Acupuncture is a type of complementary treatment that involves inserting small needles into the body. It is a component of traditional Chinese medicine (TCM).
Acupuncture is a pseudoscience, and TCM’s theories and methods have been labeled as quackery because they are not founded on scientific understanding. It is divided into two main philosophical applications and approaches, the first of which is the modern standardized form known as eight principles TCM, and the second of which is based on the ancient Taoist Wuxing, better known in the West as the five elements or phases.
It is most commonly used to try to relieve pain, but acupuncturists claim it can be helpful for a variety of other illnesses as well. It is almost always used in conjunction with other treatments.
In 2017, the global acupuncture market was valued at $24.55 billion. Europe dominated the market with 32.7 percent of the market share, followed by Asia-Pacific with 29.4 percent and the Americas with 25.3 percent. By 2023, the sector is expected to reach a market size of $55 billion.
The results of acupuncture experiments and comprehensive reviews are inconclusive, implying that treatment is ineffective. According to an analysis of Cochrane studies, it is ineffective for a variety of diseases. Medical scientists from the universities of Exeter and Plymouth did a systematic review and found no evidence of it’s usefulness in alleviating pain. Overall, the evidence demonstrates that acupuncture treatment for a short period of time has no long-term advantages.
Although certain research findings imply that acupuncture can help with specific types of pain, the preponderance of evidence demonstrates that the treatment’s apparent effects are not produced by the treatment. According to a systematic review, the analgesic effect of acupuncture lacked therapeutic value and could not be differentiated from bias. A meta-analysis indicated that it was cost-effective as an addition to standard care for chronic low back pain, while a systematic review found insufficient evidence for it’s cost-effectiveness in the treatment of chronic low back pain.
When performed by properly trained practitioners who employ clean needle techniques and single-use needles, it is generally safe. It has a low rate of primarily minor side effects when supplied properly. Accidents and infections do happen, and they’re usually linked to the practitioner’s negligence, especially when using sterile techniques. According to a study published in 2013, reports of infection transmission had increased considerably over the previous decade. Pneumothorax and infections were the most commonly reported adverse effects. Because major adverse events are still being recorded, it is suggested that acupuncturists be adequately trained to reduce the risk.
Traditional Chinese ideas such as qi, meridians, and acupuncture points also known as acupoints have no histology or physiological proof, and many current practitioners no longer believe in the reality of life force energy (qi) or meridians, which were formerly a prominent part of early belief systems. Acupuncture is thought to have begun in China in 100 BC, around the time The Inner Classic of Huang Di (Huangdi Neijing) was published, while some scholars believe it may have begun earlier.
Conflicting claims and belief systems arose over time regarding the influence of lunar, cosmic, and earthly cycles, yin and yang forces, and the body’s “rhythm” on therapeutic success. Acupuncture’s popularity in China has changed due to changes in the country’s political leadership and the country’s preference for rationality and Western medicine.
Acupuncture first arrived in Korea in the 6th century AD, then traveled to Japan via medical missionaries, and finally to Europe, starting with France. Intense spiritual parts of it that contradicted Western values were sometimes abandoned as it extended to the United States and Western countries in the twentieth century, in favor of just tapping needles into acupoints.
Acupuncture is a type of complementary medicine. It’s most typically used for pain relief, but it’s also used to treat a variety of ailments. It is almost always used in conjunction with other treatments. The American Society of Anesthesiologists, for example, states that it should only be used in conjunction with conventional therapy to address nonspecific, noninflammatory low back pain.
The insertion of tiny needles into the skin is known as acupuncture. A normal session requires lying still while five to twenty needles are implanted, with the needles remaining in place for 10 to twenty minutes in the majority of instances. It can be linked to the use of heat, pressure, or even laser light. It is traditionally customized and based on philosophy and intuition rather than scientific investigation. There is also a non-invasive therapy for children (shōnishin or shōnihari) that was created in early twentieth century Japan and uses an intricate set of tools rather than needles.
Clinical practice differs from country to country. A comparison of the average number of patients treated per hour in China (10) and the United States (9) revealed considerable discrepancies (1.2). Herbs from China are frequently used. It is practiced in a variety of ways, each with its own philosophy.
Although numerous acupuncture procedures have arisen, the approach employed in traditional Chinese medicine (TCM) appears to be the most extensively used in the United States. Acupuncture traditionally incorporates needle insertion, moxibustion, and cupping therapy, as well as other procedures including feeling the pulse and other regions of the body and checking the tongue.
Traditional acupuncture is based on the notion that the body’s “life energy” (qi) circulates along meridians. TCM and Western medical acupuncture are the most common modalities used in the UK. The phrase “Western medical acupuncture” refers to a variation of TCM-based acupuncture that is less focused on TCM. It is used following a medical diagnosis in the Western medical acupuncture method. There has been little research comparing the various acupuncture systems used in different nations to determine distinct acupuncture sites, hence there is no set standard for acupoints.
The acupuncturist determines which points to treat in traditional acupuncture by observing and interrogating the patient to create a diagnosis based on the tradition. Inspection, auscultation, olfaction, inquiry, and palpation are the four diagnostic procedures used in TCM. The tongue, in particular, is examined for size, shape, tension, color, and coating, as well as the lack of or presence of teeth marks around the edge.
Listening for certain noises, such as wheezing, and analyzing body odor are both aspects of auscultation and olfaction. Chills and fever; sweat; appetite, thirst, and taste; defecation and urine; pain; sleep; and menses and leukorrhea are the “seven inquiries” to focus on while inquiring. The goal of palpation is to feel the body for tender “A-shi” areas and check the pulse.
The most typical method of stimulating acupoints is to penetrate the skin with small metal needles that are manually handled, or the needle can be stimulated further using electrical stimulation (electroacupuncture). The needles are commonly constructed of stainless steel, which makes them flexible and prevents corrosion and breakage. To avoid contamination, needles are normally discarded after each use. When using reusable needles, make sure they’re sanitized in between uses.
In several jurisdictions, including the state of California in the United States, only sterile, single-use needles are permitted in several jurisdictions. Shorter needles are utilized around the face and eyes, and longer needles are used in places with tougher tissues; needle sizes range from 0.16 mm (0.006 in) to 0.46 mm (0.018 in), with thicker needles being used on more robust patients. Thinner needles may be more flexible, necessitating the use of tubes for insertion. To avoid breaking, the needle’s tip should not be overly sharp. Dull needles, however, produce greater agony.
Other needle kinds include three-edged needles and the Nine Ancient Needles, in addition to the standard filiform needle. Acupuncturists in Japan employ extremely thin needles that are only used on the surface of the skin, sometimes without entering it, and are enclosed by a guide tube (a 17th-century invention adopted in China and the West). Copper needles are used in Korean acupuncture, and the hand is given more attention.
Needles are put into the skin after it has been disinfected, often with the use of a plastic guide tube. Needles can be spun, flicked, or moved up and down in relation to the skin in a variety of ways. Because the majority of the pain is felt in the skin’s surface layers, a rapid insertion of the needle is recommended.
The needles are frequently agitated by hand to produce de qi, a dull, localized, aching sensation, as well as “needle grab,” a tugging sensation felt by the acupuncturist and caused by a mechanical interaction between the needle and the skin. Acupuncture is a painful procedure. The acupuncturist’s skill level may impact how painful the needle insertion is, and a sufficiently skilled practitioner may be able to do it without causing any discomfort.
The sensation of numbness, distension, or electrical tingling at the needling site is known as de-qi (Chinese: 得气; pinyin: dé qì; “arrival of qi”). If these sensations aren’t felt, it’s because the acupoint isn’t in the right place, the needle isn’t inserted deep enough, or the manual manipulation isn’t good enough. Various manual manipulation techniques are frequently used to enhance de-qi if it is not immediately seen after needle insertion (such as “plucking,” “shaking,” or “trembling”).
Once de-qi has been detected, ways to “affect” it may be applied; for example, de-qi can supposedly be transmitted from the needling site to other parts of the body by particular manipulations. Other methods attempt to “tonify” (Chinese: 补; pinyin: bǔ) or “sedate” (Chinese: 泄; pinyin: xiè) qi. In deficiency patterns, the former tactics are used, whereas in excess patterns, the latter are. In Chinese acupuncture, de qi is more significant, although Western and Japanese patients may not believe it to be a necessary aspect of the treatment.
Acupressure is a non-invasive technique of bodywork that involves applying physical pressure to acupressure points with the hand, elbow, or other devices.
Moxibustion, the burning of cone-shaped preparations of moxa (produced from dried mugwort) on or near the skin, is frequently used in conjunction with acupuncture, although not always. It was traditionally used to treat acute disorders, while moxibustion was used to address persistent illnesses.
Moxibustion might be direct (the cone was placed directly on the skin and allowed to burn, resulting in a blister and eventually a scar) or indirect (the cone was placed on the skin and allowed to burn, resulting in a blister and eventually a scar) (either a cone of moxa was placed on a slice of garlic, ginger, or other vegetable, or a cylinder of moxa was held above the skin, close enough to either warm or burn it).
Cupping therapy is an old Chinese method of alternative medicine in which a local suction is formed on the skin, with the belief that this will promote healing by mobilizing blood flow.
Tui na is a TCM technique that uses bare-handed techniques rather than needles to try to increase the flow of qi.
Acupuncture needles are linked to a device that generates continuous electric pulses in electroacupuncture (this has been described as “essentially transdermal electrical nerve stimulation [TENS] masquerading as acupuncture”).
Acupuncture with fire needles, also known as fire needling, is a practice that involves quickly inserting a flame-heated needle into bodily parts.
Sonopuncture is a type of acupuncture that uses sound instead of needles to stimulate the body. A narrow ultrasonic beam can be directed to a depth of 6–8 centimetres at acupuncture meridian sites on the body using purpose-built transducers. Tuning forks or other sound-producing equipment are also employed.
The injection of various substances (such as medications, vitamins, or herbal extracts) into acupoints is known as “acupuncture point injection.” This technique combines traditional acupuncture with an injection of an effective dose of an approved pharmaceutical medicine, and proponents suggest that it may be more effective than either treatment alone, particularly for the management of chronic pain. However, according to a 2016 assessment, most published studies of the strategy were of poor value due to methodology difficulties, and that larger trials would be required to produce relevant results.
Auriculotherapy, often called ear acupuncture, auricular acupuncture, or auriculoacupuncture, is thought to have originated in ancient China. It entails placing needles into the outer ear to stimulate specific locations. In the early 1950s, France pioneered the modern method. There is no scientific proof that it can cure sickness, and there is little evidence that it is effective.
Scalp acupuncture is a form of acupuncture that was created in Japan and is based on reflexological considerations of the scalp.
Hand acupuncture, which originated in Korea, focuses on the hand’s alleged reaction zones. Medical acupuncture stresses a more formulaic approach to acupuncture point identification, incorporating reflexological concepts, the trigger point model, and anatomical insights (such as dermatome distribution) into acupuncture therapy.
Cosmetic acupuncture is the application of acupuncture to the face in order to reduce wrinkles.
Injecting purified, diluted bee venom into acupoints is known as “bee venom acupuncture.”
Acupuncture for domesticated animals is known as veterinary acupuncture.
Acupuncture has been extensively studied; as of 2013, PubMed has about 1,500 randomized controlled studies with the term “acupuncture” in the title. However, reviews of acupuncture’s efficacy have come up with mixed results.
Sham acupuncture and research
Designing rigorous research studies for acupuncture is difficult, but not impossible. Because of the intrusive nature of acupuncture, creating a suitable placebo control group is one of the most difficult aspects of an efficacy study. “Sham” types of acupuncture, in which the patient, practitioner, and analyst are all blinded, appear to be the most acceptable way for efficacy trials to assess whether acupuncture has specific effects.
Non-penetrating needles or needling at non-acupuncture locations are used in sham acupuncture, such as on meridians unrelated to the condition being examined or in places not linked with meridians. The underperformance of acupuncture in these studies could indicate that therapeutic effects are completely due to non-specific effects, that the sham treatments are not inert, or that systematic methods provide less than ideal results.
According to a review published in Nature Reviews Cancer in 2014, “Researchers usually find that it doesn’t matter where the needles are inserted, how often they are inserted (there is no dose-response effect), or even if needles are inserted, contrary to the claimed mechanism of redirecting qi flow through meridians.” To put it another way,’sham’ or ‘placebo’ acupuncture has similar benefits to’real’ acupuncture and, in some situations, even outperforms it.” A 2013 meta-analysis revealed minimal evidence that the position of the needles, the number of needles used, the practitioner’s expertise or technique, or the circumstances of the sessions affected the effectiveness of acupuncture on pain (when compared to sham).
The same study found that the number of needles and sessions used in acupuncture is crucial, since more needles and sessions enhanced it’s outcomes when compared to non-acupuncture controls. There has been little systematic research on which aspects of an acupuncture session, such as needle placement and depth, kind and degree of stimulation, and the number of needles used, may be crucial for any therapeutic impact. According to the findings, needles do not need to stimulate the typical acupuncture points or penetrate the skin to provide the desired effect (e.g. psychosocial factors).
In the elderly, a reaction to “sham” acupuncture may be employed. However, placebos have always been seen as deceitful and hence unethical. However, some physicians and ethicists have proposed scenarios in which placebos could be useful, such as when there is a theoretical benefit to a low-cost treatment with no side effects or interactions with pharmaceuticals or other therapies. Because most types of alternative medicine, such as acupuncture, lack substantial proof, their application in traditional healthcare can be fraught with ethical issues.
Evidence-based medicine principles have been used to research acupuncture, but the results have been mixed. Some evidence suggests that acupuncture can help with pain relief, although the bulk of studies imply that the effects of acupuncture are mostly attributable to placebos. Acupuncture’s advantages, if they exist, appear to be transient. In comparison to conventional medical therapies, there is inadequate evidence to justify the use of acupuncture. In the long run, acupuncture is no better than conventional medicine.
Acupuncture has been challenged since there is little empirical evidence for explicit benefits or mechanisms for its alleged efficiency in treating any ailment that is distinguishable from a placebo. Acupuncture has been dubbed a “theatrical placebo,” and David Gorski claims that when proponents promote “harnessing of placebo effects” or “meaningful placebos,” they are effectively admitting it is nothing more.
In reviews of randomized controlled trials of acupuncture, publication bias is mentioned as an issue. A 1998 assessment of acupuncture studies indicated that trials from China, Japan, Hong Kong, and Taiwan, as well as ten out of eleven investigations from Russia, were all in favor of the treatment.
The methodological quality of most randomized controlled trials on traditional Chinese medicine, including acupuncture, was generally poor, according to a 2011 assessment of the quality of such trials (including randomization, experimental control, and blinding), particularly for trials published in Chinese journals (though the quality of acupuncture trials was better than the trials testing traditional Chinese medicine remedies).
Trials published in non-Chinese journals were also determined to be of higher quality, according to the study. Chinese authors cite more Chinese studies, all of which have been found to be positive. In a 2012 examination of 88 systematic reviews of acupuncture published in Chinese publications, it was discovered that less than half of the studies tested for publication bias, and the majority of the reviews were published in journals with negligible impact factors.
According to a 2015 study that compared pre-registered records of acupuncture trials with their published outcomes, such trials were rarely registered before the experiment began. Selective reporting of outcomes and manipulating outcome measures to generate statistically significant results were also found to be widespread in the literature.
Acupuncture and Chinese medicine in general, according to scientist and journalist Steven Salzberg, are the topics of “false medical periodicals” like the Journal of Acupuncture and Meridian Studies and Acupuncture in Medicine.
Many experiments and systematic evaluations of acupuncture have come to mostly contradictory outcomes. A systematic analysis of systematic studies published in 2011 indicated that real acupuncture was no better than sham acupuncture at reducing pain and that several evaluations had found no convincing evidence that acupuncture was an effective pain-relieving treatment. The same analysis discovered that neck pain was one of only four forms of pain for which a beneficial benefit was suggested, but warned that the original studies utilized were prone to bias. An assessment of Cochrane evaluations published in 2009 concluded that acupuncture is ineffective for a wide range of diseases.
The nocebo effect of acupuncture is clinically meaningful, according to a 2014 systematic review, and the prevalence of adverse events may be an indicator of the nocebo impact. The Acupuncture Trialists’ Collaboration published a meta-analysis in 2012 that found “relatively modest” efficacy of acupuncture (in comparison to sham) for the treatment of four different types of chronic pain (back and neck pain, knee osteoarthritis, chronic headache, and shoulder pain), concluding that it “is more than a placebo” and a reasonable referral option.
Both Edzard Ernst and David Colquhoun thought the findings of this meta-analysis were of minor clinical importance. Ernst said later that once we eliminate this bias [that operators are not blind, we might find that the effects of acupuncture are primarily a placebo reaction. The same research team updated their prior meta-analysis in 2017, finding that acupuncture was superior to sham acupuncture for non-specific musculoskeletal pain, osteoarthritis, chronic headaches, and shoulder discomfort. They also discovered that after a year, the effects of acupuncture had declined by roughly 15%.
A systematic study published in 2010 concluded that acupuncture is more effective than a placebo for the treatment of common chronic pain problems, although the authors admitted that the total benefit is not yet clinically meaningful or cost-effective. A 2010 study demonstrated that real acupuncture and sham acupuncture generate similar results, which can only be interpreted as evidence against acupuncture’s usefulness. Despite similar benefits, there is limited evidence that real acupuncture and sham acupuncture generate biological changes, according to the same review.
A systematic study and meta-analysis published in 2009 indicated that acupuncture had a minor analgesic effect that lacked clinical significance and could not be distinguished from bias. According to the same analysis, it’s still uncertain whether acupuncture lowers pain without a psychological effect from the needling ritual. According to a 2017 systematic review and meta-analysis, ear acupuncture may reduce pain after 48 hours of treatment, but the mean difference between the acupuncture and control groups was minor.
Lower back pain
A systematic review published in 2013 revealed that acupuncture may be useful for nonspecific lower back pain. However, the authors acknowledged that the studies they looked at had flaws, such as heterogeneity in study features and low methodological quality in several. A comprehensive analysis published in 2012 revealed some evidence that acupuncture was more beneficial than no treatment for persistent non-specific low back pain, but the evidence was mixed when compared to alternative treatment options.
According to a systematic review of systematic studies published in 2011, “For persistent low back pain, personalized acupuncture is no better at relieving symptoms than formula acupuncture or sham acupuncture with a toothpick that does not penetrate the skin.” In a 2010 study, sham acupuncture was found to be just as helpful as real acupuncture for chronic low back pain. Acupuncture’s specific therapeutic effects were minor, but its clinically relevant advantages were mostly related to environmental and psychological factors.
According to brain imaging studies, traditional acupuncture and sham acupuncture have different effects on limbic areas, but both have similar analgesic benefits. A Cochrane review from 2005 concluded that there was inadequate evidence to recommend either acupuncture or dry needling for acute low back pain. The same evaluation showed low-quality evidence for pain reduction and improvement in chronic low back pain compared to no treatment or sham therapy only in the short term after treatment.
According to the same study, acupuncture is no more successful than conventional therapy or other alternative medicine therapies. A comprehensive review and meta-analysis published in 2017 found that acupuncture was equivalent to conventional treatment for neck pain, and that electroacupuncture was even more effective than conventional acupuncture at reducing pain.
The review said it is “difficult to make conclusions because the included studies have a significant risk of bias and imprecision.” An analysis of systematic reviews of varying quality published in 2015 found that acupuncture can help people with chronic low back pain achieve short-term relief. This was true, according to the overview, when acupuncture was used alone or in combination with conventional medicine.
A systematic study published in 2017 for an American College of Physicians clinical practice recommendation showed low to moderate evidence of acupuncture’s effectiveness for chronic low back pain and limited evidence for acute low back pain. The evidence strength for both conditions was assessed to be low to moderate in the same review. Another clinical practice recommendation from 2017, this time from the Danish Health Authority, advised against using acupuncture for both new-onset low back pain and lumbar radiculopathy.
Headaches and migraines
Acupuncture was proven to be effective in the prevention of tension-type headaches and episodic migraines in two distinct Cochrane evaluations published in 2016. According to a 2016 Cochrane review, acupuncture has a slight benefit beyond sham acupuncture, and moderate-quality data suggests that acupuncture is at least as effective as preventative medicines for episodic migraine prevention. According to a 2012 assessment, acupuncture has been shown to be effective in the treatment of headaches, but the safety of the treatment needs to be better verified before strong recommendations can be made.
According to a 2014 study, “Current data supports the use of acupuncture as an alternative to standard analgesics in osteoarthritis patients.” A meta-analysis published in 2014 found that acupuncture may help with osteoarthritis pain, but the effects were minor when compared to sham needles. According to a 2012 evaluation, “the putative therapeutic activity of acupuncture on osteoarthritis pain does not appear to be clinically relevant.”
A 2010 Cochrane review found that acupuncture has a statistically significant benefit over sham acupuncture in the treatment of peripheral joint osteoarthritis. However, these benefits were so small that their clinical significance was questioned, and they were “probably due at least partially to placebo effects from incomplete blinding,” according to the review. A Cochrane analysis published in 2013 found low to moderate evidence that acupuncture reduces pain and stiffness in people with fibromyalgia when compared to no treatment or standard care.
According to a 2012 evaluation, “There is inadequate evidence to recommend acupuncture for the treatment of fibromyalgia.” A minor pain alleviation benefit was discovered in a 2010 systematic review that did not appear to be due to bias; acupuncture is not a recommended treatment for the management of fibromyalgia based on this review.
According to a 2012 assessment, the evidence for acupuncture’s usefulness in treating rheumatoid arthritis is “sparse and unclear.” According to a 2005 Cochrane review, “The use of acupuncture to treat rheumatoid arthritis had no effect on ESR, CRP, pain, patient’s global evaluation, number of swollen joints, number of painful joints, overall health, disease activity, and reduction of analgesics.”
With the exception of osteoarthritis, low back pain, and lateral elbow discomfort, a 2010 evaluation of systematic reviews found inadequate evidence to suggest acupuncture in the treatment of most rheumatic illnesses. A comprehensive analysis published in 2018 revealed some evidence that acupuncture could help treat rheumatoid arthritis, but the data was limited due to heterogeneity and methodological issues in the trials included.
Other joint pain
Although manual acupuncture was helpful at relieving short-term pain when used to treat tennis elbow, its long-term pain relief effect was “unremarkable,” according to a 2014 comprehensive review. A 2007 analysis indicated that acupuncture was much better than sham acupuncture at treating chronic knee pain; but, due to a paucity of large, high-quality trials, the data was not definitive.
Post-operative pain and nausea
According to a 2014 evaluation of systematic reviews, there is insufficient evidence to show that acupuncture is an effective treatment for PONV in a clinical context. According to a 2013 comprehensive review, acupuncture may be helpful in the prevention and treatment of PONV. In a 2015 Cochrane review, moderate-quality evidence indicated no difference in preventing PONV between stimulation of the P6 acupoint on the wrist and antiemetic medications.
Based on the findings of a trial sequential analysis, the evaluation concluded that more comparison trials are fruitless. It was unclear whether combining PC6 acupoint stimulation with antiemetics was useful. According to a 2014 evaluation of systematic reviews, there is little data to demonstrate that acupuncture is useful for surgical or post-operative pain.
There was conflicting evidence about the use of acupuncture for post-operative pain. A comprehensive study published in 2014 revealed some evidence for the utility of acupuncture for acute post-operative pain after back surgery, but it was limited. While the data suggested that acupuncture could be a useful treatment for postoperative gastroparesis, a clear conclusion could not be reached because the trials analyzed were of low quality, according to a 2014 systematic review.
Pain and nausea associated with cancer and cancer treatment
According to a 2015 Cochrane study, there is insufficient data to evaluate if acupuncture is an effective treatment for cancer pain in adults. A comprehensive analysis published in the Chinese Journal of Integrative Medicine in 2014 revealed that acupuncture could be useful as a complementary treatment for cancer patients receiving palliative care. A review published in the Journal of the Multinational Association for Supportive Care in Cancer in 2013 revealed evidence that acupuncture may help people with cancer-related symptoms, but it also found few rigorous trials and a lot of heterogeneity between them.
A systematic evaluation of randomised clinical trials published in the same journal in 2012 indicated that the number and quality of RCTs utilizing acupuncture to treat cancer pain were insufficient to draw firm conclusions. In a systematic review published in 2014, the effectiveness of acupuncture for treating cancer-related fatigue was found to be ambiguous. According to a comprehensive review published in 2013, acupuncture is an effective supplementary treatment for chemotherapy-induced nausea and vomiting, although more research with a low risk of bias is needed.
According to a comprehensive review published in 2013, the number and quality of RCTs available for analysis were insufficient to draw significant conclusions about the efficacy of acupuncture for cancer-related fatigue.
Acupuncture appears to help with sleep disturbances, notably insomnia, according to several meta-analytic and systematic reviews. However, because of publication bias, issues with research methods, limited sample sizes, and heterogeneity, reviewers stress that this evidence should be regarded as preliminary.