“Consider that larger clinical trials are often meant to confirm something important to change our practice. The small trials are the ones making conceptual breakthroughs that change our thinking.” Aaron Cypess, M.D., Ph.D., M.M.Sc., National Institute of Diabetes and Digestive and Kidney Diseases NIH.
The early treatment trials for long COVID look very much like early trials of anything: they tend to be small, not very rigorous and can be sketchy statistically. Case reports are common. Quite a few came from the alternative health field.
Except for a couple of surprises, many will be familiar to anyone who’s kept a close eye on the chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) fields, which appear to be having quite an impact.
The early trials may provide informed patients and doctors though, with new options and lay the groundwork for bigger, better conceived, and ultimately, more useful clinical trials.
Those trials are coming – and rapidly. Suzanne Vernon Ph.D. – scientific advisor to the Bateman Horne Clinic – reported that a short list of clinical trials the RECOVER Initiative will investigate has been created (she wouldn’t say what they were). These trials will probably be fairly small, but they will undoubtedly be rigorous, and most importantly, if successful, they will undoubtedly receive follow-up. Vernon believes we will likely get new treatment options before we know exactly what’s happening in long COVID. (Interview coming up).
This overview assesses the already published clinical trials for long COVID with an eye to the future – in particular, whether the NIH’s RECOVER Initiative will fund further trials. It’s impossible to tell at this point, of course, how receptive the ultraconservative NIH will be to alternative or unusual attempts to treat long COVID, but one imagines it will have to let its hair down a bit as it plunges ahead with treatment trials without knowing what’s going on in long COVID.
My totally uninformed guess is that it’s going to continue its conservative ways but that some unusual approaches could sneak through. Hopefully, the first treatment on the list will be one of them.
As Expected – Low Dose Naltrexone Makes a Difference
Drug – Low Dose Naltrexone
Type of study – interventional pre-post study
Size – 36 long term patients (mean – @ 1 year)
Dose – 1 mg once daily for one month; the dose was increased by 1 mg monthly to a maximum of 3 mg
Length – 2 months
Endpoints – questionnaires
Results – 6/7 parameters showed improvement (recovery from COVID-19, limitation in activities of daily living, energy levels, pain levels, levels of concentration and sleep disturbance (p ≤ 0.001); the biggest effect was in pain; low side-effects were found: 36/38 participants finished the trial.
Authors’ conclusion: “LDN is safe in patients with PCS and may improve well-being and reduce symptomatology in this cohort. Randomized control trials are needed to further explore this.”
ME/CFS/FM connection – a commonly used drug in ME/CFS/FM, not surprisingly, does well in long COVID, particularly with pain. The fibromyalgia LDN trials have been successful, but were all quite small.
Bottom Line – Definitely a winner. LDN – a compounded drug that drug companies will not support – desperately needs federal support. The question is will the NIH finally give it? After several failed efforts to get funding, Jarred Younger concluded that the NIH will never fund an LDN trial.
I would be surprised, though, if LDN wasn’t on the short list of early clinical trials of the NIH’s RECOVER Initiative given the ME/CFS experts that have been consulted. Will that be enough for the LDN-averse and ultraconservative NIH to finally launch a trial? Time will tell.
Health Rising has done many blogs on LDN. Learn more about LDN
Getting Etanercept DEEP into the Brain
Drug – Etanercept – is a biologic that is capable of ameliorating two components of neuroinflammation: microglial activation and tumor necrosis factor (TNF-a) activity. Perispinal injection of the drug – which involves injecting the drug into the cerebral spinal fluid – has been called “a new therapeutic paradigm in neurology.” The idea is that stopping TNF-A stops a vicious circle from forming.
Type of study – case report
Size – 1
Dose – 25 mg perispinal application
Length – 24 hours and 1 month later
Endpoints – Montreal Cognitive Assessment, Beck Depression Index-II (BDI-II), Fatigue Assessment Scale, Controlled Oral Word Association Test, Trail Making Tests, Timed Finger-to-Nose Test, 20 m Self-Paced Walk Test, 5 Times Sit-to-Stand Test, and Grip Strength.
Results – a dramatic improvement in 24 hours: remarkable reductions in chronic post-COVID-19 fatigue and depression, and significant measurable improvements in cognition, executive function, phonemic verbal fluency, balance, gait, upper limb coordination, and grip strength. Cognition, depression, and fatigue were examined at 29 days; each remained substantially improved.
Authors’ conclusion – “Perispinal etanercept is a promising treatment for the chronic neurologic dysfunction that may persist after resolution of acute COVID-19, including chronic cognitive dysfunction, fatigue, and depression. These results suggest that long COVID brain neuroinflammation is a potentially reversible pathology and viable treatment target. In view of the increasing unmet medical need, clinical trials of perispinal etanercept for long COVID are urgently necessary.”
ME/CFS/FM connection – a fascinating case report given that Dr. Klimas’s modeling efforts suggested etanercept should be used to bring down neuroinflammation first in ME/CFS, followed by mifepristone to reset the HPA axis. That combination is currently being trialed in Gulf War Illness and ME/CFS.
Bottom line – Very small study – big winner, given the in-depth analysis. Much larger studies are obviously needed but what a nice potential linkup with the neuroinflammation idea for both long COVID and ME/CFS. Etanercept seems like a long shot, but if Nancy Klimas – who is apparently on RECOVER panels – has some good data to share with the NIH, we might just see a trial…
Will Vagus Nerve Stimulation Finally Get the Big Trial it Needs? (Probably not)
Drug – Vagus nerve stimulation
Type of study – randomized, sham-controlled, trial
Size – 13
Dose – two one-hour sessions/ day delivered at “suprathreshold intensities”
Length – 4 weeks
Endpoints – the study was designed to treat the following symptoms: anxiety, depression, vertigo, anosmia, ageusia, headaches, fatigue, irritability, brain fog
Results – the trends in the data suggest taVNS may have a mild to moderate effect in reducing mental fatigue symptoms in a subset of individuals.
Authors’ conclusion – “This innovative study demonstrates the safety and feasibility of supervised self-administered taVNS under a fully contactless protocol”. (The study was done without anyone stepping into a clinic.)
ME/CFS/FM connection – VNS stimulates the vagus nerve, which is believed to be underactive in ME/CFS. Anything that could tamp down the ferocious sympathetic nervous system response that appears to be present would be helpful, and Lauren Stiles is very hopeful about its chances with postural orthostatic tachycardia syndrome (POTS). It just needs a lot more study.
Bottom Line – In-betweener. The results were not that promising, but the VNS field is like the Wild West – no one knows what doses and durations work best. If anything needs large, placebo-controlled studies, VNS does. Will the NIH step up? It’s taking a deep look at VNS in its SPARC program, but my guess is no.
Is it Too Early for the Best Mitochondrial Enhancer for ME/CFS (and long COVID) to Get Federal Support?
Study – Oxaloacetate Treatment For Mental And Physical Fatigue In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long-COVID fatigue patients: a non-randomized controlled clinical trial
Supplement – Oxaloacetate
Type of study – non-randomized clinical trial
Size – 76
Dose – 500 mg BID (N = 23), 1,000 mg BID (N = 29) and 1000 mg TID (N = 24) AEO for six weeks.
Length – 6 weeks
Endpoints – Chalder fatigue scale
Results – 25% – 33% reduction in fatigue
Authors’ conclusion – “As there has been little progress in providing fatigue relief for the millions of ME/CFS and Long COVID patients, anhydrous enol oxaloacetate may bridge this important medical need.”
ME/CFS/FM connection – trial conceived by an ME/CFS doctor (Kaufman) after he dug into a metabolomic study result.
Bottom Line – A winner with a lot of questions. Will pretty good study size (n=76) and results pave the way for a larger (randomized, placebo-controlled) study? Also – can oxo move the needle on other fatigue scales? And the big question – will the price of oxaloacetate (@$500/month) ever come down? (Dr. Kaufman thinks it might.) My guess is that oxaloacetate may be a bridge too far for the NIH, but time will tell.
Fixing Reddened Throats to Impact the Central Nervous System?
Treatment – Epipharyngeal Abrasive Therapy (EAT) – the application of zinc chloride as an anti-inflammatory agent to the epipharyngeal mucosa.
Chronic epipharyngitis refers to inflammation at the back of the throat which, if memory serves, Dr. Cheney – an astute diagnostician – reported was very common in ME/CFS. This is how a Japanese paper described its possible relevance to ME/CFS:
“However, because of its close link with the nervous system and both the innate and acquired immune systems, it may play an important role as a trigger for the development of neuroendocrine disorders, including chronic fatigue syndrome and other somatic symptoms. Thus, the “epipharynx-brain interaction” is worth consideration in managing patients with chronic fatigue syndrome.”
Type of study – intervention
Size – 58
Dose – A 0.5% ZnCl2 solution was applied to the epipharyngeal mucosa once a week using a sterile straight nasal cotton swab and a pharyngeal swab. To increase the effectiveness of EAT, it is important to thoroughly scrub the epipharyngeal wall with cotton swabs.
Length – 1 month
Endpoints – intensities of fatigue, headache, and attention disorder
Results – EAT significantly improved the intensity of fatigue, headache, and attention disorder.
Authors’ conclusion – “These results suggest that EAT has potential as a novel method for long COVID treatment.”
ME/CFS/FM connection – a possible treatment for a long ignored symptom that the authors believe could impact central nervous system functioning.
Bottom Line – Unusual treatment produces a good result. Not a snowball’s chance in hell that the NIH will pick this up, but doctors might give it a shot. Is it available in the U.S.?
In-depth Case Report Builds Strong Case for Plasmapheresis
Drug – plasmapheresis
Type of study – case report
Size – 1
Dose – 3 TPEs
Length – 2 months
Results – a formerly healthy 68-year-old man who was very weak, unable to walk, experienced shortness of breath, and had lung issues was able after 2nd transfusion to walk uphill with ease and jog. His brain fog disappeared, and he returned to daily work activities. After the 3rd transfusion two months later, he was back to work, feeling like his normal self, and able to exercise daily without shortness of breath.
The infusions also “increased the markers of T-cells, B-cells, NK cells, and diminished the markers of inflammatory macrophages, suggesting enhanced adaptive immunity and attenuated inflammatory response. Proteomics also revealed a striking reduction in inflammatory markers.
Authors’ conclusion – “this case study suggests that TPE may alleviate post-COVID-19 sequelae via positive shifts toward adaptive immunity and tissue repair that are concurrent with reduction of inflammation.”
ME/CFS/FM connection – no studies have been done in ME/CFS/FM. In his FM study, which found that antibodies from FM patients were able to replicate an FM-like state in mice, Goebel suggested proposed trying plasmapheresis or immunoadsorption in FM. Scheibenbogen has found some success in small studies with immunoadsorption in ME/CFS, and the BC 007 aptamer is a candidate for both ME/CFS and long COVID.
Bottom line – The dramatic results from this very in-depth case report are intriguing given suggestions that a similar approach may work in ME/CFS/FM. Could the NIH spring for a small trial? Perhaps…
English National Opera (ENO) Breathe programme fails to hit the high notes
Treatment – English National Opera (ENO) Breathe programme or usual care
Type of study – parallel-group, single-blind, randomised controlled trial
Size – 150 long COVID patients experiencing breathlessness
Endpoints – Health Related Quality of Life (HRQoL) using mental health composite (MHC) and physical health composite (PHC) scores, as well as the chronic obstructive pulmonary disease assessment test score, visual analog scales (VAS) for breathlessness, and scores on the dyspnoea-12, the generalized anxiety disorder 7-item scale, and the short form-6D.
Results – Mental health but not physical health scores improved, as did the VAS for breathlessness
Author’s conclusion – “Our findings suggest that an online breathing and wellbeing program can improve the mental component of HRQoL and elements of breathlessness in people with persisting symptoms after COVID-19. “
ME/CFS/FM connection – some people with ME/CFS experience breathlessness
Bottom Line – they tried! The most rigorous clinical trial yet, though produced an underwhelming result.
Mast Cell and Microglial Inhibiting Medical Food Makes Its Case
Study – Ultramicronized Palmitoylethanolamide and Luteolin Supplement Combined with Olfactory Training to Treat Post-COVID-19 Olfactory Impairment: A Multi-Center Double-Blinded Randomized Placebo-Controlled Clinical Trial
Supplement – Ultramicronized Palmitoylethanolamide and Luteolin Supplement (PEA-LUT 770 mg.) PEA – which has undergone numerous trials in Europe – has been held up as a case study of how the research community can ignore effective treatments it does not understand. It primarily has been used in Europe (the current study was from an Italian group) but has been making its way to the U.S. more recently. Jarred Younger included PEA in his list of potential microglial inhibitors that might be of use in ME/CFS and FM. Studies suggest PEA can reduce mast cell migration and degranulation and can shift them from their activated to their resting states. Hesselink reports that over twenty studies have elucidated PEA’s mast-cell inhibiting effects. A retrospective study found that PEA may be helpful as an add on treatment in FM.
Type of study – Multi-Center Double-Blinded Randomized Placebo-Controlled Clinical Trial
Size – 185 long COVID patients with olfactory impairment
Dose – 770 mg
Length – 90 days
Endpoints – Improvement in the ability to smell
Results – Overall, 92% of patients in the intervention group improved their olfactory scores versus 42% of controls.
Authors’ conclusion – “Among individuals with olfactory dysfunction post-COVID-19, combining PEA-LUT with olfactory training resulted in greater recovery of smell than olfactory training alone.”
ME/CFS/FM connection – PEA has been suggested for both FM and ME/CFS.
Bottom line – PEA’s ability to better improve olfactory scores than with olfactory training alone suggests PEA may be having an impact on neuroinflammation. Two studies have found PEA improved results when used as an adjunct treatment – but why the focus on adjunct treatments? PEA gets a lot of support in Europe, but I would be shocked if the NIH picked this treatment up. Find out more about PEA – what it may do and how to take it.
Perrin Technique Reduces Fatigue in long COVID
Treatment – Lymphatic drainage – Perrin technique
Type of study – Case series – first 20 long COVID patients
Size – 20
Dose – 9-10 sessions
Endpoints – symptom severity using the self-report 54-item profile of fatigue-related states (PFRS) before and after treatment.
Results – 45% and 52% improvements in men and women in fatigue-related scores with the highest reductions for fatigue subscale
Authors’ conclusion – “Our findings suggest that a specific manual lymphatic drainage intervention may help to reduce fatigue symptoms related to Long COVID. “
ME/CFS/FM connection – The Perrin lymphatic drainage technique was developed for ME/CFS.
Bottom Line – Potential winner. While no placebo controls were included, the results were promising. Hopefully, the emergence of long COVID will spur interest in this novel technique designed to restore lymphatic flows from the brain to the body, thus removing toxins in the brain. RECOVER Initiative funding chances are probably very low, unfortunately. Find out more about the Perrin technique
Not Adaptive Enough
Supplements – Chisan®/ADAPT-232 (a fixed combination of adaptogens Rhodiola, Eleutherococcus, and Schisandra)
Type of study – randomized, quadruple-blind, placebo-controlled trial
Size – 100
Length – 2 weeks
Endpoints – reduction in symptoms
Results – Chisan® decreased the duration of fatigue and pain for one and two days, respectively, in 50% of patients. Plus, significant differences between placebo and Chisan® treatment were observed only with a workout (daily walk time) and in relieving respiratory insufficiency (cough). No significant improvements were made in markers of blood coagulation or inflammation, but blood creatinine was lower.
Authors’ conclusion – “we, for the first time, demonstrate that adaptogens can increase physical performance in Long COVID and reduce the duration of fatigue and chronic pain. It also suggests that Chisan®/ADAPT-232 might be useful for preventing the progression of renal failure associated with increasing creatinine.”
ME/CFS/FM connection – adaptogens have been suggested for ME/CFS.
Bottom line – Loser. This was a serious study, but the results were middling at best. The buck probably stops with this study.
Supplement – a high-fiber formula with investigational new drug (IND) status; this is the type of product that’s typically used to increase butyrate levels and butyrate-producing bacteria.
Type of study – case report
Size – 1
Length – 2 months
Results – Severe “loss of appetite,” palpitation, and anxiety were significantly improved as were serum lipid profile, insulin level, and leptin level.
Authors’ conclusion – “Our study indicates the feasibility of alleviating gastrointestinal symptoms in patients with post-acute COVID-19 syndrome by way of nutritional modulation of their gut microbiota. ”
ME/CFS/FM connection – Low butyrate levels have been found several times in ME/CFS and could be tied to leaky gut and inflammation.
Bottom Line – In betweener. This case report helps to validate what we already know in ME/CFS – that butyrate enhancement could be helpful – but it was hard to understand from the abstract.
Call me naïve, but given the gut problems found in long COVID, and the increasing recognition of the role the gut plays in many diseases, I wouldn’t be surprised if a gut microbiome enhancement trial doesn’t make the cut in the RECOVER Initiative.
Breathing Deep Again…An Inspiratory Muscle Training Trial
Treatment – inspiratory muscle training; i.e. breathing training using a device
Type of study – randomized control; inspiratory training vs usual care
Size – 281
Length – 8 weeks
Endpoints – Health-related quality of life and breathlessness questionnaires (King’s Brief Interstitial Lung Disease (KBILD) and Transition Dyspnoea Index (TDI)), respiratory muscle strength and fitness (Chester Step Test).
Results – no difference in KBILD total score but significant and clinically meaningful improvements in breathlessness and significantly improved (but clinically meaningful?) respiratory muscle strength and estimated aerobic fitness.
Authors’ conclusion – “IMT may represent an important home-based rehabilitation strategy for wider implementation as part of COVID-19 rehabilitative strategies.” (Another case report found that 2 months of respiratory muscle training plus cardiopulmonary rehabilitation resulted in improved dyspnea, physical performance, and pulmonary function parameters and that activities of daily living rapidly improved.)
ME/CFS/FM connection – inspiratory muscle training in ME/CFS and long COVID underway now.
Bottom Line – In-betweener – the results were good but not great. (Did not meet its primary goal – total KBLID score). Still, inspiratory muscle training is cheap, readily available, can be done at home, and does not require a prescription. What’s not to try? Given its long history of effectiveness in other diseases and the lung connection in COVID, I could see the RECOVER Initiative funding a trial.
Hyperbaric oxygen treatment increases blood flows to the brain, exercise capacity, and cognition
Two Studies – Hyperbaric oxygen treatment for long coronavirus disease-19: a case report / Hyperbaric oxygen therapy for the treatment of long COVID: early evaluation of a highly promising intervention /
Treatment – hyperbaric oxygen
Type of studies – case report/intervention
Sizes – 1 / 10
Doses – 90 minutes of 100% oxygen at 2-atmosphere absolute pressure with 5-minute air breaks every 20 minutes – 5 days per week
Lengths – 60 sessions / 10 x 105-minute sessions of HBOT to 2.4 atmospheres over 12 days.
Results – Case Report – significant improvements in brain perfusion and microstructure, increased cerebral blood flow, 34% increase in the maximum rate of oxygen consumed during exercise, and a 44% improvement in forced vital capacity. Significant improvement in memory including nonverbal memory, executive functions, attention, information procession speed, cognitive flexibility, and multitasking.
Results – 10 session study – statistically significant improvement in the Chalder fatigue scale (p=0.0059; d=1.75 (very large)), global cognition (p=0.0137; d=-1.07 (large)), executive function (p=0.0039; d=-1.06 (large)), attention (p=0.0020; d=-1.2 (very large)), information processing (p=0.0059; d=-1.25 (very large)) and verbal function (p=0.0098; d=-0.92 (large)).
Authors’ conclusion (case report) – “We report the first case of successfully treated long COVID symptoms with hyperbaric oxygen therapy with improvements in cognition and cardiopulmonary function. The beneficial effects of hyperbaric oxygen shed additional light on the pathophysiology of long COVID. “
Authors’ conclusion (10-session study) – “The results presented here suggest potential benefits of HBOT, with statistically significant results following 10 sessions.”
ME/CFS/FM connection – several studies suggest hyperbaric oxygen treatment can help in FM.
Bottom Line – Winner. The case report was notable for its in-depth assessment of brain perfusion, cerebral blood flows, and oxygen consumption during exercise – just the things we’d hoped hyperbaric oxygen treatment would help. The 10-session study found improvements in fatigue and many cognitive assessments including information processing – which studies consistently show is impaired in ME/CFS.
So far so good. The big question is – will the improvements last and what is the optimum number of sessions needed to produce the most efficient results? We need big, well-designed studies to answer those questions. Will the NIH support a kind of new-agey treatment that nevertheless seems to get good results? I would be shocked if it did but hope it will.
Drug – Ozone therapy – According to one site, “ozone therapy is a procedure in which a pint to a quart of blood is drawn into a closed sterile glass device specifically made for this therapy. Medical grade ozone is added directly to the blood before being returned to the body in a 30-minute reinfusion process…(It) delivers potent extracellular and intracellular cleansing and detoxing power of ozone directly into your bloodstream, eradicating on contact all pathogens, bacteria, viruses, mold, fungi and yeast, while oxygenating and feeding your cells for a rapid and drastic improvement of your health and well-being.”
Type of study – ?
Size – 100
Dose – ?
Length – ?
Endpoints – 7-scoring Fatigue Severity Scale (FSS)
Results – reduced fatigue by 67%; 40% reportedly completely recovered
Authors’ conclusion – “Ozone therapy is able to recover normal functionality and to relief pain and discomfort in the form of PASC-associated fatigue in at least 67% of patients suffering from post-COVID sequelae, aside from sex and age distribution.”
ME/CFS/FM connection – Ozone therapy purports to oxygenate cells
Bottom Line – Inbetweener. Rudimentary statistics from an Italian study suggest that ozone therapy may be helpful with fatigue but who really can trust the stats (and an abstract written like that)? Much better studies are needed. Chance of the RECOVER Initiative taking this up? Zero.
Taming the Sympathetic Nervous System with a Shot to the Neck?
Treatment – stellate ganglion block with anesthesia could allow the regional autonomic nervous system to “reboot” , decreasing sympathetic nervous system activity, improving blood flows, etc. – thus fixing or rehabilitating a key system in ME/CFS, FM, and probably long COVID.
Type of study – case series
Size – 2
Dose – 2
Results – two quite severe long-COVID patients return to work after a couple of treatments. (Also another case report found SBG plus injections in other parts of the spine reportedly led to complete recovery of a long-COVID patient.)
Authors conclusion – “The stellate ganglion block has been used for nearly a century to treat a variety of sympathetically mediated medical conditions. Its safety profile is well established. Its application in treating Long COVID/PASC is novel but promising. The lack of effective treatments for Long COVID/PASC makes the SGB an attractive therapeutic modality that deserves further investigation.”
ME/CFS/FM connection – reportedly has worked in a few ME/CFS patients as well – could impact key processes in ME/CFS and FM.
Bottom Line – Winner. Couldn’t have said it better: “The lack of effective treatments for Long COVID/PASC makes the SGB an attractive therapeutic modality that deserves further investigation.” The RECOVER Initiative almost certainly won’t take this up, but others hopefully will.
Keep the Information Flowing! Support Health Rising
HEALTH RISING IS NOT A 501 (c) 3 NON-PROFIT