Help Identifying Problem

[3blindmic3]

My significant other has an interesting predicament that has arisen around psychoactive substances. I am interested in identifying what is taking place, and I figured Bluelight may have seen/heard of this before. Anyways, essentially drugs often have no effect on her. She drinks socially and has attempted to use other substances only a handful of times.

Case 1 - Cannabinoid receptor
She has never been able to get high. She has smoked and "shotgunned" marijuana and its synthetic cousins. She has also eaten brownies and cookies, with no side effects.

Case 2 - GABA
Alcohol sometimes has no effect on her, and other times has a profound effect in a very small dose. This problem has even been identified with the exact same bottle of alcohol.

Case 3- Serotonin/Monoamine oxidase
She has taken 4-MMC on two occasions. Once at 100mg oral and another time at 128mg orally. The first time yielded the typically associated reaction, and the second yielded absolutely nothing. These both came from the same batch, with a purity of 99.8%.

Additionally
She was told by her general practitioner that she has problems absorbing water, as she has a tendency to dehydrate and has sometimes passed out temporarily. The condition, the name is currently alluding me, is related to her heart, but her heart tests have shown the organ is very much healthy and conditioned. She was prescribed a steroid and the SSRI Sertraline, Zoloft, to help with water absorption. Seemed odd to me, but it is standard practice for the condition.

Any ideas on what this problem might be or some idea of where I could find more info on the subject matter? She has never spoken to her doctor about it, for obvious reasons.

Thanks in Advance

EDIT:
Vasovagal Syncope
http://en.wikipedia.org/wiki/Vasovagal_response

This was the condition she was diagnosed with.

 

[seep]

She was told by her general practitioner that she has problems absorbing water, as she has a tendency to dehydrate and has sometimes passed out temporarily. The condition, the name is currently alluding me, is related to her heart, but her heart tests have shown the organ is very much healthy and conditioned.

the heart? It sounded like diabetes insipidus until you mentioned the heart as the cause.

If the blood's water concentration is down, all cells will have the tendency to shrivel and this wreaks havoc on neurotransmission, even if homeostasis is regained.

 

[thesomoan]

Why would setraline be prescribed for diabetes insipidus? or any non depression/OCD/anxiety condition for that matter... it would be extremely helpful if you could perhaps consult with your doctor and post the name of the condition. Also keep in mind that physicians are sworn to keep anything you tell them private unless you indicate violence, so bringing up this problem with a third party physician other than your normal doctor (The resilience to drugs problem not the water absorption issue) might not be a bad idea since they would have access to medical records, ability to do a physical exam, and infinitely more resources than a guy on the internet.

 

[raybeez]

the heart? It sounded like diabetes insipidus until you mentioned the heart as the cause.

If the blood's water concentration is down, all cells will have the tendency to shrivel and this wreaks havoc on neurotransmission, even if homeostasis is regained.

I agree that it sounds like DI. Maybe OP meant that loss of consciousness is cardiac in origin (like an arrhythmia secondary to electrolyte imbalances).

This is pure speculation (and we don't know if she even has DI) but diabetes insipidus can be caused by a mutation in a membrane channel protein called aquaporin. Usually it's a kidney-specific aquaporin but maybe she has rare mutation in one of the blood brain barrier aquaporins which is impairing CNS uptake of drugs.

update: It looks like aquaporin-2, the most common protein carrying a mutation in DI (and the so-called "kidney-specific" aquaporin) actually has really high expression in brain.

 

[raybeez]

Why would setraline be prescribed for diabetes insipidus? or any non depression/OCD/anxiety condition for that matter... it would be extremely helpful if you could perhaps consult with your doctor and post the name of the condition. Also keep in mind that physicians are sworn to keep anything you tell them private unless you indicate violence, so bringing up this problem with a third party physician other than your normal doctor (The resilience to drugs problem not the water absorption issue) might not be a bad idea since they would have access to medical records, ability to do a physical exam, and infinitely more resources than a guy on the internet.

SSRI's cause SIADH (excess anti-diuretic hormone) and hyponatremia. MDMA does this too

Diabetes insipidus is the exact opposite state - lack of ADH (or insensitivity to it) plus hypernatremia.

 

[thesomoan]

Ah. Any reason this treatment would be favored over usage of an ADH analogue like desmopressin?

 

[raybeez]

Ah. Any reason this treatment would be favored over usage of an ADH analogue like desmopressin?

Yeah, good question.

DI can be caused by defective ADH production (fully treatable by desmopressin). Or it can be caused by a mutation in aquaporin, the receptor that responds to ADH, in which case desmopressin would do nothing (since you're dealing with an inability to responds to ADH, not ADH deficiency).

But if SSRIs cause SIADH then they work through ADH, in which case they wouldn't work for the second type of DI... and if it's the first type, why not use desmo?

 

[3blindmic3]

Vasovagal syncope is the name of the condition I was thinking of. I updated the first post with the info, as well.

 

[seep]

vasovagal won't absolutely prevent a high, but chronically hypertonic blood might. I also really like the theory raybeez puts out in his first post.

 

[thesomoan]

chronically hypotonic blood would carry with it another host of problems including malnutrition, lack of oxygen, and numerous others. While that it a definite possibility I think that drug interactions are also a reasonable explanation.
1) SSRI's generally block stimulant empathogens like MDMA and 4-MMC. They can also intensify the effects of alcohol causing someone to get drunk off of a single beer.
2)Conversely certain female hormones/steroids can block the subjective effects of alcohol (Neuropsychopharmacology (2005) 30, 1193–1203, advance online publication, 9 February 2005) resulting in her varying response to alcohol.
3)Finally marijauna effects differ greatly person to person and certainly hypotonic blood would decrease the absorption of cannabanoids. How many times has she used cannabis?

 

[seep]

^hypertonic, not hypotonic. She has problems absorbing water, thus the solute concentration in her blood would be high. This would cause crenation of her RBCs and of pretty much every other cell.

Incidentally, what's the cause of the malabsorption? It's not the vasovagal response. The logic is backwards. Dehydration triggers vasovagal syncope, not the other way around (I'm kind of cheating cuz I have a family member with vaso).

 

[thesomoan]

Well damn I am 0-2 on this one. Permanent crenation of every cell in your body would be fatal wouldn't it? There must be significant portions of time when she is at least within the acceptable range for solute concentration.

 

[3blindmic3]

chronically hypotonic blood would carry with it another host of problems including malnutrition, lack of oxygen, and numerous others. While that it a definite possibility I think that drug interactions are also a reasonable explanation.
1) SSRI's generally block stimulant empathogens like MDMA and 4-MMC. They can also intensify the effects of alcohol causing someone to get drunk off of a single beer.
2)Conversely certain female hormones/steroids can block the subjective effects of alcohol (Neuropsychopharmacology (2005) 30, 1193–1203, advance online publication, 9 February 2005) resulting in her varying response to alcohol.
3)Finally marijauna effects differ greatly person to person and certainly hypotonic blood would decrease the absorption of cannabanoids. How many times has she used cannabis?

1. I think you're probably correct on drug interaction with the SSRI point.

2. The steroid she was prescribed was Fludrocortisone.

http://en.wikipedia.org/wiki/Fludrocortisone

3. I'd say she has tried various cannabinoids ~10 times, with the main one being THC.

 

[raybeez]

1. I think you're probably correct on drug interaction with the SSRI point.

2. The steroid she was prescribed was Fludrocortisone.

http://en.wikipedia.org/wiki/Fludrocortisone

3. I'd say she has tried various cannabinoids ~10 times, with the main one being THC.

Aha! I'm fairly sure this means that has adrenal insufficiency. Fludrocortisone is the drug of choice for treating this.

Vasovagal syncope is a fancy way of saying "faints due to sudden low blood pressure". This is what causes people to faint when they see blood, get a needle, etc... sudden fear causes the autonomic system to go into overdrive, causing sudden vasodilation, blood pools in your feet, not enough blood to the brain, and you pass out.

Some people have a problem with their autonomic nervous system (dysautonomia) that causes this.

However that doesn't explain her lack of ability to retain water. In fact, it would be a symptom of her inability to retain water (low total body water -> low blood pressure -> more prone to vasovagal syncope).

Edit: anyone want to take a stab how an adrenal problem would prevent the effects of certain drugs?

 

[thesomoan]

Fludcortisone is also prescribed for idiopathic orthostatic hypotension which is a degenerative autonomic nervous system disease (http://en.wikipedia.org/wiki/Idiopathic_orthostatic_hypotension).

Steroids are known to mediate alcohol intoxication (Antagonism of the hypnotic effect of ethanol in mice by an alpha-1 adrenoceptor agonist
M.K. Menona, b and C.K. Kodamaa, b
Accepted 17 July 1985. Available online 6 November 2002. ) so Fludcortisone could at least partially block alcohol intoxication. It can also effect metabolism which would vary the rate of onset, and length of alcohol intoxication.
For marijauna it is very possible that she simply has not felt the effects yet. Steroids could certainly mediate the effects in a similiar way as it does with alcohol. If you believe it is a problem with absorption, have a doctor test her ability to absorb lipids, if it is normal, then edibles should be absorbed normally.

For all we know her conditions could be unrelated, I still do not understand why you would not ask a doctor, especially about her weird reaction with alcohol as there is no legal consequence for admitting legal and illegal drug use to a physician.

 

[raybeez]

For all we know her conditions could be unrelated, I still do not understand why you would not ask a doctor, especially about her weird reaction with alcohol as there is no legal consequence for admitting legal and illegal drug use to a physician.

No legal consequences, but financial ones. Having drug/alcohol use/abuse on your medical chart can horribly impact health insurance premiums, ability to qualify for life/disability insurance, etc.

The medical chart stays confidential, but when you do insurance paperwork you need to disclose alcohol/drug use. If you don't disclose it to the insurance companies, they will find out when you make a claim, giving them a nice justification for refusing to pay your claim (best case scenario) or reporting you to the police for fraud (worst case scenario)

 

[seep]

anyone want to take a stab how an adrenal problem would prevent the effects of certain drugs?

Though this involves coke, it's generalizable:

Addict Behav. 2005 May;30(4):859-64.

Effects of cortisol and cocaine on plasma prolactin and growth hormone levels in
cocaine-dependent volunteers.

Elman I, Lukas SE.

Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA
02478, United States. [email protected]

In rodents, corticosterone (cortisol in humans) facilitates cocaine
self-administration purportedly via enhancement of dopaminergic activity in the
brain. This study sought to assess central dopaminergic effects of cortisol in
humans and to compare them to those of cocaine. Twelve cocaine-dependent
individuals received an intravenous bolus of cortisol (0.5 and 0.2 mg/kg; n=6 for
each dose) and cocaine (0.2 mg/kg) in a double-blind randomized
placebo-controlled and counterbalanced fashion. Their plasma was assayed over the
next 120 min for prolactin and growth hormone (GH), which are two neuroendocrine
indices of dopaminergic function. Cortisol injections produced significant
increases in GH, while cocaine resulted in significant decreases in prolactin.
Placebo administration was associated with gradual declines in prolactin, but the
levels at the 90- and 120-min time points were significantly lower after cocaine
than after placebo infusion. These different neuroendocrine response profiles
point to important differences between dopaminergic effects of cortisol and
cocaine.

 

[thesomoan]

^^^ I read that to mean that cortisol and cocaine would be synergistic in their effect on the adrenal system. Can you explain how that can be generalized to other drugs impact upon that system?

 

[seep]

^it's generalizable in that cortisol is implicated in psychological addiction to a number of substances

1. Int J Psychophysiol. 2006 Mar;59(3):195-202. Epub 2006 Jan 24.

Cortisol secretion patterns in addiction and addiction risk.

Lovallo WR.

Behavioral Sciences Laboratories (151A), Veterans Affairs Medical Center, 921 NE
13th Street, Oklahoma City, Oklahoma 73104, United States. [email protected]

Addiction to alcohol or nicotine involves altered functioning of the brain's
motivational systems. Altered functioning of the
hypothalamic-pituitary-adrenocortical (HPA) axis may hold clues to the nature of
the motivational changes accompanying addiction and vulnerability to addiction.
Alcohol and nicotine show at least three forms of interaction with HPA
functioning. Acute intake of both substances causes stress-like cortisol
responses. Their persistent use may dysregulate the HPA. Finally, the risk for
dependence and for relapse after quitting may be associated with deficient
cortisol reactivity to a variety of stressors. The HPA is regulated at the
hypothalamus by diurnal and metabolic signals, but during acute emotional states,
its regulation is superseded by signals from the limbic system and prefrontal
cortex. This top-down organization makes the HPA responsive to inputs that
reflect motivational processes. The HPA is accordingly a useful system for
studying psychophysiological reactivity in persons who may vary in cognitive,
emotional, and behavioral tendencies associated with addiction and risk for
addiction. Chronic, heavy intake of alcohol and nicotine may cause modifications
in these frontal-limbic interactions and may account for HPA response differences
in seen in alcoholics and smokers. In addition, preexisting alterations in
frontal-limbic interactions with the HPA may reflect addiction-proneness, as
shown in studies of offspring of alcohol- and drug-abusing parents. Continuing
research on the relationship between HPA function, stress responsivity, and the
addictions may yield insights into how the brain's motivational systems support
addictions and risk for addictions.

but yeah, it's also directly synergistic with cocaine

 

[thesomoan]

Alright well I think we can fairly credibly explain her reaction to alcohol and 4-MMC through drug interactions. As I posted above, SSRI's and cortisone respectively increase and block alcohol intoxication resulting in a varying level of tolerance depending on which is present to a greater degree. We can also conclude that low blood pressure, and possible adrenal problems would result in changes in metabolism, and osmotic rates which would further complicate intoxication under any substance. Cannabis is the only drug which is difficult to explain. Most people do not get high the first few times they smoke anyways, but adrenaline is known to suppress cannabis intoxication, so the steroids could have some suppressant effects.