NMDA receptor antagonists: Uses, common brands, and safety info

Fascinating pharmacologic history, valid medical use for some of the most devastating neurodegenerative conditions, and the potential for illegal abuse are all features of the NMDA receptor antagonist drug class. There are three primary members of the class that are used in medical care regularly. This article will cover the class’ intriguing history and pharmacology, as well as the current use of its members, their side effects, and cost.

Other NMDA receptor antagonists

• Phencyclidine

• Dextromethorphan

• Esketamine

What are NMDA receptor antagonists?

NMDA receptor antagonists are a small but diverse family of drugs. Uses range from Alzheimer’s disease and Parkinson’s disease to anesthesia and depression treatment. Their utility is so disparate that many prescribers and patients do not know that the different members of the class are related.

How do NMDA receptor antagonists work?

N-methyl-d-aspartate receptors (NMDAR) populate our central nervous system (CNS), residing in the synapses, junctions between neurons (nerve cells). The NMDAR is actually an ion channel that opens when stimulated by the neurotransmitter glutamate or glycine to allow calcium or sodium to flow into the neuron. These neurotransmitters are amino acids that allow neurons to signal one another or other tissues. Activation of this glutamate receptor has an excitatory effect on the CNS.

NMDAR antagonists block the receptor, diminishing the excitatory potential of glutamine. 

A more potent channel blocker like Ketalar can produce sedation deep enough for surgical procedures. On the other hand, Namenda only blocks the receptor in times of overuse, and amantadine is a weak antagonist. The variation in receptor inhibition strength as well as having different concurrent neurologic mechanisms likely explains the NMDAR antagonists’ diversity of use.

What are NMDA receptor antagonists used for?

• Alzheimer’s disease

• Parkinson’s disease

• Anesthesia

• Depression

Types of NMDA receptor antagonists

Namenda

Used for moderate to severe Alzheimer’s disease, Namenda XR is an oral, extended-release product that’s a unique tool for dementia treatment. Other treatments generally fall into the acetylcholinesterase category of drugs. Excessive NMDA receptor activation, termed excitotoxicity, is thought to play a role in the progression of Alzheimer’s disease, and Namenda can provide neuroprotection by the way it attenuates NMDA receptor stimulation. 

As a weak NMDAR inhibitor, Namenda has less side effect potential compared to other members of the class. Nonetheless, the rare potential for agitation and hallucinations has been reported.

RELATED: Delirium vs. dementia

Ketamine

The potential for hallucinations is much higher with the NMDA receptor antagonist phencyclidine (PCP). PCP was discovered a century ago and ultimately tried as an anesthetic before postoperative hallucinations halted its therapeutic use. The hallucinogenic PCP has since had illicit use only. PCP has other chemical relatives with similar activity. Even the cough suppressant dextromethorphan can cause PCP-like hallucinations and confusion at higher doses.

Another derivative of PCP, ketamine, was discovered in the 1970s. While ketamine can be abused, it has maintained intravenous usage in anesthesia for decades. By being able to produce a dissociative state (a state of unawareness) and non-narcotic analgesia (pain relief), Ketalar can serve as a means of inducing and maintaining anesthesia for procedures. Unfortunately, hallucinations, noted upon awakening and similar to schizophrenia, can still be an issue.

More recently, ketamine usage in the treatment of depression has gained attention. A rapid improvement has been noted in some neuroscience studies, and further randomized clinical trials in psychiatry may better define the role of ketamine products in depression treatment. Currently, intravenous Ketalar is used off-label (without an official Food and Drug Administration indication) for severe depression that is resistant to standard options. An intranasal, spray form of esketamine, one of ketamine’s chemical enantiomers, has approval for restricted use in depression therapy. 

Interestingly, the mechanism of antidepressant action for ketamine may not even involve NMDAR blockage and may instead involve modulation of other CNS binding sites, such as being an agonist (activator) of opioid receptors. The opioid receptor stimulation by ketamine can explain why infrequent, off-label use occurs for acute and chronic pain, particularly as an analgesic for neuropathic pain.

Amantadine

The mechanism for amantadine effectiveness for Parkinson’s disease is also unknown. It may involve NMDA antagonism, or it may rely on a dopamine effect. Originally an antiviral for influenza treatment, amantadine has been repurposed for the treatment of Parkinson’s disease. It can be used both alone and along with other medications for Parkinson’s. As with other members of this drug class, confusion and hallucinations can be a problem.

Who can take NMDA receptor antagonists?

Can men and women take NMDA receptor antagonists?

Across all indications, NMDA antagonists can be used by both men and women.

Can you take NMDA receptor antagonists while pregnant or breastfeeding?

In both the setting of pregnancy and lactation, caution with or avoidance of NMDA channel blockers is advisable due to potential harm or lack of safety data.

Can children take NMDA receptor antagonists?

Ketalar can be used by children who are at least 3 months old. Amantadine previously was used as an influenza treatment for children, but it is no longer recommended in flu treatment guidelines at any age.

Can seniors take NMDA receptor antagonists?

Seniors have the highest need for and use of NMDAR antagonists based on the epidemiology of Alzheimer’s and Parkinson’s diseases.

Are NMDA receptor antagonists safe?

Black box warnings

NMDA receptor antagonists do not carry black box warnings from the FDA.

Recalls

• Dextromethorphan products [June 2020]

• Ketamine [September 2019]

• Ketamine [June 2019]

• Dextromethorphan products [May 2019]

Restrictions

Use of any NMDA antagonist is contraindicated (should not be used) in the setting of a prior history of hypersensitivity allergic reactions to the product or another member of the drug class. 

In addition, ketamine has other contraindications such as strict avoidance of use in the setting of hypertension, stroke, or intracranial mass. These are related to its potential to raise blood pressure.

Are NMDA receptor antagonists controlled substances?

According to the Drug Enforcement Administration (DEA), ketamine is a Schedule III controlled substance, and PCP is a Schedule II controlled substance. Other members of the class are not controlled substances.

Common NMDA receptor antagonists side effects

• Confusion

• Hallucinations

• Irritability, anxiety, or aggression

• Somnolence or fatigue

• Nausea or vomiting

• Diarrhea or constipation

• Dizziness or headache

• Hypertension or hypotension (high or low blood pressure)

• Depression with amantadine and memantine

• Tachycardia or bradycardia (fast or slow heart rate) with ketamine

How much do NMDA receptor antagonists cost?

NMDA receptor antagonists can be costly, with Namenda XR reaching almost $500 for a one-month supply and Ketalar almost $200 for a vial. Fortunately, they do not have to break the bank. The SingleCare discount card can make them more affordable.