Why the Menstrual Cycle may affect ADHD Medication Dosing Levels

Do hormonal fluctuations result in variable ADHD medication dosage levels across the menstrual cycle?

We have investigated the impact of gender on ADHD in a number of earlier posts. We have covered topics such as:

• Gender Based Metabolic Differences in ADHD brains

• Gender Dependent ADHD Genes, including MAOA, SLC6A2, SLC6A4 and COMT

• ADHD subtypes and Comorbid Disorders

Clearly, there are a number of boy/girl differences in the root causes, diagnoses and treatment methods for the disorder.

However, we need to investigate whether intra-individual differences are also an important factor, especially where medication treatment and medication dosing levels are concerned. Based on a number of studies, it appears that women may actually require different medication dosing levels depending on where they are in their menstrual cycle. Additionally, post-menopausal drugs such as estradiol patches may also alter the drug effects of certain ADHD medications such as amphetamines. The main culprits are most likely fluctuating levels of estrogen and progesterone.

Here are brief summaries on some of the relevant studies and their findings. Wherever possible, I will include a link to the original studies:

• The link between Estradiol treatment and amphetamine medications: This study focused on whether pretreatment with estradiol played any role in the reaction to amphetamines. The drug used in this study was D-Amphetamine, which would correspond to the medication Dexedrine, however, this is also the predominantly active compound in medications such as Adderall or Vyvanse (once this "pro-drug" is metabolized). It is unclear at the moment whether chemical "cousins" to amphetamines, such as methylphenidate (Ritalin, Concerta, Daytrana, Metadate), also exhibit these fluctuations when combined with estradiol-releasing drugs.
  
  The study found that for females who took estradiol-supplementing treatments during the early follicular phase (pre-ovulation) of the menstrual cycle experienced an overall greater "stimulating" effect of the amphetamine medication (taken as 10 mg of amphetamine). This may suggest that a slightly lower dosage during this stage of the menstrual cycle might be warranted, and (as this blogger's personal hypothesis) may actually affect the addiction potential of ADHD stimulant drugs such as amphetamines.
  
  
• Another study by the same group found that estrogen may be responsible for some of the heightened euphoric effect felt from amphetamine-based drugs. However, the hormone progesterone may actually counteract some of this euphoria. During the luteal phase of the menstrual cycle (after ovulation), high levels of both estrogen and progesterone are seen (although levels of both of these taper off going into menstruation), so the effects of estrogen may be curbed. During the late follicular phase, where progesterone levels are low and estrogen levels begin to spike, the "high" may be at its peak, especially if stimulants are involved.
  
  
• A case study found that an increase in inattentive symptoms coincided cyclically with the menstrual cycle for a patient who was undergoing treatment for newly-diagnosed ADHD with a twice-daily dosing regimen of the stimulant medication Concerta.
  
  
• The findings from these two studies suggest the possibility that a slightly smaller dosing schedule with amphetamine-based ADHD medications (such as Adderall, Vyvanse or Dexedrine) may be warranted during the follicular phase. However, during the luteal phase, when progesterone levels are higher, the amphetamine-based effects are less pronounced. This may correlate to a slightly higher dosing regimen for amphetamine-based treatment for ADHD and related disorders.
  
  
• While there is a relatively good theoretical basis for this assertion above, practical consideration measures must also be considered. Based on the relative scarcity of studies (besides the 2 mentioned above) on the amphetamine-menstrual cycle interactions, it is unclear as to how pronounced the medication change should be.
  
  For instance, should someone taking 10 mg of Adderall during the follicular phase boost up to 15 mg for the luteal phase? 20 mg? 30 mg? Additionally, hormonal fluctuations vary during the phases themselves, such as the estrogen spike during the late follicular phase. Questions abound, especially when dealing with the brief ovulatory phase as well.
  
  

This blog post hopefully introduces what may be a new consideration to women who have ADHD and are currently taking stimulant-based medication treatments. Perhaps this posting simply confirms what you have already experienced.

Nevertheless, given the fact that administering variable levels of medication based on cyclical patterns such as time of day (like ramping up methylphenidate concentrations via controlled release formulations to offset "acute tolerance" based effects), and the fact that individuals with ADHD may experience seasonal variations in symptoms, at least suggests, that variable dosing of medications across the near-monthly period of the menstrual cycle may prove to be beneficial treatment strategy for females with ADHD.

Ritalin and Cocaine: Similarities and Differences

We have previously investigated some of the similarities between the chemistry and modes of action of Ritalin and cocaine. In this past post, however, we looked more at the rates of uptake and metabolism of the two drugs and investigated a side-by-side structural comparison.

I was originally planning on continuing with posts on Daytrana, which is very similar to the more common ADHD medications Ritalin and Concerta (it is actually comprised of the same chemical agent, methylphenidate. However, I recently saw an interesting article on the topic of methylphenidate, cocaine and nicotine, and the mechanism of interaction between these different stimulants. As a result, in lieu of the Daytrana postings, I would like to discuss these findings in the next couple of posts.

Here are seven key points to be aware of regarding the similarities and differences between methylphenidate and cocaine:

1. SIMILARITY: Uptake patterns into the brain: Both methylphenidate and cocaine enter the brain at similar rates and target similar specific regions of the brain. When injected, around 7.5% of the injected compound makes it into the brain tissue for each compound at similar rates (peak uptake only takes around 2 to 8 minutes for cocaine and 4 to 10 minutes for methylphenidate in the injected form, oral administration, which will be discussed later, is significantly longer, especially for methylphenidate). The most favored target region of the brain is the striatum for both cocaine and methylphenidate (see brain diagram below). In fact, several studies have indicated that the two drugs share a number of target binding sites within the brain, to the point where the ADHD medication methylphenidate has actually been used as a treatment option for cocaine abuse.
   
   
2. Brain Regions Targeted by each drug: In addition to similar uptake patterns in the brain between the two drugs, there is a relatively large degree of overlap for particular brain regions targeted. However, there is at least one notable exception, which bears relevance to our discussion. On an interesting note, the method of delivery not only affects the speed of uptake of a drug (injected is almost always faster than snorted, which is almost always faster than ingested), but also the actual brain regions targeted by the drug. For example, another brain region, called the Nucleus Accumbens (see image below for approximate location) is targeted by cocaine and injected methylphenidate. However, when methylphenidate, such as Ritalin, Concerta or Metadate is taken orally, this nucleus accumbens region is not targeted (at least not anywhere near the level of injection).
   
   The nucleus accumbens is believed to play an important role in the addiction potential of a number of drugs, including many stimulant medications. Thus, proper use of the methylphenidate medication actually bypasses a key brain region believed to be critically involved in the "high" or addiction process of a stimulant drug. This highlights a major difference in the pharmacology between Ritalin and cocaine.
   
3. Key Difference between methylphenidate and cocaine: Rate of clearance from the striatum region of the brain: As mentioned in an earlier post, the addiction potential of a drug is typically correlated to the rate of exit or clearance from the brain. In other words, drugs that linger in the brain's receptors for extended periods of time are often much less addicting than ones which exhibit a short and rapid spike in their brain levels and then a quick drop-off in their concentration in the brain. In the striatum, the rate of clearance takes about 90 minutes for methylphenidate, and only 20 minutes for cocaine. If we go by peak concentration duration (i.e. the amount of time the highest concentration typically lasts in the brain before going back down), we see that methylphenidate's peak lasts around 15 to 20 minutes, while cocaine's is a fleeting 2 to 4 minutes. In both cases, the higher dissipation of the drug from high levels in the brain is much more pronounced in cocaine, giving this drug a much more addiction-worthy effect over methylphenidate (even when methylphenidate is abuses and either snorted or injected, it still cannot match the rates of clearance of cocaine).
   
   
4. Potency of the two drugs: The following may seem surprising at first. With regards to specific brain targets, methylphenidate is almost twice as potent as cocaine. We have discussed at length the role of the dopamine transporter protein (DAT), and its role in ADHD and related disorders. Essentially, this DAT protein is responsible for retaining a proper balance of the important brain chemical dopamine in and out of nerve cells. For individuals with ADHD, this balance is often skewed, typically with too much dopamine being taken up into the neuron cells and not enough in the gaps between the cells. Many stimulant medications remedy this problem by essentially binding to and plugging up the dopamine transporter proteins in the nervous system, which inhibits their abilities to shuttle dopamine into the cells. As a result of this medication-effected correction, dopamine balance can be somewhat restored. As a frame of reference, based on some of the current literature, it takes often takes at least a 60% saturation of these dopamine transporters with a drug to elicit the "high" (of course, there is a significant degree of variation between individuals).
   
   With regards to potency, we see that both cocaine and methylphenidate love to bind to these dopamine transporter proteins. To shut down the function of these dopamine transporter proteins to 50% of their original function (a common way of measuring the potency of a drug in pharmaceutical and laboratory testing), a 640 nanomolar concentration was needed for cocaine, while only a 390 nanomolar concentration was needed for methylphenidate to do the trick. If you're not familiar with these units of concentration, don't worry. These numbers work out to very small amounts (around the neighborhood of only 0.001 grams of drug per liter of fluid). I just put the numbers out there to show that only about half the amount of methylphenidate was needed to share the same effects with cocaine (i.e. the methylphenidate is approximately twice as potent for this particular process).
   
   
5. Difference between Ritalin and Cocaine: DAT saturation levels and perceived high: The relative saturation of these dopamine transporters are also believed to play a role in the "high" of stimulant drugs such as methylphenidate and cocaine. However, research by Volkow and coworkers found that while the level of saturation of the dopamine transporters with cocaine correlated with the "high" associated with this drug, the methylphenidate drug tells a different story. As mentioned previously, the reinforcing effects of a drug including the "high" typically correlate with the rate of clearance from the brain.
   
   We have also seen that methylphenidate clears much more slowly than cocaine. However, in the case of methylphenidate, the diminished effects of the the high occurred long before the drug had fully cleared from the dopamine transporter. In other words, there appears to be a relatively strong connection between the binding of cocaine to the dopamine transporter proteins and the perceived "high" but the effects are much less pronounced with methylphenidate. This highlights a major difference between methylphenidate and cocaine and at least suggests the possibility of a difference in mechanisms between the two stimulants.
   
   
6. Divergence in metabolic patterns between methylphenidate and cocaine: Furthering this issue a bit more, there is some evidence that the pathway of the two drugs is almost identical for the first part of the journey into the system, but their modes of action split off at some point when it comes to dopamine transporter occupancy and the corresponding reinforcement effects (see sketch below).
   
   
   
7. Difference between methylphenidate and cocaine: Drug lingering and tolerance: The persistence of methylphenidate on the dopamine transporter proteins may result in more than its reduction of abuse potential. It also appears that this "lingering" of the drug on these dopamine transporter proteins may also play a significant role in the phenomena of tolerance to methylphenidate.
   
   Acute tolerance to methylphenidate is nothing new. Newer formulations of the drug (Concerta, Metadate) were designed in part to address the problem of the reappearance of ADHD symptoms by ramping up and releasing increased levels of the drug throughout the day. This is important, because, the effects of methylphenidate appear to be best felt when its levels are climbing or building up, and not stabilizing (i.e. you do not want a constant level of methylphenidate throughout the day, but rather a constantly increasing one to maintain the same effects). Essentially, this is "micro-tolerance" to methylphenidate and is seen on a daily level. The ideal dosing strategy for methylphenidate typically entails a morning dosage which is approximately 50% of an evening dosage, i.e. a "ramping" effect of the drug throughout the day is often needed to maintain the desired results.
   
   It is suggested that this tolerance to methylphenidate may be due, at least in part to its continued presence and relatively slow clearance in specific areas, such as on the dopamine transporter proteins. Other faster-clearing drugs, such as cocaine, do not exhibit this property. However, given the fact that cocaine tolerance is also common, it is unlikely that the whole "dopamine transporter saturation" theory can fully address the issue of tolerance for stimulant drugs. Volkow and coworkers explored this role of blocking dopamine transporters with methylphenidate and the perceived high in greater detail. Nevertheless, at least in this blogger's personal opinion, the lingering effect of methylphenidate still plays some degree of significance to the process of tolerance to the drug, and the need for ramping its dosage to treat disorders such as ADHD.

How Addictive is Ritalin?

ADHD Medications

The controversy and discussion surrounding the safety of medications for ADD and ADHD is nothing new. Among the most common criticisms of these drugs are concerns about their abuse potential and their potential risks of being habit-forming drugs. Methylphenidate (the generic name for Ritalin and Concerta), has often been mentioned in the same sentence as "cocaine", especially among the "anti-medication" and "alternative treatment" sites for ADHD treatment options. While some of these comparisons are definitely warranted, the chemical structures and modes of action of ADHD stimulants such as amphetamines and the amphetamine-like methylphenidate and the illegal street drug cocaine do bear some striking resemblances. However, it is important that we do not get lost in the hype surrounding these relationships, and instead immerse ourselves in only the facts.

In the field of organic chemistry, even minor alterations to a drug's molecular makeup can result in significant functional differences. With this in mind, however, investigation into the abuse potential of stimulant ADHD medications such as Ritalin, Concerta, Daytrana, Adderall, Dexedrine, and Focalin should be carried out in a thorough, unbiased manner. A review article from the Journal of Clinical Psychiatry on the abuse potential of the ADHD drug methylphenidate investigated key properties of the drug that play a major role in abuse potential (such as drug absorption, products produced when the drug is metabolized, and how fast the drug clears from the body). Some key findings of the article on this popular stimulant medication are summarized below:

1. When injected, methylphenidate, cocaine, and d-amphetamine all produced similar reinforcing effects in human subjects (keep in mind that injections produce drug effects that occur much faster than those taken orally in almost all cases)
2. Sleep deprivation boosted the reinforcing effects of methylphenidate.
3. Methylphenidate displayed similar abuse potential to d-amphetamine for a number of studies of the general population (read "non-ADHD" population).
4. PET scans of the brain following methylphenidate and cocaine (when both were injected) showed similar absorption rates and binding levels to their target (called the Dopamine Transporter Protein or DAT. For more more info on the DAT and ADHD, please click here). However, methylphenidate was cleared much more slowly than cocaine, which correlates to a significantly lower addiction potential for the popular ADHD drug. A quick note about this: The faster a drug is absorbed in the brain, the greater the "high" is, typically. Since injections and snorting both get the drug into the system faster than when taken orally, these methods typically lead to much greater highs and addiction potentials. Additionally, the faster this drug is then cleared, the more it is "missed" by the brain, which also results in a greater addiction potential. So for a fast-acting and fast-clearing drug, the addiction potential is typically very high. For comparison sake, methylphenidate takes about 10 minutes to enter the brain when injected (for cocaine, it is about 5 minutes), and then takes about 90 minutes to clear halfway (for cocaine it is around 20 minutes). Thus, due to its slower uptake and even slower clearance rate, methylphenidate runs a much lower risk of being habit-forming than cocaine.
5. Oral administration of methylphenidate is much slower than this, often taking at least 1-2 hours to peak in concentration in the brain. Extended and slow-release versions of the drug (Concerta, Ritalin-SR) reduce the abuse potential even further.
6. Individuals with ADHD are thought to have a higher amount of binding sites (DAT, see point #4) for these stimulant medications than do those without ADHD. According to the author, this makes individuals with ADHD less susceptible than the general population to habit-forming addictions surrounding the use of the stimulant methylphenidate. A more detailed explanation for this is given below:

Further explanation for Item #6 above: Although neuroscientists still disagree over the mechanism of action of both medicated and illegal stimulants, it is believed that when this DAT protein is "plugged up" or "blocked" by these stimulants, it cannot shuttle free amounts of the brain chemical dopamine into the surrounding cells. As a result, the levels of free dopamine between neuronal cells builds up. Since dopamine plays a key role in the "reward" process, it can also play a major role in both "highs" and "addictions" (both of which seek out these "rewards").

If individuals with ADHD have more of these transporter proteins to begin with, they are less likely to oversaturate all of these transporters. As a result, they are less susceptible to this dopamine buildup and the highs and addiction potentials that go along with it. In other words, individuals with ADHD can often accommodate higher levels of stimulant medications such as methylphenidate, making them less susceptible to addiction-level effects.

Based on this article and a number of other sources I have either read or followed, here is my overall take on the topic of addictions to ADHD stimulant medications:

I earnestly believe that when properly diagnosed, properly monitored by a competent physician or related professional, and by proper compliance by the medicated individual, ADHD medications are relatively safe, and the risk of developing an addiction a medication such as methylphenidate is relatively low.

Of course, as we've seen above, individuals who are not diagnosed with ADHD and take methylphenidate for recreational purposes, the potential habit-forming effects of the drug can at least approach the levels of cocaine or amphetamines. Keep in mind that the right medication at the wrong dosage can easily be just as (or even more) damaging than having the wrong medication.

Yes, stimulant drugs prescribed for ADHD are often closely related to cocaine in both chemical structure and mode of function, but the small differences between the two are sufficient enough to form a "safety barrier". Given the fact that so many undiagnosed individuals with ADHD or other related disorders often tend to "self-medicate", the dangers of "un-treatment" are just as real and just as hazardous. Keep in mind that "self-medication" is, by nature, a much more erratic form of treatment and typically abounds in negative side effects.

This is not to say that non-medication treatments should never be explored or considered as viable options for treating ADHD. Many of the so-called "alternative treatments for ADHD" are surprisingly well-grounded and increasingly-researched. However, I remain highly skeptical to those who claim that all cases of ADHD can be handled exclusively and completely by natural means. Natural remedies can be very effective for numerous cases involving ADHD, but their scope and range of applications are somewhat limited.

Please check back later for future posts related to many of these important topics on ADHD!