Inquiry about Methylation and Mental Health Issues

[francesbe]

Hello all,

I am new to the world of methylation and am seeking guidance understanding the implications of my methylation mutation profile posted here, as it relates to mental health issues.

Thank you in advance,
B.

 

[ahmo]

@francesbe I don't have the wherewithal to comment on your profile specifically. but I can tell you that I've had excellent results in eliminating my anxiety symptoms, insomnia, mood swings, bringing a level of calm to my life that I'd thought impossible. As I increased B12/folate, the insomnia resolved and calm became my norm.

I started w/ diet, eliminating gluten and dairy, going high fat. You might need to be low sulfur, as Sterling would have indicated. I've also needed to eliminate histamines. Adding low dose lithium orotate stabilized my mood swings. Correcting for other mineral imbalances, especially for pyroluria, greatly affected my mental state. And detox provided incremental shifts in both my physical and mental symptoms, eventually de-stressing my adrenals.

As you'll no doubt have read elsewhere, it's a marathon, not a sprint. Perseverance furthers. You're at the right place for ongoing advice and support.

Linking a questionnaire re pyroluria, which could help w/ specific supps.
http://www.hputest.nl/evraag.htm Online questionnaire to suspect pyroluria

 

[francesbe]

Thank you ahmo. I'm already gluten free (mostly), but still consuming dairy. Otherwise your recommendations are in line with the plan I've formulate for myself thus far. I've started taking l-methylfolate and I should have my hydroxy B12 and lithium orotate tomorrow. What lithium orotate dose are you taking?

 

[ahmo]

I started out at 1/2 of a 10mg cap. Interestingly, after a long period of detox, most of my other mineral needs < (I dose by self-testing). but Li has >. It seems, according to comments on these threads, that it helps w/ B12 absorption. I'm currently using 5mg AM/PM.

I've just been compiling some of Freddd's most recent comments re hydroxyB12. You can see more in the guide attached to my signature. I know others recommend it. It never helped me, and here are a few of Fred's comments.

http://forums.phoenixrising.me/index.php?threads/b-12-the-hidden-story.142/page-161#post-485465
...The theory that HyCbl should work better for some genetics may come from massively reduced effectivness. It doesn’t cause all those nasty side effects of healing like low potassium symptoms, low folate symptoms and in reference to nerves, the increased feeling of pains that freshly stimulated nerves that hadn’t been working have. When an area comes back from not feeling, what is felt is the damage; with shooting pains, intense steady pain, painful tingling, more awareness of the shrinkage and therefore tightness of the muscles and all that. Again, I can only speak from repeated experience. Active healing can be painful. Shutting down the damaged nerves reduces the pain. What I said to myself 11 years ago is that the whole thing is counter intuitive. Many people say “what awful side effects” from the increased pains, the misery of low potassium and increased inflammation and pain from donut hole paradoxical folate deficiency/insufficiency and make sure that they never again do what could heal them over a period of time.

I don’t know of anybody who has healed from FMS/CFS/ME doing it with HyCbl. Many have some improvements and other things get worse. In every study done on HyCbl (and they are not designed to actually produce healing) there is about a 2/3 chance that a subject could have some improvement and 1/3 have no improvement at all for the studied symptoms. I have been offering information here and debugging my hypothesis and protocol for 5 or 6 years now. In all that time I have not seen anybody at all announce that they have corrected their problems to the point of returning to work, walking 5 miles daily, climbing a 2000 foot vertical hill, get back into decent aerobic condition and get their muscles restored. So whatever people interpreting the tests to mean advise on HyCbl doesn’t appear to work.. I can only chalk up all your apparent contradictions to various ways things work partially or not at all. The whole thing is complicated.

Where the people are having results the conversation changes all the time as they no longer have a problem with one symptoms set and turn their attention to others. That is why the active b12s and folate lead to need for more folate, need for potassium, need for a dozen other things, until it gets down to making adjustments in b1, b2 and b3 because those are what lead to specific predictable results. HyCbl rarely leads to solving a succession of half a dozen things or more. So far nobody can describe a healing path that starts with HyCbl through the flags of healing being turned on to secondary and tertiary insufficiency or over sufficiency symptoms. There are no predictions that can be made ( nervous system turning on, low potassium and folate shortly after starting) and predictions of what works for that after the initial things are cleared. And of course these are multi substance problems. In my opinion it works out better if one thinks in terms of partial methylation block, methyltrap and partial ATP block. HyCbl doesn’t generally correct these and can even cause them over time. MeCbl and cofactors can often correct these if given a chance. Damage can take years to heal if at all for some damages.

...With HyCbl it is very much a percentage thing. It works to a greater or lesser extent for some symptoms for often some while, and also dependent upon perhaps a dozen other factors. For every one of us a major part of the problem is finding an effective balance. HyCbl does cause side effects. And just like folates and other cobalamins, it happen by some number of levels, frequently giving paradoxical looking results. So with HyCbl it does clearly work on some levels for some duration for some people. It is also quite probable to have these contradictory results. And so much depends also upon dose of B1, B2 and B3 which can ramp up the low potassium effect and donut hole folate insufficiency with unpredictable results on healing. There are no hard and fast answers to anything. If one takes a look at a lot of research on HyCbl a large range of possible result occur. For some tiny percentage of people their responses are virtually identical, at least for the duration of an x-month study, to MeCbl or AdoCbl. The question is “why?”. What makes such a person predictable in that response. What happens over time to the other handful of “triage” levels some of which will be working some not. Rich thought that a lot of that has to do with cofactors, like B1, B2, B3 and many others. Whether MeCbl or AdoCbl work at all or not is whole dependent upon cofactors. Lack of an effective folate for one’s body can completely prevent MeCbl from working as can lack of AdoCbl or lack of Vit D.

HyCbl typically has a lot of effect on a few of the universe of MeCbl/AdoCbl symptoms, less effect on a bunch more and no effect or negative effect on others, and that varies from person to person. In studies, the symptoms studied have about 1/3 of subjects not responding with changes in the study symptoms, and 2/3 responding to some degree. However, when looking at the whole person with perhaps hundreds of symptoms, HyCbl hasn’t demonstrated any substantial ability to allow many people to say “I’m largely recovered from FMS/CFS and am going back to work and living my life”. That doesn’t mean it has no effects. It has partial and contradictory responses and perhaps complete responses on a few symptoms.

I would love to see a good study with various protocols going head to head with enough people to be meaningful. Then have say a series of physical activities impossible for people with CFS/FMS and see who is effectively recovered and able to do these activities. We see that happen all around us here but nobody is keeping track. I know of quite a few people restored to normal functioning. That doesn’t mean they don’t still have a variety of symptoms from damage and various deficiencies. I’m pretty normally capable for a guy my age, 66. I’m more in need of a fountain of youth rather than a “cure” for anything. My remaining symptoms are from physical damage and neurological damage from long term b12 deficiencies. I don’t have CFS or FMS any more. I don’t have the symptoms to diagnose them. I don’t feel like I have them as they are not quiet about affecting a person. That is all I’m trying to say.

 

[Critterina]

I am new to the world of methylation and am seeking guidance understanding the implications of my methylation mutation profile posted here, as it relates to mental health issues.
B.

@francesbe , Hi B.!

Mental health issues are most commonly associated with your MTHFR A1298C GG +/+ SNP. The MTHFR enzyme catalyzes (facilitates) a reversible reaction. While those with the C677T SNP have trouble turning folinic acid into methyl folate, those with the A1298C SNP have trouble turning methyl folate into folinic acid. These are sometimes called forward and reverse reactions, respectively. Although it's somewhat of an oversimplification, I think of these things as trying to maintain equilibrium. If you add more of one, it makes more of the other.

The mental health issues are not caused by the levels of methylfolate or folinic acid, but by what happens to another chemical, biopterin, when the reaction takes place. The two forms of biopterin are dihydrobiopterin (BH2) and tetrahydrobiopterin (BH4). BH4 is the "active" form used to make neurotransmitters, and a shortage of BH4 is associated with mental health issues: anxiety, depression, bipolar, schizophrenia, autism, OCD, ADHD, to name a few. (Plus other issues: irritable bowel, fibromyalgia, chronic fatigue, dementia, Parkinson's, migraines.) There are undoubtedly other mechanisms at work in these diseases, but some people, like @ahmo , fortunately find that supplements that favor creation of BH4 help relieve some of the mental health issues.

By now you might have guessed that it's the "backward reaction", the one that turns methylfolate into folinic acid and is impeded (slowed down) by having the A1298C SNP, that makes BH4. I think of it this way:

methylfolate + BH2 ---> folinic acid + BH4 (facilitated by MTHFR enzyme, slowed down by A1298C SNP)

So, by supplementing methylfolate, you force the reaction to make more BH4. More BH4 means more serotonin and dopamine. As you may know, serotonin and dopamine are important in themselves, but they also get turned into all kinds of other neurotransmitters, although the only one that comes to mind right now is melatonin.

A word of caution: in messing with your neurotransmitters, some people find that they can overdo it easily. The watch-phrase here is "Start low and go slow", meaning start with a tiny dose and increase gradually. If you start getting drastic mood swings or go too far one way or the other, time to start over and see if something else needs to be taken into consideration. And if your face/scalp starts breaking out, or there are other (different) symptoms, look up "deadlock quartet" and "paradoxical folate deficiency" - it usually means you've started healing and your body is demanding more methylfolate, not less. (This is not scientifically proven, but seems a common experience among the people on this site, including me.)

Methylfolate is available for mental health issues in prescription strengths of 7.5 and 15 mg, and over the counter in 400 mcg, 800 mcg, and 1 mg strengths. Solgar seems to be the brand preferred by many people on this forum, and it's what I use.

I usually use 1 mg/day, but can tolerate several mg/day. After using it for a couple of months, I needed more for a while. And when I didn't have any for a week, my face broke out, and now I'm back to 2 mg for a couple of weeks. Personally, I also have to supplement tryptophan, which is the precursor to serotonin (but not tyrosine, which is the precursor to dopamine - go figure!). Serum amino acid tests showed that my tryptophan went to half of low-normal when I started supplementing methylfolate. (It stayed low, even when I took 500 mg of tryptophan, so now I take 1500 mg.) I think this is valuable information, so I am glad I had the amino acid test before and during supplementation.

So, this is what I think I know. Hope you find it useful.
Crit

 

[Freddd]

Hello all,

I am new to the world of methylation and am seeking guidance understanding the implications of my methylation mutation profile posted here, as it relates to mental health issues.

Thank you in advance,
B.

Hi Francesbe,

I know of no reliable "methylation mutation profile" that will tell you what you want to know. However, deficiencies of the CSF/CNS of Methylcobalamin, Adenosylcobalamin, L-methylfolate and L-carnitine fumarate specifically can cause depression (I had lifelong depression that started relieving with the first dose of Methylcobalamin), anxiety, panic, fear, paranoia, paranoid psychosis, OCD, rage, homicidal rage, anger, rapidly shifting emotions, multi sensory hallucinations, "Parkinson's personality", psychosis ("the most florid psychosis known to mankind"), dementia, cognitive deficits of all kinds and just about every kind of personality changes and mood problems can be caused by these deficiencies or the damage done by these deficiencies.. These can be a combination of functional lack as well as neurological damage. These are all neuro psychological problems. Whether you want to consider these issues of mental health or not is a matter of definition.

There are no symptoms from HyCbl deficiency. There are no HyCbl deficiencies. The body has no need for HyCbl. There are a few functions that HyCbl can perform, but usually not as well as MeCbl and/or AdoCbl. There are a couple of hundred possible MeCbl and AdoCbl deficiencies neuropsyc symptoms. They are BOTH required to correct the functional symptoms as well as partially correcting damage from long term deficiencies. HyCbl which is at best effective for some partial body effectiveness (reducing MCV) has almost no neurological effectiveness but it can increase the biochemical problems leading to neuropsyc symptoms.

There was just a study published that linked gene variations to Schizophrenia. "The scientists identified about 128 independent genetic variants at 108 locations on the human chromosomes that contribute significantly to susceptibility to schizophrenia – 83 of these sites have never before been linked to the illness, the scientists said."
http://www.independent.co.uk/life-s...through-points-at-over-100-genes-9619638.html

This list is a general list of the symptoms that respond to the specified nutrients. It is not a detailed list of neuropsyc symptoms so much detail may be missing.

SYMPTOMS LIST

In this post this is a list of symptoms that are mine, and others experiences of these nutritional items in relieving their symptoms, and in a very few instances reflect research and successful practice, such as p5p for Hcy and Liver extract studies of several disorders in old journals. In some instances the same symptoms might have different combinations of nutrients.

These symptoms responded almost entirely or entirely with basics 5 star MeCbl – methylcobalamin – Methylb12 - Mb12 - Mecobl . Many started improving in hours. Others took 9 months to correct.

morning joint stiffness and pain
paleness
acid reflux
nausea
daily vomiting
standing with eyes closed, lose balance
hands feel gloved with loss of sensitivity - glove anesthesia
feet feel socked by loss of sensitivity - stocking anesthesia
glove and stocking anesthesia
neuropathic bladder
unable to release bladder, mild to severe
unable to fully empty the bladder
fecal incontinence - occasionally to frequently
diminished hearing - gradual onset or present for life, sudden return possible
tinnitus - ringing in ears
always feeling cold
intolerance to loud sounds
intolerance to multiple sounds
sleep disorders
non restorative sleep
Night terrors
Prolonged hypnagogic or hypnopompic states transitioning to/from sleep
Sleep paralysis
alteration of touch all over body, normal touch can be unpleasant and painful
alterations and loss of taste
taste hallucinations
smell hallucinations
sound hallucinations
visual hallucinations
alterations and loss of smell
loss of smell and taste of strawberries specifically
loss or alteration of smell and taste of potato chips specifically
roughening and increased raspiness of voice, mb12 can smooth in mid word
blurring of vision - can be sudden onset and sudden return
Visual impairment can be seen; ophthalmological exam may show bilateral visual loss
optic atrophy
centrocecal scotomata
hypersensitivity/intolerance to bright light
intolerance to loud sounds
intolerance to multiple sounds
burning muscle pain
diminished hearing - gradual onset or present for life, sudden return possible
tinnitus - ringing in ears
sore burning tongue

This is a list of symptoms that are mine, and others experience of these nutritional items in relieving their symptoms, and in a very few instances reflect research and successful practice, such as p5p for Hcy and Liver extract studies of several disorders in old journals. In some instances the same symptoms might have different combinations of nutrients.

These symptoms responded strongly first to 5 star MeCbl and then Metafolin with basics. Many started improving in hours. Some took 7 years to correct.

Bursitis
stomach not emptying
frequent vomiting
acid regurgitation
dyspepsia
flatulence
altered bowel habits
abdominal pain
loss of appetite for meat, fish, eggs, dairy, the only b12 containing foods
nutrient specific anorexia
intermittent constipation
intermittent diarrhea
irritable bowel syndrome
sores, ulcers and lesions along entire GI tract or any part
anorexia
Bulimia
Hypersensitivity to touch
Hypersensitivity to odors
Hypersensitivity to tastes
Hypersensitivity to clothing texture
Hypersensitivity to body malfunctions, symptoms
Hypersensitivity to sounds and noises
Hypersensitivity to light and visual stimuli
Hypersensitivity to blood sugar changes
Hypersensitivity to internal metabolic changes
Hypersensitivity to temperature changes
burning bladder (no UTI)
painful urgency (no UTI)
burning urethra (no UTI)
Low blood serum level - below 550pg/ml, Japanese Standard
elevated MCH (Mean Corpuscular Hemoglobin)
elevated LDH
big fat red cells (when said this way usually with happy or healthy modifying it completely misinterpreting results of MCV
platelet dysfunction, low count
white cell changes, low count
hyper segmented neutrophils
headaches
inflamed epithelial tissues - mucous membranes, skin, GI, vaginal, lungs
inflamed endothelial tissues - lining of veins and arteries
mucous becomes thick, jellied and sticky
asthma
chronic cough that mimics asthma but isn't
chronic sinus congestion
dermatitis herpetiformis, chronic intensely burning itching rash
frequent infected follicles or acne type lesions all over body
chronic infections, many varieties possible
Seborrhic dermatitis
dandruff
eczema
dermatitis
skin on face, hands, feet, turns brown or yellow if anemia occurs
poor hair condition
thin nails
transverse ridges on nails, can happen as healing starts
mouth sensitive to hot and cold
sore burning tongue
beef-red tongue, possibly smoother than normal
sore mouth, no infection or apparant reason
teeth sensitive to hot and cold
canker sores


with p5p added

Elevated blood serum Hcy, borderline or higher


These symptoms responded relatively partially first to 5 star MeCbl and then very strongly to Metafolin with basics. Many started improving in hours. Some took 7 years to correct.




splits/sores at corners of mouth -angular cheilitis
impaired white blood cell response
poor resistance to infections
easy bruising
pronounced anemia
macrocytic anemia
megablastic anemia
pernicious anemia
decreased blood clotting
MCV > 93 first warning,
MCV > 97 alert
MCV > 100 outright macrocytosis
MCV > 105 urgently needs treatment, severe problem

Plus Vitamin E
Child with neural tube defects

mother of child with neural tube defect

These symptoms responded not at all first to 5 star and then very strongly to Metafolin with basics. Many started improving in hours. Some took 7 years to correct.


lack of dreaming
MCV > 100 outright macrocytosis
macrocytic anemia
metallic taste in mouth
Widespread body & muscle pain responding to NSAID
Joint pain responding to NSAIDS
splits/sores at corners of mouth -angular cheilitis


Sexual related symptoms, both men and women – These responded with the most response to lesser responses in order to MeCbl, Metafolin (l-methylfolate), AdoCbl, L-carnitine fumarate

reduced libido - loss of sexual desire
loss of orgasmic intensity
unsatisfying orgasms
inability to orgasm
loss and/or change of genital sensations
burning genital skin sensation
unable to feel aroused
numb genital skin
low sex hormones

MEN

In order of response – MeCbl, AdoCbl
low testosterone men

In order of response – MeCbl, Metafolin, AdoCbl, L-carnitine fumarate
erectile disfunction men

In order of response – MeCbl, Metafolin, AdoCbl
low sperm count
poor sperm motility
Poor sperm quality
no sperm


WOMEN

In order of response – MeCbl, AdoCbl
low testosterone
low estrogen

In order of response – MeCbl, Metafolin, AdoCbl, L-carnitine fumarate
post partum depression
post partum psychosis

In order of response – MeCbl, Metafolin, AdoCbl
Frequent miscarriage

In order of response – MeCbl, Metafolin
False positive pap smears, defective cells
menstrual symptoms


Approximate timing of my startup of individual items that being considered here, this gives a quite distinctive pattern for each nutrient or set of nutrients: 03/04/13, Version 1.1

Others mentioned similar patterns and variations.

1. Initially – Mecbl

2. +5 months 400mcg SAM-E

3. + 4 months AdoCbl

4. + 3 months titrate +50mg zinc

5. +4 years 400mcg Metafolin

6. +1 year LCF

7. + 1 month TMG 1000mg/day

8. 30mg MeCbl injections (3 or 4) daily,

9. +0 Reduce SAM-e to 200mcg

10. + 4 years remove TMG

11. +6 months increase SAM-E to 800mcg

12. Next 1 year titrating Metafolin and finding all the reasons I get folate insufficiency, early partial methylation block by effect.



These symptoms are what responded very well to CNS penetrating doses of MeCbl either as 50mg sublingual single 4-5 hour dose or 4 x 7.5mg or 3 x 10mg or for some 2 x 15mg subcutaneous MeCbl injections. Metafolin in some way enhances retention of AdoCbl and MeCbl with excretion visibly decreased. A sublingual dose of 1-2 tablets each hour added for 12 hours appears to generate substantial CNS penetration as well.



CNS penetrating dose MeCbl – AdoCbl – Metafolin – Omega-3 oils


Elevated CSF Hcy
Low CSF cobalamin
limbs feel stiff
Drowsy


CNS penetrating dose MeCbl – AdoCbl
dimmed vision - usually not noticed going into it because change can be very slow or present for life
Clumsiness


CNS penetrating dose MeCbl – AdoCbl - Metafolin


Slow to adapt to night vision


CNS penetrating dose MeCbl – AdoCbl – Metafolin – LCF


Difficulty in word finding



CNS penetrating dose MeCbl – AdoCbl – Metafolin – Omega-3 oils


Brainstem or cerebellar signs or even reversible (with mb12) coma may occur
demyelinated areas on nerves
subacute combined degeneration
axonal degeneration of spinal cord
unsteadiness of gait
ataxic gait, particularly in dark
positive Romberg
positive Lhermittes
Loss of motor control over some or all of toes
Loss of motor control over part or all of feet
Loss of sense of joint position
sudden electric like shocks/pains shooting down arms, body, legs shooting down from neck movement
sudden "ice pick" pain
decreased reflexes
brisk reflexes
Foot Drop
tripping over toes
injuring toes catching top of toes on floor
general feeling of weakness


Approximate timing of my startup of individual items that being considered here, this gives a quite distinctive pattern for each nutrient or set of nutrients: 03/04/13 Version 1.1

Others mentioned similar patterns and variations.

1. Initially – Mecbl

2. +5 months 400mcg SAM-E

3. + 4 months AdoCbl

4. + 3 months titrate +50mg zinc

5. +4 years 400mcg Metafolin

6. +1 year LCF

7. + 1 month TMG 1000mg/day

8. 30mg MeCbl injections (3 or 4) daily,

9. +0 Reduce SAM-e to 200mcg

10. + 4 years remove TMG

11. +6 months increase SAM-E to 800mcg

12. Next 1 year titrating Metafolin and finding all the reasons I get folate insufficiency, early partial methylation block by effect.


These symptoms are what responded very well to L-carnitine fumarate AND AdoCbl for the first two items


L-carnitine fumarate – AdoCbl – Metafolin - MeCbl


weight loss involuntary
muscular atrophy
exercise does not build muscle



L-carnitine fumarate – Metafolin – AdoCbl - MeCbl

weight gain, watery fat
edema


L-carnitine fumarate – AdoCbl – MeCbl – Metafolin


mild to extremely severe fatigue
continuous extremely severe fatigue
easy fatigability
severe abnormal muscle fatigue up to and including apparent paralysis leading to death
weakness
muscle pain especially around attachment points to bones
Eighteen severely tender muscle spots of FMS



AdoCbl – L-carnitine fumarate


exercise debilitates for up to a week, making things much worse
accumulating muscle pains following exertion
sore muscles throughout body
lack of muscle recovery after exercise
High urinary MMA



AdoCbl – L-carnitine fumarate – Metafolin

congestive heart failure
Elevated CSF MMA
Elevated uMMA


Approximate timing of my startup of individual items that being considered here, this gives a quite distinctive pattern for each nutrient or set of nutrients: 03/05/13, Version 1.1

Others mentioned similar patterns and variations.

1. Initially – Mecbl

2. +5 months 400mcg SAM-E

3. + 4 months AdoCbl

4. + 3 months titrate +50mg zinc

5. +4 years 400mcg Metafolin

6. +1 year LCF

7. + 1 month TMG 1000mg/day

8. 30mg MeCbl injections (3 or 4) daily,

9. +0 Reduce SAM-e to 200mcg

10. + 4 years remove TMG

11. +6 months increase SAM-E to 800mcg

12. Next 1 year titrating Metafolin and finding all the reasons I get folate insufficiency, early partial methylation block by effect.





MeCbl - AdoCbl – L-carnitine fumarate – Metafolin

shortness of breath, oxygen hunger
heart palpitations


MeCbl - AdoCbl – L-carnitine fumarate

extremely sore neck muscles reversing normal curvature of neck
painfully tight, stiff muscles, especially legs and arms
frequent muscle spasms anywhere in body
weak pulse



MeCbl - AdoCbl

Confusion
Disorientation
Difficulty in word finding


MeCbl - AdoCbl - Metafolin

irritable
depression
SAD - Seasonal Affective Disorder
mental slowing
personality changes
chronic malaise
poor concentration
moodiness
tiredness
mood swings
memory loss
listlessness
impaired connection to others
mentally fuzzy, foggy, brainfog
dizziness - even unable to walk
Vertigo


MeCbl – Metafolin – AdoCbl – L-carnitine fumarate

psychosis, including many of the most florid psychoses seen in literature, megaloblastic madness
Alzheimer's
delirium
dementia
paranoia
delusions
hallucinations - multisensory
anxiety or tension
nervousness
mania
Widespread pain throughout body



A caution, those with anxiety and panic symptoms may respond with extreme moods of increased fear, anxiety, panic, anger rage, homicidal rage and profound depression, usually in repeatable sequences following LCF or ALCAR even at levels of 1mg oral. A micro titration of carnitine would be cautious. While most find the moods intolerable, certain persons have been able to tolerate these (both past) and current, to find they can fade after some months of consumption. A few people may find similar, maybe somewhat lesser, response to MeCbl or more likely AdoCbl. As these are less controllable than LCF which can be micro dosed, they should be considered first.