Is Anesthesia Risky For People With MTHFR?

Anesthesia is a medical treatment used to block pain or reduce awareness during medical procedures. It is given to patients undergoing surgery, diagnostic testing, biopsies, or dental work.

There are four main types of anesthesia in clinical practice: general, regional, local, and sedation.

• General anesthesia involves intravenous and/or inhaled drugs to induce unconsciousness, so the patient is unarousable to verbal, tactile, and painful stimuli.
  
  
• Regional anesthesia targets major nerves or the spinal cord (e.g., spinal, epidural, and peripheral nerves) to numb a larger body area, such as an arm, a leg, or everything below the waist while the patient remains awake or slightly sedated.
  
  
• Local anesthesia uses the same drugs injected into or applied onto a small area (skin, tooth, minor wound), which causes the area to lose sensation while the patient is fully conscious.
  
  
• Sedation (monitored anesthesia care) involves IV sedatives and often opioids to induce relaxation, reducing awareness for procedures such as endoscopy or minor surgery. This can range from mild sedation through to deep states of relaxation similar to being under general anesthesia.

There are several classes of anesthesia, which work in different ways.

• Intravenous (IV): Drugs such as propofol, barbiturates, and etomidate are injected directly into the bloodstream to rapidly induce unconsciousness. These drugs work primarily by targeting specific ion channels and receptor proteins, either enhancing gamma-aminobutyric acid (GABA, the inhibitory neurotransmitter) and/or blocking glutamate, the excitatory neurotransmitter. This results in amnesia and immobility.
  
  
• Inhalational: Inhalants such as sevoflurane, desflurane, isoflurane, and nitrous oxide are breathed in by the patient at a concentration that prevents movement (known as minimum alveolar concentration or MAC). These drugs pass quickly into the bloodstream and work by altering brain activity to induce unconsciousness, amnesia, and muscle relaxation.
  
  
• IV sedatives (conscious sedation). Administered intravenously to produce anxiolysis, sedation and amnesia without complete anesthesia. Usually include benzodiazepines, which enhance the effect of GABA.¹
  
  
• Synthetic opioids: Usually given for brief medical procedures that do not require skeletal muscle relaxation and can be utilized as a pre-anesthetic for the induction of general anesthesia when combined with other general anesthetic agents.
  
  Drugs such as fentanyl and sufentanil work by binding to specific pain‑related receptors in the brain and spinal cord, dampening pain signals.
  
  
• Neuromuscular blocking drugs: These drugs temporarily block nerve signals from muscles, causing paralysis during surgery.  Patients must also receive separate drugs to block pain and awareness.

Each class of anesthesia has distinct mechanisms, and some may have more adverse effects than others.

• Oxygen is the most commonly used adjunctive in anesthesia. It is delivered via mask, usually before the anesthetic is given. Oxygen supplementation normally continues throughout the intraoperative period and after surgery at least into the recovery room.
  Adverse effects are uncommon unless delivery is prolonged or at very high concentration.
• Isoflurane: Inhaled volatile that enhances the relaxing effects of GABA and glycine while dampening glutamate. May cause hypotension and respiratory depression at high intake. 
• Nitrous oxide (N₂O): Inhaled gas (also known as laughing gas) that reduces pain and awareness by blocking NMDA‑type glutamate receptors, which are usually involved in transmitting excitatory signals in the brain.
  Recreational use of N₂O (known as nangs, whippets, balloons)
  Side effects include postoperative nausea and diffusion hypoxia. Repeated or prolonged nitrous oxide exposure oxidizes and inactivates B12 and disables methionine synthase. This causes a functional B12 deficiency even if B12 levels are normal. Over time, this deficiency can lead to demyelination of the spinal cord and peripheral nerves, followed by neuropathy.²

• Ketamine: Ketamine is given into a vein or muscle and blocks pain while inducing deep calm. It can cause vivid dreams or hallucinations upon waking, and often raises blood pressure and heart rate. Common side effects include nausea, vomiting, dizziness, vision issues, drowsiness, depression, and confusion.
• Propofol: Enhances GABA which suppresses brain activity, causing significant sedation. May cause hypotension and respiratory depression; prolonged high‑dose use can cause propofol infusion syndrome.
• Thiopental: Intravenous barbiturate that enhances GABA and rapidly induces unconsciousness. Adverse effects include hypotension, respiratory depression, and prolonged sedation.

• Lidocaine (lignocaine) Can be injected or given topically depending on the area being treated. Lidocaine temporarily inhibits pain signals by blocking electrical channels in the nerve cell membrane. This effect only lasts while the drug is present at the nerve at a high enough concentration.
  Signs of toxicity may include loss of consciousness, low blood pressure, slowed heart rate, and breathing difficulties.³
• Bupivacaine: Long‑acting amide local anesthetic used for larger areas of the body (epidurals, spinals, nerve blocks). Toxicity may lead to arrhythmias and reduced heart contractility. Other adverse effects may include itching, constipation, nausea, vomiting, dizziness, drowsiness, headache, paresthesia, and tinnitus.

Nitrous oxide inactivates vitamin B12 by oxidizing its cobalt ion, which impairs its function as a cofactor. This leads to functional vitamin B12 deficiency, even in patients with normal levels, and also irreversibly inactivates methionine synthase, which is required for many processes necessary for everyday health.

Recent studies show that a standard anesthetic dose of N₂O inactivates methionine synthase rapidly, and homocysteine levels rise within a few hours. In patients with normal B12 levels, plasma homocysteine levels may return to normal within a week.⁴ However, people with B12 deficiency, nitrous oxide may pose a high risk of complications both during and after administration.

People with the MTHFR genetic mutation are also often more likely to have low B12 levels.⁵ Some research has suggested that nitrous oxide may increase the risk of elevated homocysteine more in people with MTHFR variants due to low function of the MTHFR enzyme, which is an independent risk factor for cardiovascular events including ischemia and thrombosis.⁶

B12 is essential for folate metabolism and conversion of homocysteine to methionine, which is required for synthesis of DNA, neurotransmitters, and myelin.⁷ Lack of B12 thus prevents methylation of myelin proteins, which can then result in demyelination in the peripheral and central nervous systems and subacute combined degeneration of the spinal cord.⁸

Loss of myelin is significantly associated with severe neurological conditions, including myelopathy, subacute combined degeneration (SCD) of the spinal cord, white matter lesions in the brain, and peripheral neuropathy.⁹

Chronic misuse of nitrous oxide is commonly associated with nerve damage disorders such as numbness, weakness, decreased sensation, and urinary retention.¹⁰ Psychiatric complications are also common and can include depression, mania, hallucinations, and sleep disorders.¹¹

Prolonged exposure to N₂O can result in megaloblastic changes and macrocytic anemia.¹²

Recreational use of nitrous oxide has led to dangerously high homocysteine levels and thrombosis even in young adults due to deficient B12.¹³

Researchers have noted that patients at higher risk of B12 deficiency (those with malabsorptive disorders, vegans/vegetarians, and the elderly) should be monitored when given nitrous oxide.

Alternative sedation options to nitrous oxide in dentistry may be administered by inhalation, orally, or intravenously, ranging from minimal to deep sedation. 

Oral sedation involves taking sedative medications (usually as tablets) before a procedure. Most commonly used medications include diazepam, triazolam, lorazepam, and hydroxyzine. 

Intravenous sedation is administered directly into the bloodstream through a vein, inducing rapid sedation. This may be given for intensive procedures or patients with anxiety. 

For very complex dental surgeries, general anesthesia may be used.

People with an MTHFR genetic mutation who have to use nitrous oxide for a procedure should consult with their health practitioner regarding their B12, homocysteine levels, and MMA (Methylmalonic Acid) levels. Elevated homocysteine and MMA markers will represent deficiency in B12.

If nitrous oxide must be used, supplementation with intramuscular Vitamin B12 and methylfolate (active folate) prior to and following surgery may be recommended to improve tissue stores.

Intravenous vitamin B12 before surgery may help to reduce homocysteine levels.¹⁴ However, as this is not readily available at all clinics, patients should consider other bioavailable forms of B12 such as sublingual supplementation, which is shown to increase B12 levels as effectively as intravenous forms.¹⁵

Recent clinical observations have suggested that patients who are given N₂O while taking vitamin B12 supplementation have significantly lower homocysteine levels even after the initial increase, with a rapid decrease observed within the following hours. Normal homocysteine levels tend to return within a week after N₂O use.¹⁶

Combining methylfolate with B12 and B6 is more effective in reducing homocysteine than B12 alone, so supplementation with both is recommended.¹⁷

In some cases, a known history of B12 deficiency may require an alternative anesthetic in order to avoid the risk of nerve damage.