How nutrition can influence Ivermectin's neurological risks and side effects

nerd

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Ivermectin (IVM) is an allosteric modulator of GABA-A receptors (GABAaR), glycin receptors (GlyR), and nicotinic acetylcholine receptors (nAChR) (10.1113/JP275236). These receptors don't only play a role in the brain but also in the spinal cord (10.1016/S0165-6147(96)01013-9; 10.1016/B978-012370880-9.00169-9). Both, the spinal cord and the brain are susceptible to increased permeability from their blood barrier by trauma, infection, hypoxia, malnutrition, etc. (10.1007/s00726-001-0137-z; 10.1038/nrneurol.2010.74).

IVM normally doesn't get into the brain or spinal cord in toxic amounts because of the P-glycoprotein (P-gp), which is prevalent in the endothelium of the blood-brain and blood-spinal cord barrier (BBB). This is why it is speculated that IVM neurotoxicity might be due to genetic mutations of the P-gp's gene (ABCB1 aka. MDR-1) as known in certain dog breeds (10.1097/00008571-200111000-00012), or by competitive proteins that exhibit a higher affinity towards the P-gp, either by drugs or by endogenous proteins from mutated genes (10.1186/1475-2883-2-S1-S8). This is why drug-drug interactions should always be carefully checked before taking IVM. There is only little data on genetic mutations, but frameshifts in the ABCB1, the CYP3A4, and the CYP3A5 genes indicate a relative risk, though it isn't known which other genes might also be affected.

I could also imagine that people with weakened endothelia and with increased risks for brain aneurysms are also at greater risk for IVM permeability. The risk for brain aneurysms can be genetically assessed (10.1038/s41588-020-00725-7). COVID-19 is known to damage the endothelium significantly, though the anti-inflammatory properties of IVM and its effects on the Angiotensin system might counteract this eventually (10.1016/j.atherosclerosis.2020.10.014). In the treatment of long haulers, some doctors prescribe anti-inflammatories such as acetylsalicylic acid (Aspirin) preceding IVM (Dr. Kory Interview). ARBs and ACE inhibitors are also discussed for this purpose (10.1016/j.atherosclerosis.2020.10.014).

To assess the neurological risks and side effects of IVM, I have to assume that a low percentage of it somehow crosses the BBB. In the brain or spinal cord, IVM will allosterically modulate the GABAaR, GlyR, and nAChR. This causes neurological symptoms and possibly neurotoxicity in extreme cases because GABAaR and GlyR are inhibitory receptors, and nAChR is an excitatory receptor. An overactivation of these inhibitory receptors acts like a sedative overdosing (GABAa agonists such as diazepam in particular). An overactivation of the nAChR could be compared to the effect of severe smoking and nicotine overdosing on the brain (10.1007/s40429-015-0042-2). IVM neurotoxicity combines both. But this normally doesn't happen and I will make the assumption of a mild overactivation with mild adverse effects, which still is very unlikely.

Since it hasn't been studied yet how mild side effects of IVM could be alleviated, the closest and well-studied drug that I could come up with is ethanol (consumable alcohol). Ethanol is known for its neurological effects as a recreational drug, so it is well understood how overdoses and chronic exposure affect the brain. Similar to IVM, ethanol is an allosteric modulator of GABAaR (pmid:12921221), nAChR (pmid:10215652), and GlyR (10.1016/j.phrs.2015.07.002). To be clear, these two drugs are only comparable for their effects on these three receptors and in the case of IVM crossing the BBB. Liver and cell toxicity of them are not comparable. Due to the synergic effects of ethanol and IVM in the brain, it is not surprising that severe adverse effects (SAE) often coincide with alcohol (and/or cannabinoid/hemp) consumption (10.1186/s40360-019-0327-5). These might be considered part of daily "nutrition" but can still increase the risk of side effects.

What else can influence GABA receptors? Without any drug interaction, GABAaR are normally activated by the neurotransmitter GABA (pmid:15704348). The precursor of GABA is Glutamate, though while GABA acts as an inhibitory neurotransmitter, Glutamate acts excitatory (10.1177/1073858402238515). These neurotransmitters should be in an effective balance. The active form of Vitamin B6 (Pyridoxal-5'-Phosphate) enables the synthesis of GABA from Glutamate (10.14581/jer.15018). Thus, high doses of B6 during IVM neurotoxicity might be counterproductive. Glutamate levels are also recycled from and to glutamine and α-ketoglutarate (10.1016/j.aninu.2015.08.008). α-ketoglutarate indirectly depends on glutamine intake and the activation of the citric acid cycle.

Thiamine is an essential cofactor of α-ketoglutarate dehydrogenase, which catalyzes α-ketoglutarate to Succinyl-CoA, and pyruvate dehydrogenase, which breaks down pyruvate to Acetyl-CoA, which ensures that glucose metabolites are integrated into the citric acid cycle (CAC). This ensures that α-ketoglutarate is readily available after glycolysis and glutamate utilization (10.1007/s13312-019-1592-5). This utilization depends on the metabolic phase and cognitive enablement. Without thiamine, the CAC will be blocked and channeled into the GABA pathway due to the accumulation of α-ketoglutarate. This causes a short excitatory phase and a subsequent long inhibitory phase with potential excitotoxicity since the CAC can not balance but only replenish glutamate levels then (10.1111/nyas.13919). The blocked CAC will additionally reduce ATP availability.

There is a third thiamin-dependant enzyme, i.e. transketolase, in the pentose-phosphate pathway (PPP). If transketolase is impaired due to thiamine deficiency, the recycling of cytosolic glutathione levels via the 6-phosphogluconate dehydrogenase can not contribute to ER function and protein secretion via VCP (10.1016/j.chembiol.2019.05.006). Additionally, Glucose-6-phosphate could not sufficiently be recycled from 6-phosphogluconate, which makes glycolysis the only Glucose-6-phosphate source. Thereby, glutathione recycling and the lipid metabolism become dependant on glycolysis.

Also, this glycolysis-channeled utilization of the PPP without transketolase recycling will lead to a buildup of ribose-5-phosphate, erythrose-4-phosphate, and xylulose-5-phosphate, which can be catalyzed to ribose-5-phosphate as well via isomerase and epimerase (10.5653/cerm.2012.39.2.58). The buildup of erythrose-4-phosphate only serves pathogens that encode the shikimate pathway and can utilize this metabolite as an energy source. The buildup of ribose-5-phosphate can be compensated by the human metabolism by channeling it into the purine and pyrimidine pathways.

To summarize the effects of TD on the PPP, it causes mitochondrial dysfunction, disrupted protein synthesis, makes glutathione recycling and lipid metabolism dependant on glycolysis activation, thereby impairs the endogenous response to oxidative stress, and it might also provide energy to certain pathogens. This affects myelin sheaths in particular and thereby opens a door for neuropathy (10.1172/JCI106727). Via glycolysis and the CAC, TD causes a neurotransmitter imbalance with potential excitotoxicity and reduces ATP availability. Long-term TD also reduces glutamate and GABA levels and makes glutamate replenishment dependant on glutamine.

Animal models can also give us more insight into the effects of TD on GABA and its receptors. In goats, the density of GABAaR binding sites increased dominantly in the motor cortex under Amprolium-induced TD (10.1007/bf02080930). Similarly, the density of NMDA-glutamate receptor binding sites decreased in the motor cortex most dominantly. A potential similar observation could be made in the visual cortex but without sufficient statistical and reproducible significance. The blindness observed in thiamine deficient goats supports this argument. Another study on rats showed that diet-maintained TD indeed decreases glutamate and GABA in the brain (10.1079/bjn19890027). The inconsistent results on binding activities don't allow any conclusions, though.

Concluding, I interpret thiamine deficiency as a risk factor for the use of GABA agonists and modulators. However, this does not mean that thiamine can be used to alleviate neurotoxic symptoms of them. On the contrary, thiamine supplementation during such symptoms could even enhance the excitotoxicity by a subsequent rapid metabolic neurotransmitter flux. In the case of thiamine deficiency, the metabolism needs sufficient time to adapt to healthy thiamine levels before other interventions take place. Vitamin B6 administration would be counterproductive during GABA excitotoxicity as well.

Fortunately, there are other options that could potentially alleviate symptoms of GABAaR overactivation, namely GABAaR antagonists and negative allosteric modulators. There is a number of herbal-based GABAaR antagonists available, some of which are extracted from poisonous plants, e.g. Bicuculline from Dutchman's breeches, Picrotoxin from Anamirta cocculus, Thujone from Wormwood, Puerarin from Kudzu, Bilobalide and Ginkgolides from Ginkgo biloba (Encyclopedia of Neuroscience; 10.1073/pnas.070042397; 10.1016/s0091-3057(03)00114-x).

Among these, Ginko extracts are the best-studied option. Contrary to pure GABAaR antagonists, Bilobalide from Ginko has also an anticonvulsant and not a convulsant effect. It is speculated that this is due to an inhibition of glutamate release. This makes it a good choice for mild symptoms of GABA agonists and allosteric modulators. So it is not surprising that a compound with a Ginko extract showed significant improvement as a hangover remedy (10.1136/bmjnph-2019-000042), though this might also be due to other extracts in the compound.

Kudzu is also interesting because puerarin is not a GABAaR antagonist but a blocker of allosteric GABAaR modulators (10.1016/s0091-3057(03)00114-x). Puerarin didn't show to inhibit the GABAaR stimulation from GABAaR agonists (i.e. muscimol), but it inhibited the binding of an allosteric modulator (i.e. flunitrazepam) and its function. So it could be speculated that this is translatable for many allosteric GABAaR modulators, which would make it a specific and targeted choice without any efficacy when no modulating drug is involved. An argument that speaks for the translatability is that this has been used as an alcohol hangover remedy in China for many centuries. The protective effect of puerarin from alcohol toxicity and GABA activation is also confirmed in one study on mice (10.1590/1414-431X20144250). Ethanol is not very similar to typical benzodiazepines such as flunitrazepam. If the flunitrazepam finding can be translated for ethanol, it is also likely translatable for IVM.

I hope this gave you a better understanding of the neurotoxic mechanism of IVM and why its toxicity in the brain is dose-dependant, just as it is dose-dependant for sedatives and alcohol intake. IVM, however, normally doesn't cross the BBB as ethanol does. Vitamin status, the one of thiamine in particular, can make a difference but this has to be adjusted many days before taking such drugs, and overdoses of vitamins can be as harmful as deficiencies. I've listed two herbal remedies (i.e., Ginko, and Kudzu) that might not only help with an alcohol-induced hangover but also with mild side effects of IVM. Of course, this only applies if and once side effects happen that are consistent with GABAaR overactivation. It's unlikely to help with joint pain and immunologically-mediated side effects, which can also occur after taking IVM. I've also clarified why alcohol should not be taken with IVM, from a neurological perspective alone. I'm certain that there are metabolic reasons as well, especially due to ethanol's effect on thiamin-dependant enzymes such as transketolase (pmid:591201). Remember, this is no medical advice. Please talk with your physician before you change anything in your drug intake schedule based on the information I provided.

I think that the vitamin status might have been overlooked when it comes to the side effects of IVM. The reported adverse effects vary drastically in African countries, e.g. from 1.3% in Liberia to 91.8% in Tanzania (10.1016/s1201-9712(03)90013-0). I intended to cross-evaluate the hypothesis that this is partially due to TD, but it was impossible to acquire sufficient demographical data on TD. It probably is common in poor countries, but I have no way to check this. Poorness per se isn't indicative enough because the national cuisine and food programs confound this. This makes it still very speculative.
 
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Hipsman

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I only got half through this, damn brain fog. Looks like there is some risk for taking ivermectin if you have specific genome mutations, witch can result in mild side-effects.

@nerd I read a bit at the end about not taking alcohol with ivermectin, is it ok to take alcohol 12h after taking ivermectin?

edit: from here.
[GENERALLY AVOID: Alcohol may increase the plasma concentrations of ivermectin. The mechanism of interaction is unknown. In 20 healthy, nonsmoking patients with onchocerciasis, mean plasma ivermectin concentrations at 1, 3 and 4 hours post-dose (150 mcg/kg) were approximately 34% to 40% higher in the group given the medication with 750 mL of beer (4.5% v/v alcohol) than in controls who ingested the medication with water. There were no side effects in either study or control subjects. However, there have been anecdotal reports of increased central nervous system adverse effects and postural hypotension in patients who combined ivermectin with alcohol.

MANAGEMENT: Patients receiving ivermectin therapy should preferably avoid the consumption of alcohol to prevent any undue adverse effects of ivermectin.]
 
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nerd

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I only got half through this, damn brain fog. Looks like there is some risk for taking ivermectin if you have specific genome mutations, witch can result in mild side-effects.

@nerd I read a bit at the end about not taking alcohol with ivermectin, is it ok to take alcohol 12h after taking ivermectin?
I would not take alcohol with CFS/ME. I would not take it with pain killers or Ivermectin. Even 12h after taking Ivermectin, your blood concentration will be quite high. Even if your plasma concentration is low, days later, there will be a high tissue concentration and alcohol can dissolve it from the tissue. But my concern was primarily focused on the interaction of ethanol and Ivermectin on the same brain receptors, possibly worsening potential neurotoxicity.
 
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Hipsman

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I would not take alcohol with CFS/ME.
Agree, I only take a glass of wine rarely, I asked because I plan to give ivermectin to my whole family, vaccines rollout is slow and virus mutates too quickly, so my family is OK with taking it.
 

Hipsman

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Someone reported on side-effects from higher dosages:
I'm suffering from mild-moderate ME/CFS (currently housebound), POTS and SFN since 8.5 years.

I'm taking 15-40 mg (0,2-0,6 mg/kg) ivermectin daily (most often divided to 2 doses with food) for nearly 4 months. So far it's the most effective thing I've ever taken. It completely abolished my low-grade fever and flu-like malaise episodes (which lasted even for few months).

Unfortunately there are side effects proportional to dosage - visual disturbances similar to HPPD at the higher end of dosage range (tracers, stroboscopic effect in the peripheral vision).
 

nerd

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Someone reported on side-effects from higher dosages:
Thanks for sharing. It's quite a high dose to take daily. I take 0.2 mg/kg 1-2 times weekly. I don't feel as much of a difference though. I have the impression that my inflammation is better for ca. 2 days, so dependant on the plasma half-time, not the tissue half-time.

By taking 0.6 mg/kg daily for a long time, they really push the limits. As far as I remember, Ivermectin has a high affinity for the eye tissue or optical nerve, so this is the first one of the first places where nervous symptoms would show up.
 
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Ivermectin (IVM) is an allosteric modulator of GABA-A receptors (GABAaR), glycin receptors (GlyR), and nicotinic acetylcholine receptors (nAChR) (10.1113/JP275236). These receptors don't only play a role in the brain but also in the spinal cord (10.1016/S0165-6147(96)01013-9; 10.1016/B978-012370880-9.00169-9). Both, the spinal cord and the brain are susceptible to increased permeability from their blood barrier by trauma, infection, hypoxia, malnutrition, etc. (10.1007/s00726-001-0137-z; 10.1038/nrneurol.2010.74).

IVM normally doesn't get into the brain or spinal cord in toxic amounts because of the P-glycoprotein (P-gp), which is prevalent in the endothelium of the blood-brain and blood-spinal cord barrier (BBB). This is why it is speculated that IVM neurotoxicity might be due to genetic mutations of the P-gp's gene (ABCB1 aka. MDR-1) as known in certain dog breeds (10.1097/00008571-200111000-00012), or by competitive proteins that exhibit a higher affinity towards the P-gp, either by drugs or by endogenous proteins from mutated genes (10.1186/1475-2883-2-S1-S8). This is why drug-drug interactions should always be carefully checked before taking IVM. There is only little data on genetic mutations, but frameshifts in the ABCB1, the CYP3A4, and the CYP3A5 genes indicate a relative risk, though it isn't known which other genes might also be affected.

I could also imagine that people with weakened endothelia and with increased risks for brain aneurysms are also at greater risk for IVM permeability. The risk for brain aneurysms can be genetically assessed (10.1038/s41588-020-00725-7). COVID-19 is known to damage the endothelium significantly, though the anti-inflammatory properties of IVM and its effects on the Angiotensin system might counteract this eventually (10.1016/j.atherosclerosis.2020.10.014). In the treatment of long haulers, some doctors prescribe anti-inflammatories such as acetylsalicylic acid (Aspirin) preceding IVM (Dr. Kory Interview). ARBs and ACE inhibitors are also discussed for this purpose (10.1016/j.atherosclerosis.2020.10.014).

To assess the neurological risks and side effects of IVM, I have to assume that a low percentage of it somehow crosses the BBB. In the brain or spinal cord, IVM will allosterically modulate the GABAaR, GlyR, and nAChR. This causes neurological symptoms and possibly neurotoxicity in extreme cases because GABAaR and GlyR are inhibitory receptors, and nAChR is an excitatory receptor. An overactivation of these inhibitory receptors acts like a sedative overdosing (GABAa agonists such as diazepam in particular). An overactivation of the nAChR could be compared to the effect of severe smoking and nicotine overdosing on the brain (10.1007/s40429-015-0042-2). IVM neurotoxicity combines both. But this normally doesn't happen and I will make the assumption of a mild overactivation with mild adverse effects, which still is very unlikely.

Since it hasn't been studied yet how mild side effects of IVM could be alleviated, the closest and well-studied drug that I could come up with is ethanol (consumable alcohol). Ethanol is known for its neurological effects as a recreational drug, so it is well understood how overdoses and chronic exposure affect the brain. Similar to IVM, ethanol is an allosteric modulator of GABAaR (pmid:12921221), nAChR (pmid:10215652), and GlyR (10.1016/j.phrs.2015.07.002). To be clear, these two drugs are only comparable for their effects on these three receptors and in the case of IVM crossing the BBB. Liver and cell toxicity of them are not comparable. Due to the synergic effects of ethanol and IVM in the brain, it is not surprising that severe adverse effects (SAE) often coincide with alcohol (and/or cannabinoid/hemp) consumption (10.1186/s40360-019-0327-5). These might be considered part of daily "nutrition" but can still increase the risk of side effects.

What else can influence GABA receptors? Without any drug interaction, GABAaR are normally activated by the neurotransmitter GABA (pmid:15704348). The precursor of GABA is Glutamate, though while GABA acts as an inhibitory neurotransmitter, Glutamate acts excitatory (10.1177/1073858402238515). These neurotransmitters should be in an effective balance. The active form of Vitamin B6 (Pyridoxal-5'-Phosphate) enables the synthesis of GABA from Glutamate (10.14581/jer.15018). Thus, high doses of B6 during IVM neurotoxicity might be counterproductive. Glutamate levels are also recycled from and to glutamine and α-ketoglutarate (10.1016/j.aninu.2015.08.008). α-ketoglutarate indirectly depends on glutamine intake and the activation of the citric acid cycle.

Thiamine is an essential cofactor of α-ketoglutarate dehydrogenase, which catalyzes α-ketoglutarate to Succinyl-CoA, and pyruvate dehydrogenase, which breaks down pyruvate to Acetyl-CoA, which ensures that glucose metabolites are integrated into the citric acid cycle (CAC). This ensures that α-ketoglutarate is readily available after glycolysis and glutamate utilization (10.1007/s13312-019-1592-5). This utilization depends on the metabolic phase and cognitive enablement. Without thiamine, the CAC will be blocked and channeled into the GABA pathway due to the accumulation of α-ketoglutarate. This causes a short excitatory phase and a subsequent long inhibitory phase with potential excitotoxicity since the CAC can not balance but only replenish glutamate levels then (10.1111/nyas.13919). The blocked CAC will additionally reduce ATP availability.

There is a third thiamin-dependant enzyme, i.e. transketolase, in the pentose-phosphate pathway (PPP). If transketolase is impaired due to thiamine deficiency, the recycling of cytosolic glutathione levels via the 6-phosphogluconate dehydrogenase can not contribute to ER function and protein secretion via VCP (10.1016/j.chembiol.2019.05.006). Additionally, Glucose-6-phosphate could not sufficiently be recycled from 6-phosphogluconate, which makes glycolysis the only Glucose-6-phosphate source. Thereby, glutathione recycling and the lipid metabolism become dependant on glycolysis.

Also, this glycolysis-channeled utilization of the PPP without transketolase recycling will lead to a buildup of ribose-5-phosphate, erythrose-4-phosphate, and xylulose-5-phosphate, which can be catalyzed to ribose-5-phosphate as well via isomerase and epimerase (10.5653/cerm.2012.39.2.58). The buildup of erythrose-4-phosphate only serves pathogens that encode the shikimate pathway and can utilize this metabolite as an energy source. The buildup of ribose-5-phosphate can be compensated by the human metabolism by channeling it into the purine and pyrimidine pathways.

To summarize the effects of TD on the PPP, it causes mitochondrial dysfunction, disrupted protein synthesis, makes glutathione recycling and lipid metabolism dependant on glycolysis activation, thereby impairs the endogenous response to oxidative stress, and it might also provide energy to certain pathogens. This affects myelin sheaths in particular and thereby opens a door for neuropathy (10.1172/JCI106727). Via glycolysis and the CAC, TD causes a neurotransmitter imbalance with potential excitotoxicity and reduces ATP availability. Long-term TD also reduces glutamate and GABA levels and makes glutamate replenishment dependant on glutamine.

Animal models can also give us more insight into the effects of TD on GABA and its receptors. In goats, the density of GABAaR binding sites increased dominantly in the motor cortex under Amprolium-induced TD (10.1007/bf02080930). Similarly, the density of NMDA-glutamate receptor binding sites decreased in the motor cortex most dominantly. A potential similar observation could be made in the visual cortex but without sufficient statistical and reproducible significance. The blindness observed in thiamine deficient goats supports this argument. Another study on rats showed that diet-maintained TD indeed decreases glutamate and GABA in the brain (10.1079/bjn19890027). The inconsistent results on binding activities don't allow any conclusions, though.

Concluding, I interpret thiamine deficiency as a risk factor for the use of GABA agonists and modulators. However, this does not mean that thiamine can be used to alleviate neurotoxic symptoms of them. On the contrary, thiamine supplementation during such symptoms could even enhance the excitotoxicity by a subsequent rapid metabolic neurotransmitter flux. In the case of thiamine deficiency, the metabolism needs sufficient time to adapt to healthy thiamine levels before other interventions take place. Vitamin B6 administration would be counterproductive during GABA excitotoxicity as well.

Fortunately, there are other options that could potentially alleviate symptoms of GABAaR overactivation, namely GABAaR antagonists and negative allosteric modulators. There is a number of herbal-based GABAaR antagonists available, some of which are extracted from poisonous plants, e.g. Bicuculline from Dutchman's breeches, Picrotoxin from Anamirta cocculus, Thujone from Wormwood, Puerarin from Kudzu, Bilobalide and Ginkgolides from Ginkgo biloba (Encyclopedia of Neuroscience; 10.1073/pnas.070042397; 10.1016/s0091-3057(03)00114-x).

Among these, Ginko extracts are the best-studied option. Contrary to pure GABAaR antagonists, Bilobalide from Ginko has also an anticonvulsant and not a convulsant effect. It is speculated that this is due to an inhibition of glutamate release. This makes it a good choice for mild symptoms of GABA agonists and allosteric modulators. So it is not surprising that a compound with a Ginko extract showed significant improvement as a hangover remedy (10.1136/bmjnph-2019-000042), though this might also be due to other extracts in the compound.

Kudzu is also interesting because puerarin is not a GABAaR antagonist but a blocker of allosteric GABAaR modulators (10.1016/s0091-3057(03)00114-x). Puerarin didn't show to inhibit the GABAaR stimulation from GABAaR agonists (i.e. muscimol), but it inhibited the binding of an allosteric modulator (i.e. flunitrazepam) and its function. So it could be speculated that this is translatable for many allosteric GABAaR modulators, which would make it a specific and targeted choice without any efficacy when no modulating drug is involved. An argument that speaks for the translatability is that this has been used as an alcohol hangover remedy in China for many centuries. The protective effect of puerarin from alcohol toxicity and GABA activation is also confirmed in one study on mice (10.1590/1414-431X20144250). Ethanol is not very similar to typical benzodiazepines such as flunitrazepam. If the flunitrazepam finding can be translated for ethanol, it is also likely translatable for IVM.

I hope this gave you a better understanding of the neurotoxic mechanism of IVM and why its toxicity in the brain is dose-dependant, just as it is dose-dependant for sedatives and alcohol intake. IVM, however, normally doesn't cross the BBB as ethanol does. Vitamin status, the one of thiamine in particular, can make a difference but this has to be adjusted many days before taking such drugs, and overdoses of vitamins can be as harmful as deficiencies. I've listed two herbal remedies (i.e., Ginko, and Kudzu) that might not only help with an alcohol-induced hangover but also with mild side effects of IVM. Of course, this only applies if and once side effects happen that are consistent with GABAaR overactivation. It's unlikely to help with joint pain and immunologically-mediated side effects, which can also occur after taking IVM. I've also clarified why alcohol should not be taken with IVM, from a neurological perspective alone. I'm certain that there are metabolic reasons as well, especially due to ethanol's effect on thiamin-dependant enzymes such as transketolase (pmid:591201). Remember, this is no medical advice. Please talk with your physician before you change anything in your drug intake schedule based on the information I provided.

I think that the vitamin status might have been overlooked when it comes to the side effects of IVM. The reported adverse effects vary drastically in African countries, e.g. from 1.3% in Liberia to 91.8% in Tanzania (10.1016/s1201-9712(03)90013-0). I intended to cross-evaluate the hypothesis that this is partially due to TD, but it was impossible to acquire sufficient demographical data on TD. It probably is common in poor countries, but I have no way to check this. Poorness per se isn't indicative enough because the national cuisine and food programs confound this. This makes it still very speculative.
Very helpful post. Are there any herbs we should avoid while taking ivermectin?
 

nerd

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Very helpful post. Are there any herbs we should avoid while taking ivermectin?
Taurine could be counterproductive. Antihistamines as well (indirectly due to histamine-GABA interaction). Just during the initial period when you/they don't have a feeling for it yet. As I mentioned, it's extremely unlikely that toxic effects happen.

My research has lead me to evidence suggesting that certain HDACs regulate GABA receptor activity or expression. This is why Cannabinoids also have indirect positive effects on GABA receptor activity. GABA itself inhibits HDACs as well, which creates kind of a circular GABA regulatory system, with differing effect times.

Besides Cannabinoids and GABA, there are also caffeic acids, Quercetin, butyrates, and certain neurological medications that inhibit HDACs, so could possibly enhance the neurotoxicity.

I could try and run a database of drugs against their potential at the different GABA binding sites, but this requires a lot of time and the issue with herbs is that they don't consist of single ingredients. They contain a wide range of potentially active ingredients in varying doses, so there's not much else than speculation when it comes to herbs. I guess that herbs that are known to make you sleepy, calm, or drowsy might be counterproductive in the case of GABAergic neurotoxicity.
 
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