cannabis has since been controlled by the National Institute on Drug Abuse (NIDA), and the only federally approved cannabis source for decades has been from a farm at the University of Mississippi, who has had an ongoing contract with the federal government since 1968.

Through the 1990s-2000s, there was growing commentary from leading physicians and journals supporting cannabis for medicinal purposes. This has been accompanied by a growing push by medical organizations to reschedule cannabis to allow research and for patients who need it when they have failed all conventional treatments. Some of these organizations include American Academy of Neurology (AAN), American Medical Association (AMA), Epilepsy Foundation, American Journal of Public Health, and American Academy of Pediatrics (AAP).

In 2013, Dr. Sanjay Gupta MD, CNN Chief Medical Correspondent, issued a public apology article retracting his previous anti-marijuana stance which can be read here. He noted that “of more than 20,000 papers published in recent times, only 6% of the studies look at potential benefits of cannabis, while all the rest investigate potential harm, leading to an inherent bias and a profoundly distorted view.” He went on to further say:

“Well, I am here to apologize. I apologize because I didn’t look hard enough, until now. I didn’t look far enough. I didn’t review papers from smaller labs in other countries doing some remarkable research, and I was too dismissive of the loud chorus of legitimate patients whose symptoms improved on cannabis. Instead, I lumped them with the high-visibility malingerers, just looking to get high. I mistakenly believed the DEA listed marijuana as a Schedule 1 substance because of sound scientific proof. Surely, they must have quality reasoning as to why marijuana is in the category of the most dangerous drugs that have “no accepted medicinal use and a high potential for abuse.” They didn’t have the science to support that claim, and I now know that when it comes to marijuana neither of those things are true. It doesn’t have a high potential for abuse, and there are very legitimate medical applications. In fact, sometimes marijuana is the only thing that works. We have been terribly and systematically misled for nearly 70 years in the United States, and I apologize for my own role in that.”

Dr, Gupta has done a series of documentaries on CNN about the medicinal benefits of cannabis and are very enlightening to watch. This change in Dr. Gupta’s public opinion was also occurring along with spreading anecdotal cases of children with refractory pediatric epilepsy who were improving dramatically with CBD extracts from cannabis. One of these children, Charlotte Figi, became the poster child for this movement. In fact, the cannabis strain bred and extracted for high CBD for these purposes (Charlotte’s Web), was named after her. Unfortunately, she died 4/7/20 at the age of 13, and was remembered here.

The legal use of medicinal cannabis continues to increase globally, including the United States. In 1996, CA became the 1st state to pass the Compassionate Use Act, allowing the legal use of cannabis for medicinal purposes. Since that time, legalized cannabis has continued to grow. Medical use of cannabis is legal in 33 states (AK, AR, AZ, CA, CO, CT, DE, FL, HI, IL, LA, ME, MD, MA, MI, MN, MO, MT, ND, NH, NJ, NM, NY, NV, OH, OK, OR, PA, RI, UT, VT, WA, WV) + Washington DC. Recreational (“adult use”) is approved in 11 states (AK, CA, CO, IL, MA, ME, MI, NV, OR, VT, WA) + Washington DC. Despite a number of states legalizing cannabis use at the local level, it is still illegal federally in all states.

States which have medical cannabis programs have a list of qualifying conditions, which vary by state. The State Medical Board certifies doctors to “recommend” medical cannabis (Certificate to Recommend; CTR). The physician then confirms the qualifying condition and signs a “recommendation” form for potential benefit from medical cannabis. The patient then takes the recommendation to the local dispensary (which are also highly regulated by the state) and the patient discusses the best options there. However, it is important to remember that under the CSA (Controlled Substances Act), cannabis remains a schedule I drug, so doctors can’t “prescribe” cannabis. They can only “recommend” it. Also, interstate travel with any amount of cannabis or plant extract (including CBD products with THC content >0.3%) violates federal law and could potentially result in federal drug trafficking charges with stiff penalties of prison time and fines.

In 2009, the Justice Department sent a memorandum to federal prosecutors stating that patients and their providers should not face federal prosecution if they are following state law. In 2013 the Cole Memorandum was sent to US Attorney Generals, reinforcing that the Justice Department would not enforce federal prosecution in legal states who are following their state laws. In 2018, the Cole Memorandum was rescinded by Attorney General Jeff Sessions, which sent shockwaves through the industry. However, President Trump has continued to reinforce his support in protecting states that have legalized cannabis from federal prosecution. There have been discussions of re-evaluating the rescheduling of cannabis to remove the federal schedule 1 illegality, and it is suspected to be only a matter of time until this eventually happens.



In medical cannabis registries, the most commonly reported reason for cannabis use is chronic pain of various types. Because of the increasing evidence of cannabis in the treatment of pain, the Canadian Pain Society revised their consensus statement in 2014 to recommend cannabinoids as a third-level therapy for chronic neuropathic (nerve) pain based on the abundance of supporting evidence and a NNT (number needed to treat) estimated at approximately 3 (the number of patients needed to treat for 1 of them to receive benefit). In 2017, The U.S. National Academies of Sciences, Engineering, and Medicine published a statement that the use of cannabis for the treatment of pain is supported by well-controlled clinical trials and that there is substantial evidence that cannabis is an effective treatment for chronic pain in adults. In February 2019, the World Health Organization (WHO) recommended that cannabis be rescheduled and removed from the most restrictive scheduling category.

Cannabis works through our endocannabinoid system. The endocannabinoid system is a normal and important biological system within everyone which helps to maintain homeostasis. It plays a role in many regulatory physiological processes across all organ systems, and is widely distributed throughout the central nervous system (brain and spinal cord) and peripheral nervous system (nerves outside of the spinal canal). This system is involved in the “runner’s high” as well. Notably, it plays a very strong role in pain pathways. This system works by the interaction of our own natural endocannabinoids turning on or turning off various endocannabinoid receptors throughout our body.

Over 540 phytochemicals have been described in cannabis, 18 different chemical classes, and more than 100 different phytocannabinoids. THC and CBD have been the most researched and are considered the major cannabinoids. There are many additional cannabinoids referred to as minor cannabinoids. The quantities of major and minor cannabinoids are widely variable between different types of cannabis chemovars. There is evidence for analgesic and anti-inflammatory effects in many of the cannabinoids. Cannabinoids are unique to the cannabis plant, and can be thought of as the “plant equivalents” of our own endocannabinoids. So, they interact with the same endocannabinoid receptors in our body as our own endocannabinoids do. The existing literature and research on the treatment of pain have primarily studied cannabis itself with its variable and often undefined combinations of THC, CBD, other cannabinoids, terpenes, and other constituents. These compounds, especially cannabinoids and terpenes, play significant roles in influencing one another and working together. The synergy and interactions between these compounds are referred to as the “cannabis entourage effects”. Thus, the medicinal benefits of cannabis are suspected to be from the “entourage effects”, more so than any of the individual components alone.

THC is a major cannabinoid and the most researched in cannabis. THC causes the psychoactive qualities (“high”) of cannabis. THC has been shown to be 20 times more anti-inflammatory than aspirin and 2 times as anti-inflammatory as hydrocortisone. It is also a potent anti-emetic (anti-nausea), which is why there are two FDA-approved synthetic THC medications for chemotherapy related nausea and vomiting (Dronabinol, Nabilone). THC is the cannabinoid which is tested for in drug tests. It is important to know that most CBD products contain trace amounts of THC, although there are some varieties that do not. It is typically a negligible amount unlikely to show up on a drug test, but it is not completely risk free. You can read about the different types of CBD products here. THC can be detected by a variety of ways, although most commonly it is tested in the urine. Here are the general timeframes that it will show positive:

  • Blood:
    • Few hours to 1-2 days after a single use
    • In heavy users (multiple times a day), possibly up to a week
  • Saliva:
    • Appears in saliva an hour after use, detectable for up to 1-2 days
  • Urine:
    • 5-12 days after one-time use
    • 11-18 days when used 2-4 days/week
    • 33-48 days when used 5-6 days/week
    • Around 50-65 days if used daily (stored in adipose tissue)
  • Hair:
    • Generally 90 days, but some hair follicle tests can go back years

CBD is the other major cannabinoid and has gained a lot of attention as a therapeutic agent over the past several years given a wide range of reported anecdotal benefits. It is discussed in much greater detail here. In contrast to THC, CBD is non-intoxicating (no “high”). Furthermore, it helps to neutralize some of the negative THC side effects. CBD has been shown to be several hundred more times anti-inflammatory than aspirin. Greater than 65 molecular receptor targets and greater than 80 mechanisms of action have been identified. There have been scientific, animal models, and very limited human clinical trials documenting its anti-inflammatory and analgesic (pain-relieving) properties. However, there are no high-quality research studies to date evaluating isolated pure CBD in any pain, migraine, or other headache disorders. So, it is unclear how much benefit CBD in isolation provides outside of the presumed entourage effects that it contributes to.

In November 2017, The World Health Organization (WHO) concluded that CBD exhibits no evidence for abuse or dependence potential, and that there is no evidence of public health related problems associated with its use. In January 2018, the World Anti-Doping Agency (WADA) removed CBD from their prohibited list, no longer banning use by athletes. In December 2018, the Agriculture Improvement Act (Farm Bill) was signed into law. This legalized the agricultural growth and use of hemp (cannabis strains containing 0.3% THC or less) and hemp derivatives such as CBD. The Farm Bill also removed hemp from the Controlled Substances Act, making it no longer an illegal substance under federal law. Up until the Farm Bill was passed, any form of cannabis or cannabis derivatives (including CBD) have been federally illegal since the Controlled Substance Act of 1970. Therefore, it is important to remember that cannabis chemovars and CBD oils with greater than 0.3% THC are still illegal federally, require a medical cannabis card for use, and are illegal to cross state lines with. In May 2019, TSA began to allow travel with CBD products containing 0.3% or less of THC.

The terpenes account for many of the pharmacological properties of cannabis, as well as many medicinal herbs, plants and essential oils. They are the source of flavors, aromas, and other characteristics that help differentiate cannabis cultivars. Terpenes are often used in many household products such as limonene (citrus), pinene (pine, conifer), and linalool (lavender) to name just a few. Similar to the cannabinoids, many have anti-inflammatory and analgesic properties.



As discussed at the beginning of the blog above, there are many types of cannabis chemovars that vary widely in the composition of cannabinoids, terpenes, flavonoids, and other compounds. These components work synergistically to produce wide variations in benefits, side effects, and chemovar characteristics. Different chemovars have different ratios of these compounds, and thus have different characteristics.

The older cultivar (strain, breed) classification system was based on strain appearance, smell, and clinical effects. Cannabis Sativa strains were generally described by patients as uplifting, energetic, creative, euphoria, spacey, cerebrally-focused effects, and better for day use, while cannabis Indica strains were typically described as calming, relaxing, sedative, full body effects such as “body buzz”, and better for night use. Cannabis ruderalis (hemp) strains were considered predominantly or purely high CBD without any real clinical use effects.

However, biochemical studies of specific strain names often do not accurately distinguish CBD and THC content, which was the predominant basis for strain classification. Strain characteristics and clinical effects are dependent on varying ratios of major and minor cannabinoids and terpenes, not only from CBD:THC ratios, as there are no significant differences in CBD:THC ratios between many Sativa and Indica strains when studied chemically. Most strains used today are hybrid strains genetically cross-bred for standardized CBD, THC, terpenes, and minor cannabinoid content.

The older cultivar classification system has evolved to the newer and more scientific chemovar (chemotype) classification system, and is divided into type I-III chemovars. This system allows medical users to find a chemical profile better matching their pharmacological needs.

Type I chemovars are THC predominant. They are high THC (>0.3%, but generally >10-20%), and low CBD (<0.5%, but generally <2%). They are very intoxicating, and associated with recreational more than medical use. They are moderately-heavily psychedelic with changes in perception and sensory awareness and have the potential for significant physiological changes in heart rate and blood pressure. They can intensify relief from symptoms like nausea or pain, so terminal cancer patients may be one of the few true medical uses for these chemovars.

Type II chemovars are more balanced THC and CBD. They are high THC (>0.3%, but generally 3%-10%), and high CBD (>0.5%, but generally 1%- 14%). They are intoxicating to a lesser degree than Type I chemovars. They can be mildly-moderately psychedelic with milder cerebral and cognitive changes in perception and sensory awareness possible. In general, they can be more effective at treating symptoms with less negative side effects.

Type III chemovars are CBD predominant. They are low THC (<0.3%, but generally 0%-1%), and high CBD (>0.5%, but generally 5%-20% or more). They have low to no intoxication side effects. There is little to no cognitive impairment for most, but there can be possible mild effects in sensitive users, depending on the THC content.



                  The benefits of cannabis/cannabinoids in various chronic pain disorders has been well established. These benefits are suspected to likely extrapolate to headache disorders including migraine given overlapping neurobiological pathways of pain. There are some notable interactions and synergies between the cannabinoid receptors and pathways of migraine involving the trigeminovascular system (including the same receptors that the triptans work on) and serotonergic system. A more detailed discussion of this physiology can be read here and here. The medical literature regarding treatment of headache, migraine, and facial pain disorders shows limited supporting evidence for cannabis/cannabinoids in the treatment of chronic headaches, migraine including chronic migraine, medication overuse headache, cluster headache, idiopathic intracranial hypertension, and multiple sclerosis (MS) associated trigeminal neuralgia. However, the majority of this limited supporting evidence consists primarily of case series, case studies, case reports, surveys, clinical/anecdotal reports, and one retrospective analysis. There have been no placebo-controlled studies of cannabis for headache disorders or migraine thus far. There are only two prospective trials containing a control group evaluating the use of cannabinoids in the treatment of headache disorders, both of which showed benefit. The details and references of these studies and all of the smaller case studies mentioned can be read here and here.

Part of the difficulty in these types of trials, besides the federal illegality and the schedule 1 status of cannabis, is that there are so many variations of chemovars. It is unknown what chemovars and varieties of cannabis might be most helpful for migraine treatment. Most likely, it is not a one size fits all. Similar to how patients have a wide variety of therapeutic responses to abortive and preventive migraine treatments (what works for one person often does not work for another, etc.), responses to chemovars is probably similar. One person may respond very well to a specific chemovar, while another may respond better to a different one. Everyone is different, so like the trial and error process of trying different medications to see which may work best, cannabis chemovars most likely have a similar process.

With that said, there have been a couple studies evaluating a large medical cannabis registry, in an attempt to determine what chemovars patients with migraine and headache prefer to use. In one study, which can be read here, chemovars with high THC and low CBD were most preferred. “OG Shark” was the most preferred chemovar and consisted of high THC/THCA (tetrahydrocannabinolic acid) and low CBD/CBDA (cannabidiolic acid), with predominant terpenes β-caryophyllene and β-myrcene. This could reflect the potent analgesic, anti-inflammatory, and anti-emetic properties of THC, with anti-inflammatory and analgesic properties of β-caryophyllene and β-myrcene. Notably in that study, many headache patients replaced pharmaceuticals with cannabis, most commonly opiates/opioids (43.4% in headache patients, and up to 73% in chronic pain patients), anti-depressant/anti-anxiety (39%), NSAIDs (21%), triptans (8.1%), anticonvulsants (7.7%), muscle relaxers (7%), and ergots (0.4%).

In a follow up study (publication pending) 6 of the top 8 preferred chemovars were again high THC/low CBD, with “Headband” (22-24% THC, <1% CBD), “Warlock CBD” (8-11% THC, 8-11% CBD), and “Master Kush” (24-26% THC, <1% CBD) all tied for the top preferred cannabis chemovar. All three of these chemovars again had β-caryophyllene as one of their top 3 predominant terpenes, along with a mix of linalool, limonene, β-myrcene, bisabolol, and humulene as one of the top 3 predominant terpenes between them. There were 2 preferred chemovars which had high CBD and lower THC. They were “Warlock CBD” (8-11% THC, 8-11% CBD) which was in a 3-way tie for top preferred chemovar as mentioned above, and “Cannatonic” (3-7% THC, 6-10% CBD).



Cannabis can be used by smoked, vaporized, oral, oral-mucosal, topical, or rectal routes of administration. Oral routes cause a slower onset of action and a prolonged duration of action. Smoking and vaporizing cause the fastest onset of action and the shortest duration of action. Smoking is not recommended due to the production of unhealthy respiratory irritants and toxins. Vaporizing is a newer technique with a goal of suppressing irritating respiratory toxins by heating cannabis to a temperature where active cannabinoid vapors form, but below the point of combustion where smoke and associated respiratory toxins are produced.

Start low on the dose, go slow, and stay on as low of a dose as possible. This promotes tolerance to the THC psychoactive effects. Use the lowest dose THC possible, and use CBD and THC together because CBD helps to neutralize some of the negative THC side effects. Approximately 15-20% CBD with less than 1% THC is a good starting point to consider. CBD predominant preparations are better for working and daytime use, while THC predominant preparations are better for after work and at bedtime. Long acting oral formulations are better for chronic conditions and symptoms. Vaporization can be an as needed (prn) for episodic symptom exacerbations. Driving should be avoided for at least 4 hours after inhaled cannabis, 6 hours after ingested cannabis, and 8 hours if euphoria is experienced.

Common dosing quantities and terminology include one joint = 0.3-0.5 grams, one eighth = 3.5 grams, one quarter = 7 grams, and one ounce = 28 grams. Based on peer-reviewed literature, the majority of patients using smoked or orally ingested cannabis for medical purposes have been observed to use between approximately 10-20 grams of cannabis per week, 1-3 grams per day, and a frequency of 3-4 times daily. With that said, specific dosing recommendations are not available, and this is one area of much needed research in order to determine the best dosing for various disorders.

For THC dosing, 1-2.5 mg is a good starting dose. For example, starting at bedtime and increase 1-2.5 mg every few days at bedtime or daytime (depending on treatment goals) until benefits or side effects are reached. At 5 mg THC, many will experience benefit without excess side-effects. At 10 mg, most will have side effects. At 15 mg or more it may cause psychiatric side effects. As a loose reference, a 0.5-1 g cannabis cigarette may contain approximately 0.2-4.4 mg THC. However, THC content has gotten much higher in many chemovars over the years, so this can be much higher. The total daily THC dose should be less than 20-30 mg to limit adverse effects and tolerance. In addition, THC should preferably be used with CBD as mentioned above. Use of high dose THC chemovars more than 5 grams per day of flower suggests possible tolerance or misuse, and is usually unjustified medically unless perhaps an end stage cancer patient.

For CBD Dosing, starting at 5-20 mg/day divided once to three times daily, and titrating to effect is suggested. It is suspected that high doses are likely needed for pain and inflammation disorders, but this needs to be clarified with research. There are no established dosing guidelines or max doses established. For reference, doses of 400-600 mg/day showed benefit in anxiety, doses of 600-800 mg/day showed benefit in psychosis, and doses up to 2500 mg/day (25-50 mg/kg) have been used in epilepsy studies.



Side effects are influenced by dose, method of administration, patient tolerance, chemovar of cannabis, ratios of THC to CBD, cannabinoids, terpenes, production quality control (toxins, fungus, bacteria, heavy metals, etc.) to name a few. Many studies have been inconclusive or contradictory in terms of association with stroke, heart attack. This publication provides the most comprehensive review of cannabis and its recognized side effects. The most common side effects (which vary depending on the chemovar) include dizziness, dry mouth, increased appetite, disturbances in concentration, and sedation/drowsiness. Less common side effects can include incoordination, euphoria, anxiety, and paranoid thinking. In the majority of trials, side effects have been well tolerated, mild to moderate, transient, and not bothersome enough that many patients withdrew from studies. Overdose can occur and is typically from high THC content and oral dosing. Signs may include tachycardia, arrhythmia, confusion, panic attack, extreme paranoia, and hallucinations.

From existing research, there is concern for possible long-term cognitive side effects of cannabis use during adolescent years when the brain is still rewiring, pruning, and organizing itself. Studies suggest a decline in IQ/neurocognitive function when used frequently under age 18. In adults, a larger study suggested problems in verbal memory recall after chronic cumulative use (after 5 years of cumulative frequent/chronic use, 1 in 2 people may recall 1 word less from a list of 15 words). Current users had both decreased verbal memory and processing speed.

According to “The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research”, published by the National Academies of Sciences, Engineering, and Medicine in January 2017, the following are conclusions regarding cannabis side effects based on existing literature reviews.

For cardiovascular risk, there is limited evidence of cannabis triggering an acute MI (heart attack), ischemic stroke, or subarachnoid hemorrhage. There is no evidence to support or refute chronic cannabis use and increased risk of acute MI.

For cancer risk, there is moderate evidence of no association between the incidence of lung cancer (cannabis smoking), or the incidence of head and neck cancers. There is no or insufficient evidence to support associations with other cancers.

For respiratory disease risk, there is substantial evidence for worse respiratory symptoms and more frequent chronic bronchitis episodes (long-term cannabis smoking).

For neurocognitive risk, there is moderate evidence of impairment in the cognitive domains of learning, memory, and attention with acute cannabis use, but limited evidence for persistent impairments in cognitive domains of learning, memory, and attention after sustained cannabis abstinence.

For mental health risk, there is substantial evidence for development of schizophrenia or other psychoses in those at risk genetically, with the highest risk among the most frequent users. There is moderate evidence for increased symptoms of mania and hypomania in bipolar disorder. There is a small increased risk of depressive disorders and an increased incidence of social anxiety disorder. There is an increased incidence of suicidal ideation and suicide attempts with higher incidence in heavier users, and an increased incidence of suicide completion.

For prenatal, perinatal, and neonatal exposure, there is substantial evidence between maternal cannabis smoking and lower birth weight. During lactation, the amount reaching the infant is very low, although the effects of this are unknown. Therefore, it is recommended to not use cannabis in either pregnancy or breastfeeding.

There is substantial evidence for an increased risk of motor vehicle crashes. There is moderate evidence for increased risk of overdose, especially among pediatric populations. There is no or insufficient evidence for all-cause mortality, and there has been no documented death exclusively attributed to cannabis overdose or use. Cannabis has been shown in toxicology studies to be 114 times less lethal than alcohol. In fact, the deadliest substances in one toxicology study in order were alcohol, heroin, cocaine, tobacco, ecstasy, methamphetamine, and lastly, cannabis.



Cannabis hyperemesis syndrome (CHS) has become increasingly seen as states legalize cannabis. It presents with clinical symptoms of cyclical nausea/vomiting, diffuse abdominal pain, and the need to take frequent hot showers (this is a pathognomonic sign).

Episodes of these symptoms last 24-48 hours, may last 7-10 days, and often recur with re-exposure of cannabis. CHS tends to be associated with high-dose, high-THC regular cannabis use. It can be confused with CVS (cyclical vomiting syndrome), and is differentiated by a history of chronic cannabis use and frequent hot bathing which produces temporary relief. The etiology (cause) of CHS is not fully understood. It has been theorized that there is a dysregulation of the endogenous cannabinoid system by downregulation of CB1 (cannabinoid 1) receptors, and in the GI (gastrointestinal) tract this may slow gastric motility, causing hyperemesis. Genetic differences in the cytochrome P450 system (enzymes in the liver which metabolize drugs) has also been proposed. The TRPV1 receptor in our bodies interacts with the endocannabinoid system. More specifically, anandamide (our main natural endocannabinoid) works at this receptor (one of many). Interestingly, this receptor is also the capsaicin receptor, and is activated by heat such as in hot peppers (which contain capsaicin). Therefore, it has also been proposed that perhaps the fact that these patients take frequent hot showers/baths for relief is because they are indirectly activating their endocannabinoid system.

Treatment of CHS revolves around cannabis cessation. There is no way around it. Supportive therapy can assist with fluid resuscitation. Capsaicin 0.075% topically to areas of the abdomen, back of arms, and areas that hot water gives symptom relief have shown some benefit (not using on private areas or mucosal surfaces). Antipsychotics such as Haloperidol and Olanzapine showed some temporary benefit. Conventional antiemetics, antihistamines, serotonin antagonists, benzodiazepines have shown limited evidence for effectiveness, and opiates should be avoided.



Comparative addiction rates between substances have included tobacco 32%, heroin 23%, cocaine 17%, alcohol 15%, and lastly cannabis 9% (but 17% when used in adolescence, and 25-50% in adolescents who are using daily). Tolerance develops much faster with high potency high THC chemovars.

The DSM-5 recognizes 5 cannabis-associated disorders:

-Cannabis Use Disorder

-Cannabis Intoxication

-Cannabis Withdrawal

-Other Cannabis-Induced Disorders (Cannabis Intoxication Delirium, Cannabis Induced Psychotic Disorder, Cannabis Induced Anxiety Disorder, Cannabis Induced Sleep Disorder

-Unspecified Cannabis-Related Disorder

An estimated 3-4% of users meet criteria for Cannabis Use Disorder. The prevalence decreases with age, with the highest ages 18-29 years old (4.4%), and lowest ages 65 and older (0.01%). Cannabis Use Disorder is divided into mild (2-3 criteria), moderate (4-6 criteria), and severe (7 or more criteria). These criteria include any of the following:

  • Cravings and urges to use cannabis
  • Failure to fulfill major role obligations (work, school or home)
  • Unsuccessful attempts to quit/cut down
  • Spends excessive time in acquisition, using or recovering from use
  • Using Cannabis in larger amounts or for longer than you meant to (tolerance)
  • Continued use despite consistent social or interpersonal problems
  • Recurrent use in hazardous situations
  • Important social, occupational, or recreational activities are given up or reduced because of cannabis use
  • Needing more cannabis to get the effect you want (Tolerance)
  • Uses despite negative effects (physical or psychological)
  • Development of withdrawal symptoms, which can be relieved by taking more of the substance






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Last updated on October 24th, 2020 at 12:08 am




Menstrual migraine is very common, and one of many forms of migraine. Overall, migraine is estimated to effect about 18% of women and 6% of men. That is a 3:1 ratio. Much of that uneven ratio is due to the hormonal influence of migraine in women, particularly estrogen. Even more specifically, it is the drop in estrogen during the menstrual cycle which is the most common culprit for menstrual migraine (migraines during menses and outside of menses) and menstrual migraine (migraines during menses only).

Let’s first talk about some basic oral contraceptive facts. Estrogen and progestin are the components in combination oral contraceptives (COC). In most COCs, the estrogen is ethinyl estradiol (some older ones use mestranol). Most COCs nowadays are low dose COCs (35 mcg (micrograms) or less of ethinyl estradiol), which has less risk of thromboembolic (blood clot) events.

Combined hormonal contraception (CHC) also come as patches (Ortho Evra) and vaginal rings (Nuvaring). Patch users may be exposed to 60% more estrogen than in a 35 mcg ethinyl estradiol oral contraceptive, levels may not remain steady and peak values may be lower. The vaginal ring delivers 15 mcg ethinyl estradiol and 120 mcg etonogestrel, and is replaced every 4 weeks.

Contraceptive doses of hormones suppress ovarian function, prevent ovulation and pregnancy, and often provide “supraphysiologic” doses of hormones.

Hormonal therapy (such as ethinyl estradiol 20 mcg): do not suppress ovarian function, do not prevent pregnancy, and are for more physiologic doses. They are meant as estrogen replacement. Endogenous ovarian hormonal production is typically still occurring.



Most menstrual migraines occur in association with the drop in estrogen during the menstrual cycle. This occurs just prior to ovulation, at the end of the luteal phase if pregnancy does not occur, and during the placebo pill of oral contraceptives. It is recommended to use a monophasic pill containing 35 mcg or less of ethinyl estradiol (20-35 mcg of ethinyl estradiol is typical for most common formulations). Some data suggest 20 mcg pills may not sufficiently suppress ovulation. For women over 160 lbs, the 35 mcg ethinyl estradiol pills will be more protective than those with less than 35 mcg.

Here are a few options (certainly not an all-inclusive list) to discuss with your doctor to try to decrease menstrual migraine with combined hormonal contraception adjustments if you are using oral contraceptives:


1) Continuous extended release contraception:

-Cycle off to have withdrawal bleeding only as needed. Most commonly this is done every 3 months.

-Seasonale (levonorgestrel 150 mcg, ethinyl estradiol 30 mcg): 12 weeks of active contraceptive pill, followed by 1 week of placebo. This essentially results in 4 yearly menstrual cycles.

-Lybrel (levonorgestrel 90 mcg, ethinyl estradiol 20 mcg): active contraceptive pill taken continuously with no placebo intervals.


2) Add-back estrogen the week of placebo to minimize drop in estradiol:

-Mircette (desogestrel 150 mcg, ethinyl estradiol): 3 weeks of 20 mcg ethinyl estradiol; 2 days placebo; 5 days of 10 mcg ethinyl estradiol.

-Seasonique: Continuous extended-release oral contraceptive pill of 30 mcg ethinyl estradiol for 12 weeks followed by 1 week of low dose ethinyl estradiol 10 mcg.

-Ethinyl estradiol 10 mcg patch during placebo week.


3) Extended dosing regimens:

-Yaz (drospirenone 3000 mcg, ethinyl estradiol 20 mcg): 24 active oral contraceptive pills followed by 4 days placebo.

-Loestrin 24 (norethindrone 1000 mcg, ethinyl estradiol 20 mccg): 24 active oral contraceptive pills followed by 4 days placebo.



Women younger than age 45 who have migraine with aura, have a 2 fold increased risk of stroke, although this risk is still very low. This risk increases to 6 fold in the setting of oral contraceptive use containing estrogen, and rockets to more than 9 fold with combined smoking and oral contraceptive use. So, if you have migraine with aura, you can absolutely NOT be a smoker and use estrogen containing contraception, especially if you are under age 45!!! Women who are smokers and have migraine with aura should consider estrogen containing oral contraception a contraindication. You can read about migraine aura here. Notably, migraine without aura does not appear to have the same increased risk.

Oral contraceptive use in non-smoking women with migraine with aura is more controversial. The World Health Organization (WHO) and American College of Obstetrics and Gynecology (ACOG) suggest that in non-smoking women under age 35 with migraine with aura, there is an acceptable low risk of oral contraceptive use. However, in women over age 35, the risk is unacceptably higher and oral contraceptive use is contraindicated. According to the International Headache Society (IHS), in non-smoking women with migraine with aura who are either younger or older than age 35, taking into account other cardiovascular (heart disease) and cerebrovascular (stroke) risk factors should  individualize the decision for oral contraceptives with weighing the risks vs. benefits. These risks would include ischemic heart disease, family history of early heart disease at a young age of less than 45 years old, heart disease with concern for emboli such as atrial fibrillation, uncontrolled hypertension, hyperlipidemia, diabetes, obesity, systemic disease associated with increased stroke (connective tissue disease, sickle cell, hypercoagulability (blood clots)), etc. In women with an increased risk of stroke, and especially with multiple vascular risk factors, non-estrogen methods of birth control such as progesterone-only forms of contraception are recommended.

It is also suggested to avoid in women (and men) with prolonged migraine aura (greater than 60 minutes), migraine with focal neurologic symptoms (such as hemiplegic migraine), and basilar migraine (now known as migraine with brainstem aura).

The bottom line is if you have typical migraine with aura without any atypical features (for example, aura does not extend more than 60 minutes), are not a smoker, and do not have cardiovascular or cerebrovascular risk factors as mentioned above, estrogen containing contraceptives are not an absolute contraindication. However, you and your doctor should ultimately decide whether the benefits outweigh the risks. If these medications are used, the recommendation is to use the lowest dose possible, 35 mcg or less. Higher doses of estrogen have quite clearly been associated with increased stroke risk (many earlier studies showing this connection were done with higher doses such as 50 mcg or more). Migraine associated stroke (migrainous infarction)  is also discussed here. On the other hand, if you have migraine with aura, are under age 45, and are a smoker, the recommendation would be to avoid any estrogen containing contraception. Lastly, there doesn’t seem to be an increased risk with a progesterone-based pill. So, this is an alternative option to consider if you cannot use estrogen-based contraception, along with the many other non-estrogen options you can discuss with your gynecologist.



Lastly, here are a few tricks (but certainly not an all-inclusive list) often used only during the menstrual cycle (after discussing with your doctor) to try to decrease migraine frequency. These are called “mini-prophylaxis” strategies since these medications are used daily, but only around the menstrual cycle, as opposed to a daily continuous preventive medication taken for months at a time (which is always a good option too). The goals of these strategies is use medications that have a longer duration of action (last longer) in hopes of preventing migraine recurrence/return within 24 hours, typical of menstrual migraine, and to target the long duration (often multiple days) commonly seen with menstrual migraines:


Naratriptan (Amerge) 1.25 mg twice daily (half of a 2.5 mg tablet) beginning 1-2 days before expected onset of menstrual migraine, and maintained for several days through period. In addition, you may use Naratriptan 2.5 mg for breakthrough migraines, but no more than once daily (2 total doses per 24 hours).


Frovatriptan (Frova) 1.25 mg twice daily (half of a 2.5 mg tablet) beginning 1-2 days before expected onset of menstrual migraine, and maintained for several days through period. In addition, you may use Frovatriptan 2.5 mg for breakthrough migraines, but no more than once daily (2 total doses per 24 hours).


Naproxen Sodium (Anaprox) 550 mg twice daily beginning 2 days before expected onset of menstrual migraine, and maintained through period. Take with food. In addition, you may use your triptan at earliest sign of breakthrough migraines and may repeat once in 2 hours if needed.


Methergine (Methylergonovine) 0.2 mg three to four times daily beginning 2 days before expected onset of menstrual migraine and continuing through cycle.


DHE Nasal Spray (Migranal): 1 spray in each nostril by pointing away from face and not sniffing. Then, repeat one spray in each nostril in 15 minutes for a total of 4 sprays per dose. Repeat this dosing twice daily beginning 2 days before expected onset of menstrual migraine, and continue through period.


Cafergot (Ergotamine 1 mg/Caffeine 100 mg): 2 tablets at migraine onset, followed by 1 tablet every half hour until relief occurs. Do not take more than 6 tablets per headache attack or 10 tablets in a 7-day period.


Ergomar (Ergotamine): 2 mg sublingually followed by 1-2 mg every half hour until relief occurs. Do not exceed 6 mg per day and no more than 10 mg per week.


Rizatriptan (Maxalt) 10 mg + Dexamethasone 4 mg at menstrual migraine onset.


Nurtec ODT (Rimegepant) 75 mg starting 1-2 days before start of menstrual migraine and continue once daily for a few days during menses. There is no evidence for this currently and it is not commonly done, but given that Nurtec ODT seems to provide relief for 48 hours with a single dose, it could be worth trying given the long duration and high 24 hour recurrence typically seen in menstrual migraine. Ubrelvy (Ubrogepant) could be another consideration.

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Last updated on October 20th, 2020 at 06:52 am




Worldwide, migraine affects more than 10-12% of the population, with approximately 700 million migraineurs estimated worldwide.1 It is estimated that there are 38 million migraineurs in the US, accounting for 12% of the US population. Migraine affects 18% of women and 6% of men2,3. Nearly 25% of U.S. households include someone with migraine.


In 2016, migraine was determined to be the 2nd leading cause of all global disability, and the 2nd leading cause of all neurological disease burden4. Migraine accounts for 50% of all neurologic disability. Furthermore, chronic pain in general is the largest contributor to years lived with disability globally5, and is associated with tremendous negative impacts on social, economic, and personal function.


In addition to the attack-related disability, many sufferers live in fear because their migraines disrupt their ability to work, go to school, partake in social activities, or care for their families, and this significantly limits their overall quality of life. More than 90% of migraine sufferers are unable to work or function normally during their attacks. American employers lose more than $20 billion each year as a result of 113 million lost workdays due to migraine.6


Migraine treatment is divided into acute and preventive (prophylactic) therapy. Most existing preventive therapies are adopted from anti-epileptic, antidepressant, and antihypertensive medications. However, many of these medications are not well tolerated, resulting in poor compliance. Adherence to oral migraine preventative medication is around 26% at 6 months and declines to 17% at one year.7 This is often due to intolerable side effects. Many patients, due to lack of efficacy of preventative treatments, often resort to overuse of acute medications. This results in additional decline in quality of life and economic burden.8 Onabotulinumtoxin-A is currently the only FDA-approved treatment available for chronic migraine. However, most patients must fail at least three preventative treatments prior to receiving Onabotulinumtoxin-A. As such, Onabotulinumtoxin-A is typically a fourth line option for the prevention of chronic migraine. In addition, it is not approved for patients who have episodic migraine. There are 4 calcitonin gene related peptide (CGRP) monoclonal antibody antagonists that have been approved for the prevention of migraine.  There also exists a limited number of neuromodulatory devices. Lack of insurance coverage of these devices precludes their routine use in clinical practice.  This confers a large unmet need for additional preventive migraine treatments and additional therapeutic targets.


Migraine prevention is a key aspect to maintaining a good quality of life.  Abnormal neuronal membrane ion channels, low ionized magnesium levels, increased excitatory glutamatergic activity, and mitochondrial dysfunction with abnormal energy metabolism are associated with migraine. The goal of nutraceuticals is to target these factors in order to improve energy metabolism and reduce neuronal hyperexcitability in the brain. Patients often seek complementary and alternative medicine (CAM) for prevention of their headaches after finding standard prescription treatments intolerable due to side effects, or just ineffective. Many patients feel that “natural” substances are less toxic than prescription medications. Thus, the nutraceutical and herbal supplement industry is a multibillion-dollar industry. CAMs include, but are not limited to, nutraceuticals (vitamins and supplements such as magnesium, coenzyme Q10 (CoQ10), vitamin B2 (riboflavin), alpha lipoic acid, vitamin D, 5-HTP, fish oil, melatonin), and herbal preparations (butterbur, feverfew, ginger, and cannabidiol).


The use of CAMs has been significantly rising in the US and Europe9–12, and is becoming more evident especially in patients with migraine and other headache disorders. In a recent questionnaire-based survey in Germany and Austria, 81.7% of patients seen in tertiary outpatient headache clinics reported use of CAM13.  There are a multitude of different migraine related supplements on the market with variable combinations or sold separately as the individual components. Below, we discuss the most commonly used and studied supplements for migraine prevention.



  1. Magnesium

Magnesium has a Level B (2nd highest) evidence recommendation for migraine prevention by the American Academy of Neurology and American Headache Society.14 It is also rated highly and recommended by the Canadian Headache Society.15 This is a higher evidence recommendation than many of the prescription medications we use for migraine prevention. More than 325 enzymes are magnesium dependent, many of which are brain enzymes. Magnesium is involved in all reactions that involve the formation and utilization of adenosine-5′-triphosphate (ATP) in energy metabolism16–19. Proper magnesium levels are known to help normalize blood pressure, have anticoagulant, anti-platelet aggregating effects, regulate cell proliferation, protein synthesis, cellular energy and cell membrane stability, as well as blood sugar levels19–21. Studies have shown low levels of brain magnesium22,23 may be a contributor to migraine pathophysiology. Magnesium influences multiple steps in the current understanding of migraine pathophysiology including cortical spreading depression, serotonin receptor activity, neurotransmitter release, interference with inflammatory mediators, nitric oxide production, platelet aggregation, vascular tone, NMDA receptor interaction, production and release of substance P which activates pain fibers24–31. Magnesium is a mineral that functions as a coenzyme for various neurologic functions and other physiologic mechanisms.    According to two double-blind studies, high-dose oral magnesium supplementation appears to be effective in migraine prophylaxis. Trials have shown that magnesium supplementation is very effective in migraine treatment, with migraine attack reductions of up to 42%.32–37 Other studies have also shown benefit in migraine prevention when combined with coenzyme Q10 and feverfew as well.38 Magnesium (250 mg twice a day or 500 mg at bed) has a relaxant effect on smooth muscles such as blood vessels. We often give intravenous magnesium to patients who come into the emergency department for migraine because it helps to break the migraine. Three trials found 40-90% average headache reduction when used as a preventative. Magnesium also demonstrated the benefit in menstrually related migraine. Magnesium is part of the messenger system in the serotonin cascade and it is a good muscle relaxant. Some forms can be useful for constipation which can be a side effect of other medications used to treat migraine. Good sources include nuts, whole grains, and tomatoes.


There are different forms of magnesium, and we’ll discuss the most common types. Magnesium types can be tailored to patient characteristics as follows.39 Magnesium glycinate is a good choice for those with a sensitive stomach who have gastrointestinal side effects such as diarrhea with other forms of magnesium. It is anecdotally also helpful with anxiety and sleep. Magnesium threonate also has low risk of gastrointestinal side effects and anecdotally helpful with cognitive function and brain fog symptoms. Magnesium malate has low gastrointestinal side effects and is reportedly more energizing and anecdotally often helpful in fibromyalgia and chronic fatigue syndrome. Magnesium citrate is one of the most studied, popular, and well-absorbed forms of magnesium. It can also be mixed easily with liquids if you can’t take pills. However, it comes with a higher risk of diarrhea and gastrointestinal side effects, although this could be helpful for those with constipation. Magnesium oxide is also well studied, cheap, and often used for heartburn and indigestion. However, it is not well absorbed and can have some laxative side effects as well, so can also be helpful for constipation.


Dosing should generally be somewhere between 400-800 mg daily. It should preferably contain 24 mmol (600 mg) of elemental magnesium daily as magnesium citrate​ based on trials that showed benefit with this specific one more than others, and this is the recommendation of the Canadian Headache Society.15 If this type is not tolerated, other forms of magnesium as discussed above are certainly acceptable.


  1. Vitamin D3 (Cholecalciferol)

Vitamin D deficiency is a worldwide problem. Vitamin D is not actually a vitamin, but a hormone that the body makes from a type of cholesterol in the skin when it is exposed to UVB radiation from the sun. Small amounts also come from diet. It has anti-inflammatory activities, analgesic effects, may reduce nitric oxide and assists in magnesium and calcium absorption. Deficiency is suspected to play a role in mechanisms responsible for migraine and other pain syndromes, and vitamin D levels have been shown to be low in chronic migraineurs40. The best form is vitamin D3 (cholecalciferol) anywhere from 1,000 to 4,000 IU daily.


  1. 5-HTP (5-Hydroxytryptophan)

This is an amino acid that is made by the body from tryptophan (amino acid you get from your diet), and is involved in mood, sleep, and pain regulation. 5-HTP is typically produced from the seeds of the Griffonia simplicifolia plant. 5-HTP is converted into serotonin (5-hydroxytryptamine), an important brain neurotransmitter involved in migraine pathways and other neurologic pathways. 5-HTP is also converted into melatonin which aids in sleep, as well as dopamine, another important neurotransmitter. The effects of 5-HTP are felt to be similar to the antidepressants that are thought to increase the amount of serotonin available to the brain, and thus a mood enhancing chemical. Some studies have suggested that 5-HTP was as effective as some prescription migraine medications such as propranolol and methysergide (75% improvement in methysergide vs. 71% improvement in 5-HTP) in reducing the frequency and severity of migraines41–45. Side effects can include nausea, diarrhea, and stomach pain, and it should be used cautiously with medications which increase serotonin levels (such as most antidepressants) due to potential risk of serotonin syndrome. Typical doses are around 100–200 mg, 2–3 times per day with meals.


  1. Fish oil (Eicosapentaenoic acid (EPA) + Docosahexaenoic acid (DHA))

Fish oils are found in the tissues of fish. They contain a certain type of fat called omega-3. Potential mechanisms for anti-inflammatory effects of fish oil include inhibition of inflammatory mediators (eicosanoids and cytokines), and synthesis of lipid suppressors of inflammation (resolvins)46. Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DHA) give rise to these resolvins which are anti-inflammatory and inflammation resolving47. These compounds may relieve joint pain and stiffness in a similar way as non-steroidal anti-inflammatory drugs (NSAIDs)46,48. One study reported dramatic decreases in headache frequency (15 per month down to 2 per month) and decreases in headache severity (reduction from 5 to 3 on a 7-point scale)49. Fish oils have also been studied and found to be useful in other inflammatory conditions such as rheumatoid arthritis46,48,50–53. Large trials have showed a significant beneficial effect on pain, morning stiffness, number of painful and/or tender joints and NSAID consumption50. Recommended dosing consists of 30% EPA and DHA with a ratio of EPA to DHA of 1.5. Research suggests the minimum dose needed to reduce the joint inflammation associated with arthritis is 2.7 grams of omega-3 (EPA + DHA) daily, which could also be divided such as 900 mg EPA and 450 mg DHA twice daily.


  1. Melatonin:

Increasing evidence shows correlation between melatonin secretion and headache conditions. Melatonin supplementation has shown decreased headache intensity and duration. It is widely used as a sleep aid. Sleep is nature’s way of dealing with migraine. A dose of 3 mg is recommended to start for headaches including cluster headache. Higher doses up to 15 mg has been reviewed for use in cluster headache and have been used, if not making too groggy in the morning. The rationale behind using melatonin for cluster is that many theories regarding the cause of cluster headache center around the disruption of the normal circadian rhythm in the brain. This helps restore the normal circadian rhythm. It should be taken at least 2 hours before bedtime.



Mitochondria are the powerhouses within all cells of the body. These crucial metabolic organelles use oxygen to produce ATP, which is the primary energy source for the cell, and thus, for your body. Mitochondrial dysfunction leads to impaired oxygen metabolism and is suspected to play a role in migraine pathophysiology. Some migraineurs have been shown to have reduced mitochondrial activity which may lead to altered neuronal processing, and therefore a lower threshold for migraine attacks54–58. Riboflavin (vitamin B2), CoQ10 (ubiquinone; CoQ10), and alpha lipoic acid (thioctic acid) all play key roles in mitochondrial activity, and therefore have been implicated in migraine treatment by optimizing mitochondrial functioning.


  1. Riboflavin (Vitamin B2)

Riboflavin assists nerve cells in the production of ATP, a principal energy storing molecule. Riboflavin is an essential precursor to coenzymes involved in electron transport in oxidation reduction reactions within the Krebs cycle. This metabolic cycle is critical in production of ATP and generation of energy in the mitochondria, oxidative metabolism, maintaining membrane stability, and for all energy-related cellular functions59,60. It is necessary for many chemical reactions in the body. Brain riboflavin metabolism is suspected to affect migraine pathophysiology via several mechanisms, providing migraine preventive benefit.36,37


Riboflavin has a Level B (2nd highest) evidence recommendation for migraine prevention by the American Academy of Neurology and American Headache Society.14 This is a higher evidence recommendation than many of the prescription medications we use for migraine prevention. The Canadian Headache Society Guidelines strongly recommend B2 for migraine prevention as well.15 There have been at least 3 clinical trials of riboflavin using 400 mg per day all of which suggested that migraine frequency can be decreased. All 3 trials showed significant improvement in over half of migraine sufferers. Trials of riboflavin have suggested significant improvements in migraine by up to 59%61. Riboflavin (Vitamin B2): 200 mg twice a day (or 400 mg daily). The supplement is found in bread, cereal, milk, meat, and poultry. Most Americans get more riboflavin than the recommended daily allowance, however riboflavin deficiency is not necessary for the supplements to help prevent headache. One side effect to be aware of is that it can turn your urine bright neon yellow, although this is not harmful. Recommended dosing is 200 mg twice daily (or 400 mg once daily).


  1. Coenzyme Q10 (Ubiquinone; Ubiquinol; CoQ10)

CoQ10 is present in every membrane of all cells in the body62. Similar to riboflavin, CoQ10 plays a crucial role in electron transport and energy metabolism given its heavy involvement in mitochondrial function. CoQ10 is incorporated into the mitochondria, where it facilitates the transformation of fats and sugars into energy, thus it is often marketed to be an “energy enhancer”. Studies have shown that a nutritional supplement of CoQ10 can reduce the frequency of migraine attacks by improving the energy production of cells as with riboflavin. It also functions as an antioxidant by protecting against toxic oxidative reactions in the body, and CoQ10 tissue levels are known to decrease with age19,63. In one study, CoQ10 was found to be low in about 1/3rd of patients studied, and when replaced, headache frequency improved64. Migraine frequency was shown to improve significantly in more than 61% of patients in one study65, and 50% of patients in another study,66 supporting use for migraine prevention.36 Other studies have also shown benefit in migraine prevention when combined with magnesium and feverfew as well.38 The Canadian Headache Society guidelines strongly recommend use of CoQ10.15 Suggested dosing is around 150 mg-200 mg twice a day.


  1. Alpha Lipoic Acid (Thioctic Acid)

Alpha lipoic acid enhances the metabolism of oxygen and energy production by mitochondria67, and has shown reduction of migraine frequency68 when studied. Doses are typically around 300 mg twice daily.



  1. Feverfew (Tanacetum parthenium)

Feverfew is a common garden herb native to Europe and popular in Great Britain as a treatment for disorders typically controlled by aspirin. The mechanism of action is unknown but is believed to be related to a chemical called parthenolide which helps the body use serotonin more effectively. Serotonin helps prevent migraine and assists with resolution when it occurs. Parthenolide also inhibits the release of histamine which is linked to pain and inflammation. Consistency of active ingredients in different products can be a problem. Some formulations don’t have the active ingredient (parthenolide) that prevents migraine. A parthenolide content of 0.2% is generally recommended.


Feverfew has a Level B (2nd highest) evidence recommendation for migraine prevention by the American Academy of Neurology and American Headache Society.14 This is a higher evidence recommendation than many of the prescription medications we use for migraine prevention. The anti-migraine action36–38,69–75 of Feverfew is felt to be related to the parthenolides within the leaves. Studies have shown that the parthenolides provide anti-inflammatory and analgesic effects through several mechanisms involved in the migraine process that normally lead to pain. These include inhibition of phospholipase A, prostaglandin biosynthesis and platelet aggregation, and actions on serotonin including release of serotonin from platelets and white blood cells, as well as interaction at various serotonin receptor subtypes19,76–89. Study results have been variable based on wide variations in the strength of the parthenolides and differences in the stability of feverfew preparations used. However, a new, more stable feverfew extract (MIG-99) was created and showed a significant improvement in patients with high-frequency migraine90,91. The recommended dosing is generally around 50 mg twice daily (standardized to a high parthenolide content of 0.7% and stability measures of parthenolide), or, preferably MIG-99 6.25 mg three times daily if it can be found.


  1. Butterbur Extract (Petasites hybridus)

Butterbur is an extract derived from the petisides hybridus root, which has been used for medicinal purposes since ancient times. Butterbur is a well-researched and proven herbal supplements for migraine prevention36,69,70,92. For many years, it was the only supplement with a Level A (highest) evidence recommendation for migraine prevention by the American Academy of Neurology and American Headache Society,14 with a higher evidence recommendation than many of the prescription medications we use for migraine prevention. However, this recommendation was withdrawn a few years ago given a small handful of cases of liver failure reported in Germany. Although it is classified as an herbal supplement in the US, it is a licensed pharmaceutical medicine in Germany (Petadolex). Its two active compounds, petasin and isopetasin, help reduce cerebral blood vessel spasm and stop the inflammatory cascade which occurs in migraine93–95. Butterbur is thought to act through anti-inflammatory inhibition of leukotriene biosynthesis for its analgesic effects but also has calcium channel regulatory properties, both of which play a role in migraine19.


Studies have also shown anti-inflammatory effects mediated through inhibiting the additional inflammatory enzymes cyclooxygenase and prostaglandin production96. Notably, this is also what gives aspirin its anti-inflammatory effect. Trials have shown very positive results with significant decreases in migraine frequency of up to 58-77%, with 91% reporting overall improvement97–100. Side effects can include burping/belching. Raw butterbur root contains toxic chemicals that must be filtered out during the manufacturing process. To be sure you are choosing a safe product, look for a formulation that does not contain pyrrolizidine alkaloids since these are toxic to the liver. Recommended dosing is typically around 75 mg twice daily (free of Pyrrolizidine Alkaloids (PAs), standardized to contain a minimum of 7.5 mg of petasin and isopetasin).


  1. Ginger (Zingiber Officinale)

Ginger has anti-histamine and anti-inflammatory properties such as blocking pain-producing prostaglandins101,102, and helps with circulation and potentially headache. It is also widely used to treat nausea and vomiting, which accompany migraine103, and this is what it is primarily useful for. Recommended dosing ranges from 100-200 mg three times per day to 150 mg twice daily (standardized to contain 20% of gingerol and shogaol (dosage).


  1. CBD (Cannabidiol)

There have been a multitude of studies documenting the analgesic and anti-inflammatory benefits of medicinal cannabis across many chronic pain syndromes104–106, and it has been a historical treatment for headache and migraine for centuries.105–109 The vast majority of supporting evidence of cannabis and cannabinoids involves various chronic pain syndromes. These benefits are hypothesized to extend to headache disorders such as migraine given overlapping neurobiological pathways of pain. Some data suggests that cannabinoids appear to work uniquely within the inherent anatomical pathways of migraine (including serotonergic triptan pathways) and pain.104,105,107–139 Unfortunately, the majority of data supporting the use of cannabis and cannabinoids in migraine and headache disorders is based on case series, case reports, surveys and anecdotal evidence.105,107,145–154,108,155–161,134,135,140–144 There has been one retrospective study of cannabis use in the treatment of migraine which reported strong statistically significant findings of benefit.162 There have been only two limited prospective trials of cannabinoids containing a control group in headache disorders. One reported significant benefit in chronic daily headache associated with medication overuse headache,163 and the other reported significant benefit in both the acute and preventive treatment of chronic migraine.164


Given the growing evidence of cannabis and cannabinoids in the treatment of chronic pain and other medical conditions, in February 2019 The World Health Organization (WHO) recommended that cannabis be rescheduled and removed from the most restrictive scheduling category. In January 2017, the National Academies of Sciences, Engineering, and Medicine concluded that the use of cannabis for the treatment of pain is supported by well-controlled clinical trials and that there is substantial evidence that cannabis is an effective treatment for chronic pain in adults.165 In 2014, the Canadian Pain Society revised their consensus statement to recommend cannabinoids as a third-level therapy for chronic neuropathic pain based on the abundance of supporting evidence and a NNT (number needed to treat) estimated at approximately 3.166


Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the two predominant cannabinoids found in cannabis and are discussed in more detail here. CBD is several hundred more times anti-inflammatory than aspirin.104 There have been scientific, animal models, and limited human clinical trials documenting its anti-inflammatory and analgesic properties.167–176 In contrast to THC, CBD is non-intoxicating (no “high”).167 In November 2017, The World Health Organization (WHO) concluded that CBD exhibits no evidence for abuse or dependence potential, and that there is no evidence of public health related concerns associated with its use.177 In January 2018, the World Anti-Doping Agency (WADA) removed CBD from their prohibited list, no longer banning use by athletes.178


In December 2018, the Agriculture Improvement Act (Farm Bill) was signed into law in the United States. This legalized the agricultural growth and use of hemp (cannabis strains containing 0.3% THC or less) and hemp derivatives such as CBD, as well as removed hemp and its extracts (including CBD) from the Controlled Substances Act, making it no longer an illegal substance under federal law.


Thus, the use of CBD products has been exploding and is a new industry projected to exponentially increase into a multi-billion dollar industry179,180. Many patients are using these products for a variety of reasons181,182, most commonly in pain, including migraine prevention, given their easy access and availability. However, there are no studies evaluating CBD alone in treatment of migraine or any other headache disorders, so this is purely anecdotal. CBD products can readily be purchased online from a multitude of companies, in local health food and drug stores, and common retail pharmacies.183 CBD and suggested dosing (which are not currently clearly known) are discussed in much greater detail here.



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