A handful of peptides have been used in medicine for decades: First and most famously, insulin was made available in the 1920’s. Other well-known peptides include oxytocin, ACTH and vasopressin. Today, there are actually more than 150 peptides available or in development. The latest are creating a palpable stir; and many are pretty-readily available to our patients directly. Including on Amazon (caution!).
There are several colleagues of mine that are early adopters. Indeed, the promise of peptides, training on peptides, dialogue on peptide therapy- it’s all very enticing. I too, am excited for their potential. But what should we, as FxMed clinicians, know about these new peptides – How might they be applied? What are their success rates? What are the risks? Are they really ready for prime time FxMed?
A Brief Primer on Peptides
Peptides represent a truly gargantuan family of natural and synthetic amino acid chains (<50 amino acids in order to qualify under this nomenclature). They have a huge span of biological activities and include intra- and intercellular signaling molecules, glycopeptides, neuropeptides, antimicrobial peptides, digestion-specific, and hormonal peptides.
Most peptides in our bodies are products of human gene expression, made endogenously and cleaved from proteins. They can also be ingested from foods including fermented foods, dairy, grains and fish. Breastmilk is rich in peptides. Most orally-ingested peptides are not generally thought to be absorbed intact due to digestion.
Peptides’ relatively low molecular weights and simple amino acid structures give them “small molecule” passports to travel with some degree of freedom in the body and through molecular barriers that are off-limits to larger, more complex compounds.
Natural as well as synthetic peptides are increasingly investigated for their therapeutic/drug potential. Here’s a quick tour of a couple of those garnering most attention, and some of the experience being had in our community with their application:
BPC-157 – for GI Healing and Tissue Repair
BPC stands for Body Protection Compound and, though BPC-157 is considered a synthetic peptide, a portion of its sequence is derived from gastric juice; it is one of the peptides that remains stable within the challenging gastric environment. BPC-157 is a relative newcomer on the scene – as yet, a PubMed medical science library search yields fewer than 150 hits, mainly in preclinical research. However, to me it is one of the most exciting, especially for its gastro-protective and tissue repair properties. And for the reports I am hearing on its effectiveness –
This from a West-Coast Functional Medicine physician and respected colleague when I originally asked her about her use of peptides at the start of this year (she’s given me the all-clear to use her remarks):
“I just had a patient come back yesterday who I had put on BPC 157 for severe debilitating muscle and nerve pain from a car accident years ago but without any findings on MRI that would warrant surgery. She said that after 2 months on the peptide her pain is 70% improved. Several other patients are coming back who had been on the BPC for GI related inflammation and they also report significant improvements. I will be starting to use Thymosin alpha* in autoimmune disease. Very exciting!”
*More on Thymosin alpha to come below..
And this, when I pinged her more recently for an update:
“Yes, I am still using the peptides, specifically the BPC 157. Many of the other peptides are not cleared in California yet. I mainly use the BPC along with SBI Protect or L glutamine and a functional approach for gut issues and the BPC by itself for orthopedic injuries (e.g rotator cuff tears, tennis elbows, pre and post surgery etc). I still find that it works very well and have story after story of healing. Sometimes patients feel better within just a few days and other times (especially with gut issues) it takes a bit longer-4-6 weeks before they notice a difference.”
Until very recently, studies using BPC-157 came from researchers almost exclusively from the University of Zagreb in Croatia, who have been publishing on this peptide since the early 1990s. Their teams’ publications still dominate the limited literature circulation, even though a handful of researchers from China (since 2010) and the UK/US (since just 2019) have now published too.
Here’s a summary of the science on BPC-157:
Animal research on BPC-157 is very promising. In rodents, BPC-157 is considered primarily a gastroprotective factor, though some research also indicates potential for intestinal and even extra-intestinal healing of soft connective tissue and more. Its varied potential mechanisms are thought to include interaction with inducible and/or endothelial nitric oxide-generating systems, by influencing serotonin, dopamine, GABA, and/or opioid metabolism, and/or by directly aiding blood flow, repair, regrowth, angiogenesis, and remodeling. Its safety profile in lab animals has been very good. Here are some of the successful rodent applications of BPC-157 to date:
- NSAID-related intestinal damage, liver and brain lesions
- Ulcerative colitis (anastomosis, short bowel syndrome and fistula)
- Esophageal fistula
- Perforated cecum
- Achilles tendon injury
- Ligament damage post-surgery
- Skeletal muscle injury
- Spinal cord injury
- Hemorrhage and thrombocytopenia following amputation
- Acetaminophen overdose (brain toxicity)
Very few human peer-reviewed data are as yet forthcoming. A small, 7-day clinical trial, published in 2002 offered very little information other than the reporting of ‘no significant adverse effects.’ Results from a clinical safety and pharmacokinetics study on BPC-157 registered with clinicaltrials.gov in 2015 have not yet been released (study status reported as ‘unknown’).
So here’s the rub: Our knowledgebase on 157 in humans is limited to clinical reports. Make no mistake, clinical reports are the first step in generating a testable hypothesis. I am very much in favor of this type of investigation when we know the safety profile of the compound(s) is good. If you are aware of studies in process or completed but not yet published, let me know in the comments.
Thymosin β4 (Tβ4) – for Inflammation and Tissue Repair
Tβ4 is an intriguing and multi-purpose endogenous peptide, also available as a synthetic pharmaceutical. Tβ4 is one of the active peptides from the thymosin fraction 5 group of polypeptides involved in T-cell function. The natural human version is a member of the highly evolutionarily-conserved beta-thymosin family, and is encoded by the Thymosin beta 4 X-linked gene (TMSB4X), though this portion is interestingly (and importantly?) not silenced in females (via X inactivation) even though the Y chromosome also contains a homologous region.
Tβ4 is considered a major actin-sequestering protein that, working in concert with the kinetic/motor protein myosin, strongly influences the cellular cytoskeleton that supports cellular shape, motility, migration, and adhesion. Tβ4 appears to be involved in the formation of the coronary vessels and microvasculature during fetal development. It increases ATP levels at the surface of human endothelial cells, and appears to be involved in purinergic signaling to help regulate cellular growth, differentiation, and other aspects of the cell life cycle. Tβ4 is upregulated in many instances of trauma and seems particularly closely related to the body’s response to physical stresses or damage and the subsequent recruitment of a (ideally proportionate) immune response and tissue renormalization.
Defined mechanisms through which Tβ4 operates include reduced inflammation (including inhibition of NFκβ and restoration of autophagy), reduced ROS, increased cell migration/maturation, reduced apoptosis, increased angiogenesis. Its ability to reduce inflammation and oxidative stress, combined with trophic repair factors, give it a very broad range of potential applications.
Here is a skim over of the current research on Tβ4:
Animal and in vitro research
- In animal models of stroke, traumatic brain injury, and multiple sclerosis, Tβ4 has demonstrated neuroprotective and regenerative properties like supporting axonal growth, remyelination, and angiogenesis, and upregulating expression of tight junction proteins that contribute to blood-brain barrier integrity; in one study, it even seemed to coordinate with microRNA to improve brain progenitor cell survival and production of myelin basic protein.
- In an animal model of fetal alcohol disorders, Tβ4 expression was upregulated in protective microglial cells of the stress-sensitive hippocampus, and giving exogenous Tβ4 reduced activation of pro-inflammatory networks and their secretion of cytokines including TNFα, IL-1β, and iNOS.
- In mice, it inhibited functional and structural liver changes induced by acetaminophen toxicity. Human observational research suggests that Tβ4 plays a ‘defensive’ role in liver inflammation (specifically in combined chronic hepatitis B and NAFLD).
- In an animal model of type 2 diabetes, Tβ4 administration improved OGTT results as well as HbA1c, adiponectin, and triglyceride levels.
- Tβ4 itself can be enzymatically cleaved to release a specialized peptide called Ac-SDKP, which has been seen in animal research to inhibit induced lung fibrosis, seemingly through altering genetic expression related to matrix metalloproteinases and the tissue matrix constituents collagen and fibronectin, and in animal models of myocardial infarction, Tβ4 and Ac-SDKP may actually work together to encourage cardiac repair mechanisms.
- One cell study found that Tβ4 may be downregulated in inflamed human periodontal ligament cells, and that pretreatment with Tβ4 downregulated the inflammatory response and osteoclast proliferation (associated with bone deterioration).
- A small, controlled study of heart endothelial progenitor cell transplant patients (n=10) found that pretreating the transplanted cells with Tβ4 correlated with further improved cardiac function at 6 months post-surgery.
- A controlled study of 73 patients with venous ulcers reported that the intervention group with (topical Tβ4 0.03%) accelerated wound healing and led to 25% of patients experiencing complete wound healing within 3 months.
- A 2015 review cites evidence supporting its investigational use for skin repair, myocardial healing, and after brain or corneal injury.
- Clinical research on Tβ4 is still in progress for several cardiovascular, dermal, and ocular applications. Findings are as yet unpublished from these studies.
Tβ4 appears to have a good safety profile in clinical trials both as a topical agent and injectable. A study that injected Tβ4 into healthy volunteers for 14 days, for instance, found it to be ‘well tolerated with no evidence of dose limiting toxicity’. It’s a start – more data on any potential longer-term effects would of course lend reassurance.
A note on thymosin α1, mentioned by our colleague above
Like Tβ4, thymosin α1 is from the thymosin fraction 5 polypeptide group, and it was originally isolated from thymus tissue. It signals through the toll-like receptor (TLR) system to activate an immune response, and some researchers feel it may therefore have application in sepsis or in immunosuppressive conditions (such as HIV infection).
Research to date
In one research trial conducted in China on subjects with a form of chronic hepatitis B, thymosin α1 therapy was found to improve production of several cytokines, especially interferon-γ and IL-4. A Cochrane Database Systematic Review gives brief mention to thymosin α1 for periodontal healing and tooth survival after replanted permanent front teeth, though it notes the study was at high risk for bias. In animals, it has also been seen to inhibit angiotensin-converting enzyme (ACE), scavenge reactive oxygen species, and interfere with transmission of inflammation-related pain signaling, potentially through modulating GABA/glutamate transporter functions.
What are the potential downsides?
It does all sound too good to be true, doesn’t it? Potentially effective tools to help address some of the most challenging medical situations are powerfully alluring. There are, however, some reasons to cool the fires and keep a level head:
Unwanted trophic effects
Many therapeutic peptides have significant trophic activity, including angiogenesis. Many of their benefits are linked to this, in fact. However, the same tropic activity may also promote unwanted effects such as tumorigenesis. Higher levels of Tβ4, for example, have been correlated with sleep apnea, rheumatoid arthritis, knee osteoarthritis, and cancer. Whether its role is beneficial, or in these cases it’s ‘gone rogue,’ isn’t possible to say. BPC-157 also promotes angiogenesis, but intriguingly it has also been shown to inhibit the growth of several tumor lines and may counteract tumor cachexia. Bottom line – the jury is still out.
Peptides as performance-enhancing drugs
There is already pressure from athletic communities to tap into the soft tissue healing capabilities of peptides such as BPC-157, especially for sports injuries. However, there is the concern that the use of synthetic peptides by athletes could be considered performance-enhancing and therefore problematic.
Practicalities of using peptides
Delivery: The same colleague as above, more experienced in using peptides, had this to say about BPC-157 delivery:
“I would suggest injecting it SQ close to the site of pain/injury along with maybe some topical pain meds. The first month I usually have patients inject twice daily (if they can afford it) and then scale back to once per day.”
In research, BPC-157 has been successfully applied using subcutaneous, oral, topical, intra-peritoneal, intragastric, intracolonic, intrarectal, and intra-articular injectable forms. Apart from gastric-stable peptides like BPC-157, oral delivery is typically considered problematic due to their inherent instability and inconsistent navigation through the human digestive tract. After all, breaking down proteins is just what gastric acid and protease enzymes were designed to do.
Some final thoughts
Peptides cannot be universally labelled good or bad actors. This is nicely illustrated by the amyloid beta peptides implicated in the pathological processes of Alzheimer’s disease.
That said, the early indications of peptides such as those we’ve touched on above are positive – my ongoing collegial discussion above shows really nice turnaround and I’m keen to see their utility for myself. Of course, they won’t replace the foundational FxMed principles that we use with all patients – addressing nutrient imbalances, stress, sleep disturbance, exercise, smoking and other lifestyle variables. In fact, getting those foundations right almost always makes higher-level interventions (such as peptides) more successful.
For us, the bottom line is that we will be approaching peptides cautiously – short term use in high potential-impact situations such as trauma or refractory and severe inflammatory conditions. Careful monitoring of outcomes a given.
What about in your practice? Have you started using peptides yet? What are your thoughts, experiences?