Optimal Conventional Treatments: Drug and Nondrug Approaches

Conventional Treatment Options: What’s Most Likely to Work?

Modern medicine is prescriptive. Patients are diagnosed by a licensed doctor or other primary care provider and receive a pharmaceutical drug prescription. In the case of Long COVID, however, drugs don’t work well or at all.

Conventional medical approaches proved inadequate in addressing the needs of individuals suffering from Long COVID. Similarly, these approaches also failed to provide effective solutions for those with ME/CFS (Myalgic encephalomyelitis/chronic fatigue syndrome). Likewise, no proven effective treatment or medication is available for individuals with chronic Lyme Disease. And some autoimmune conditions have similar symptoms, such as Multiple Sclerosis (MS), and are also treated ineffectively.

Therefore, I’m not surprised that standard approaches offer limited options for Long COVID cases, so patients seek alternative solutions. In this chapter, I review conventional options, including drug and nondrug approaches, used to treat Long COVID. In the next chapter, I’ll discuss alternative natural approaches.

Antiviral Drugs

Antiviral drugs help minimize the symptoms and duration of active viral infections. However, antiviral drug development lagged the progress of antibiotics used to treat bacterial infections. One reason is that viruses have a protein coat surrounding a nucleic acid genome. The protein coat is called a capsid. Instructions for making the protein subunits of the capsid are encoded in the nucleic acid genome of the virus.

It’s a simple construction but highly effective for rapid replication. And is an obstacle that makes it difficult for drugs to eliminate or inhibit viruses.

Another reason antivirals don’t work well is unlike bacteria, viruses are not living things. They do not share the hallmarks of living things like metabolism or the ability to reproduce independently. To reproduce, a virus infects a living cell causing the cell to create copies of the virus. This characteristic makes it challenging to design antivirals to target viruses without killing normal cells. In addition, antiviral drugs have the potential for serious side effects. For example, Paxlovid provides some benefits during acute COVID but can cause diarrhea, abdominal pain, nausea, malaise, and other adverse symptoms.

However, over time, researchers were not idle. They found ways to target critical enzymes, like reverse transcriptase in HIV. Reverse transcriptase is an enzyme encoded from the genetic material of retroviruses that catalyzes the transcription of retrovirus RNA into DNA. But even these highly effective antiretroviral drugs don’t eliminate the virus. They control its growth and spread, indirectly improving immune status and reducing symptoms, but do not completely destroy the virus. HIV patients must take antiretrovirals for life.

Other successful antiviral drug treatments are those for Hepatitis C Virus (HCV).  There’s no effective vaccine for HCV, but direct-acting antiviral cures more than 95% of those infected with HCV.

In the original SARS epidemic of 2003, over 90 percent of patients in Hong Kong, an epicenter of the disease, were treated with Ribavirin, one of the only broad-spectrum antiviral drugs available at that time. However, it caused anemia in more than half of patients, failed to lower viral load, and was ineffective in most cases—this misconception about effectiveness resulted in the contagious spread to healthcare workers. Twenty years later, in the era of the COVID-19 pandemic, we’re only slightly better at controlling SARS coronaviruses.

Antiviral Drugs For SARS-CoV-2

There is no antiviral drug that targets the virus that causes COVID. One reason is that SARS-CoV-2 quickly generates lots of mutations resistant to antivirals. Some antivirals worked when first used on patients, but treatment failure developed due to rapid variant and sub-lineage evolution. The most used antivirals, Paxlovid and Molnupriavir, provide only modest benefits.

  • Paxlovid: A combination of two antivirals, nirmatrelvir and ritonavir, was approved as a five-day course to treat acute COVID. It’s used to prevent Long COVID but is largely ineffective. However, it can reduce persistent low-grade viral activity. Yale School of Medicine is conducting a Paxlovid for Long COVID study (PAX LC). The typical Paxlovid dosage is two tablets (300 mg) of nirmatrelvir and one tablet (100 mg) of ritonavir by mouth twice daily for five days. There’s no established daily dose for Long COVID patients. However, variants of SARS-CoV-2 have shown drug resistance to nirmatrelvir.
  • Molnupriavir: A drug with antiviral activity against RNA viruses, like SARS-CoV-2, it helps reduce the risk of hospitalization and death in unvaccinated adults. But it’s only moderately effective, and 30 percent experience adverse effects. Overusing partially effective antivirals like molnupiravir may drive variant mutations that prolong the pandemic. A study in Science found that molnupiravir has limited benefits and supercharges viral evolution.
  • Monoclonal Antibodies: During the early months of the COVID-19 Pandemic, monoclonal antibodies (mAbs) worked fast for acute infection, effectively neutralizing viral spread. I referred several of my patients for this expensive intravenous treatment, and they experienced dramatic improvement within a few days. However, new variants rapidly evolved resistant to mAbs. For this reason, Sotrovimab is no longer authorized in the US to treat SARS-CoV-2. In a 2022 study, the mAb Leronlimab, an HIV drug, reduced some Long COVID symptoms. However, no current studies exist, and the use of mAbs has yet to progress for the treatment of post-SARS-CoV-2 infection.
Long COVID Treatment

Drugs for Symptom Control

Treating symptoms is standard practice in allopathic medicine. Symptoms of Long COVID are so numerous that drugs are limited to the main symptoms. These drugs include wakefulness drugs for drowsiness and fatigue, analgesics and anti-inflammatories for joint pain, and antidepressants for mood changes.

  • Anti-inflammatory Drugs: A 2022 study found that colchicine, a drug used for gout, did not significantly improve acute COVID patients’ symptoms but may have reduced complications and deaths. However, a 2023 clinical study found it improved brain fog, fatigue, and joint aches in Long COVID patients.
  • Fluvoxamine: SARS-CoV-2 can invade the nervous system and enter the brain, causing an imbalance in serotonin, a neurotransmitter linked to depression and fatigue. Selective serotonin reuptake inhibitors (SSRIs), like fluvoxamine, have shown minor benefit for improving mood in some Long COVID patients.

In my clinical experience, the benefits of symptomatic use of pharmaceutical drugs are modest, and there is concern for cross-reactions when taking too many prescriptions. At the time of this blog, we’re still looking for better symptomatic treatments.

Off-label and Repurposed Drugs

Patients are requesting, and some doctors are prescribing off-label meds since there’s no FDA-approved drug for Long COVID. However, the options are limited, and the results are marginal.

  • Chochicine: A few case studies in adolescents with recurring fevers post-COVID infection were successfully treated with Chochicine in managing symptoms in some cases.
  • Guanfacine: FDA approved in 2009 for ADHD, guanfacine strengthens prefrontal cortex connections and helps executive functioning (decision making) and memory (brain fog). It also has a blood pressure-lowering effect. Arman Fesharaki-Zadeh, MD, PhD at Yale, combines Guanfacine with NAC 600 mg once daily. Taken together, they have a synergistic impact on calming neuroinflammation and reducing brain fog. The starting dose of Guanfacine is 1 mg once daily at bedtime, and after one month, it is increased to 2 mg.
  • Leronimab: A monoclonal IgG4 antibody originally used to treat HIV infection, Leronlimab belongs to a group of drugs called CCR5 antagonists.CCR5 antagonists block HIV from getting into and infecting specific immune system cells, preventing the virus from multiplying in the body. It may help some Long COVID patients by restoring normal immune function and downregulating inflammation.
  • Low-dose Naltrexone (LDN): Approved for opioid addiction and alcohol use disorder, LDN can reduce chronic inflammation. LDN is the most frequently prescribed off-label drug for Long COVID. Some patients experience less pain and more energy, decreased brain fog, and less fatigue. The starting dose is 1.5 mg daily. Gradually increase to 4.5 mg. A course of treatment is 2-3 months. There are few side effects.
  • Maraviroc and Pravastatin: Dr. Bruce Patterson and colleagues use this combination of drugs to target vascular inflammation. Specifically, it addresses CD16+ monocytes, which express both CCR5 and fractalkine receptors (CX3CR1), that play a role in vascular homeostasis and endothelial immune surveillance. Dr. Patterson and colleagues found that tiny clots in capillaries trigger symptoms of Long COVID. I’ll discuss this concept in more detail in a later chapter.
  • Metformin: One of the most promising is repurposing a treatment for type 2 diabetes. Metformin has a history of repurposing for weight loss, lowering lipids, and improving blood vessel integrity. It’s also a favorite drug for its anti-aging metabolic benefits. Its benefit for treating acute COVID and Long COVID is likely due to its ability to positively impact metabolism, making it ideal for treating overweight and metabolically compromised patients. The starting dose for prevention is 500 mg on day 1, then 500 mg twice daily from days 2-5, and on days 6-14, 500 mg in the morning and 1000 mg in the evening. The average safe dose for longevity is 1000 mg of extended-release tablets.
  • Rivaroxaban: Marketed as Xarelto, it’s a commonly prescribed blood thinner used to treat microclots in the brain and prevent stroke. Several trials found rivaroxaban helpful in preventing complications, including Long COVID, in hospitalized patients when 10 or 20 mg is taken for 14-30 days post-discharge.

Drugs In Development

Long COVID is a sizeable market, so it’s not surprising that drugs are in the pipeline. One is a peptide-based drug, NACE2i, developed by QIMR Berghofer to treat persistent inflammation. NACE2i can stop viral replication and protect against re-infection. It can also prevent inflammation and promote lung tissue repair. It sounds impressive. But FDA approval is pending.

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What Drugs Are Most Likely to Help Beat Long COVID?

None of these pharmaceutical drugs target specific disease processes that cause Long COVID. Though non-specific drug treatments, like LDN, may help reduce symptoms in some cases. However, all drugs have side effects, which I call the ‘limited benefit but high-risk potential’ method for Long COVID treatment.

Note About Glucocorticoids in Acute COVID Infection: High doses of steroids were used in SARS and MERS but caused more harm than benefit. Chinese studies in early 2020 found methylprednisolone effective in reducing deaths among hospitalized COVID patients. However, subsequent negative experiences with steroid drugs resulted in guidelines against the routine use of glucocorticoids for COVID patients. However, in a reversal of policy, in late 2020, the WHO recommended glucocorticoids for 7-10 days in critically ill patients. Do risks outweigh benefits?

Synthetic glucocorticoids can cause long-lasting HPA axis disruption in some patients. Adrenal function shuts down, so less cortisol is produced. The main symptom is severe persistent fatigue. Some cases will return to normal in time. Others may have a permanently weakened adrenal function, causing a chronic fatigue state like in ME/CFS and Long COVID.

Since the HPA axis is already disrupted and cortisol levels tend to be low, I do not recommend glucocorticoids for Long COVID cases.


Thoughtful clinicians in the field of persistent Lyme disease, ME/CFS, chronic EBV, and now Long COVID admit these are challenging conditions to diagnose and treat effectively. They emphasize that their understanding is evolving, but there is no cure so far.

In my clinical experience, the off-label drugs that offer the most symptom control are LDN and metformin. These are relatively safe with few side effects and are inexpensive. Though they don’t address the root cause of Long COVID, they positively influence metabolism and chronic pain, allowing some patients to return to their regular daily routine.

If you want to try off-label drugs, find an experienced doctor using these drugs to help safely manage your prescriptions. Remember, none of these drugs addresses the underlying biological reasons or mechanisms that cause Long COVID, so benefits are limited to symptomatic improvement.

For a thoughtful YouTube video, see the interview with Akiki Iwasaki, PhD, the leading researcher in Long COVID.

Selected Citations

Banerjee I, Robinson J, Sathian B. Treatment of Long COVID or Post COVID syndrome: A Pharmacological approach. Nepal J Epidemiol. 2022 Sep 30;12(3):1220-1223. PMCID: PMC9659683. https://pubmed.ncbi.nlm.nih.gov/36407052/

Bhimraj A, Gallagher JC. Lack of Benefit of Fluvoxamine for COVID-19. JAMA. 2023;329(4):291–292. https://doi:10.1001/jama.2022.23954 

Bonilla H, Peluso MJ, et al. Therapeutic trials for long COVID-19: A call to action from the interventions taskforce of the RECOVER initiative. Front Immunol. 2023 Mar 9;14:1129459. PMID: 36969241; PMCID: PMC10034329. https://pubmed.ncbi.nlm.nih.gov/36969241/

Brzdęk, M., Zarębska-Michaluk, D., Invernizzi, F., Cilla, M., Dobrowolska, K., & Flisiak, R. (2023). Decade of optimizing therapy with direct-acting antiviral drugs and the changing profile of patients with chronic hepatitis C. World Journal of Gastroenterology, 29(6), 949-966. https://doi.org/10.3748/wjg.v29.i6.949

Capela Santos D, Jaconiano S, Macedo S, Ribeiro F, Ponte S, Soares P, Boaventura P. Yoga for COVID-19: An ancient practice for a new condition – A literature review. Complement Ther Clin Pract. 2023 Feb;50:101717. Epub 2022 Dec 13. PMID: 36525872; PMCID: PMC9744485. https://pubmed.ncbi.nlm.nih.gov/36525872/

Chatterjee, S., Bhattacharya, M., Dhama, K., Lee, S., & Chakraborty, C. (2023). Resistance to nirmatrelvir due to mutations in the Mpro in the subvariants of SARS-CoV-2 Omicron: Another concern? Molecular Therapy. Nucleic Acids, 32, 263-266. https://doi.org/10.1016/j.omtn.2023.03.013

Fung KW, Baye F, Baik SH, McDonald CJ. Nirmatrelvir and Molnupiravir and Post–COVID-19 Condition in Older Patients. JAMA Intern Med. 2023;183(12):1404–1406. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2811092

Hashimoto K. Overview of the potential use of fluvoxamine for COVID-19 and long COVID. Discov Ment Health. 2023;3(1):9. https://doi:10.1007/s44192-023-00036-3 Epub 2023 Mar 21. PMID: 36968793; PMCID: PMC10029802.

Hashimoto, K. (2023). Overview of the potential use of fluvoxamine for COVID-19 and long COVID. Discover Mental Health, 3(1). https://doi.org/10.1007/s44192-023-00036-3

Hector Bonilla, Lu Tian, Vincent C. Marconi, Robert Shafer, Grace A. McComsey, Mitchel Miglis, Philip Yang, Linda N. Geng

Low-Dose Naltrexone use for the management of post-acute sequelae of COVID-19.

medRxiv 2023.06.08.23291102; doi: https://doi.org/10.1101/2023.06.08.23291102

Karatza, E., Ismailos, G., & Karalis, V. (2021). Colchicine for the treatment of COVID-19 patients: Efficacy, safety, and model informed dosage regimens. Xenobiotica; the Fate of Foreign Compounds in Biological Systems, 1-14. https://doi.org/10.1080/00498254.2021.1909782

O’Kelly B, Vidal L, McHugh T, Woo J, Avramovic G, Lambert JS. Safety and efficacy of low dose naltrexone in a long covid cohort; an interventional pre-post study. Brain Behav Immun Health. 2022 Oct;24:100485. doi: 10.1016/j.bbih.2022.100485. Epub 2022 Jul 3. PMID: 35814187; PMCID: PMC9250701.

Pan P., et al. SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce hyperinflammation. Nat Commun. 2021; 12: 4664. https://doi.org/10.1016/j.jaip.2023.02.03

Patterson BK, et al. Case series: Maraviroc and pravastatin as a therapeutic option to treat long COVID/Post-acute sequelae of COVID (PASC). Front Med (Lausanne). 2023 Feb 8;10:1122529. PMID: 36844201; PMCID: PMC9944830. https://www.frontiersin.org/articles/10.3389/fmed.2023.1122529/full

Sanderson, T., Hisner, R., Donovan-Banfield, I. et al. A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes. Nature (2023). https://doi.org/10.1038/s41586-023-06649-6

Toro-Huamanchumo CJ, Benites-Meza JK, Mamani-García CS, Bustamante-Paytan D, Gracia-Ramos AE, Diaz-Vélez C, Barboza JJ. Efficacy of Colchicine in the Treatment of COVID-19 Patients: A Systematic Review and Meta-Analysis. J Clin Med. 2022 May 6;11(9):2615. PMID: 35566737; PMCID: PMC9105993. https://www.mdpi.com/2077-0383/11/9/2615

Tu, W. J., et al. (2023). In vivo inhibition of nuclear ACE2 translocation protects against SARS-CoV-2 replication and lung damage through epigenetic imprinting. Nature Communications, 14(1), 1-21. https://doi.org/10.1038/s41467-023-39341-4

Wen Juan Tu et al, In vivo inhibition of nuclear ACE2 translocation protects against SARS-CoV-2 replication and lung damage through epigenetic imprinting, Nature Communications (2023). DOI: 10.1038/s41467-023-39341-4