If you’re in your local pharmacy, looking for overpriced razor blades for example, it’s difficult to avoid them: a multitude of herbal and homeopathic remedies, naturopathic, ayurvedic and traditional medicines, pills and potions promising help with every possible health problem – fatigue, insomnia, impotence, pain, indigestion, inflammation, depression, fever, low immunity, you name it. What do they have in common? Placebo effects (placebo from the Latin meaning “I please”) that are not only essential to the commercial success of retail pharmacies but to modern medicine as a whole.
Single Exit Pricing
Twenty five years ago, drugs accounted for 31.8% of private sector medical scheme spend. Through Single Exit Pricing (SEP), government sought to reduce drugs costs to end users. By 2018, dispensed medicines comprised only 15.6% of total paid benefits, according to CMS annual reports.
SEP instantly shrank retail pharmacy revenues but the CAM (Complementary and Alternative Medicine) industry, (2016 sales: R3.8 billion; 13.5% annual growth rate) came to the rescue, offering multiple products unrestricted by SEP – and less restrained by evidentiary standards.
Main Road, Wynberg, Cape Town. Dr Abdalla is probably an effective user of placebo effects in his diverse service offering.
Why so popular with consumers?
CAM products help meet the consumer demand for convenient relief of symptomatic minor ailments. Such complaints typically resolve in time without intervention, but medicines often get the credit.
The proliferation of herbal supplements and homeopathic remedies is also associated with their perceived “natural” and “holistic” benefits.
As Schedule 0, 1 or 2 drugs, CAMs are available without a doctor’s prescription. They are regulated, however: adherence to SAHPRA[1] guidelines for safety, efficacy, quality, and labelling[2] is officially required.
Manufacturers of low Schedule drugs cannot make “medical claims” (of a therapeutic effect)[3] but this doesn’t mean consumers don’t assume that they occur.
Placebo effects are powerful
A common misconception is that placebos work on a purely psychological basis – they’re “all in the mind”. But really, they’re “in your head”: they move molecules in the brain. And the brain is linked to, well, the body.
Some people call these “non-specific effects” but they operate in specific ways, involving expectations of benefit, conditioned responses and social learning.
Numerous studies document neurological effects, via brain scans, and in clinical trials. The brain effects are linked to identifiable changes in other body systems – digestion, cardiovascular, immune, for example – and therefore, in diseases affecting those systems.
Placebo-mediated effects have been extensively studied in the field of pain, the experience of which is highly influenced by psychological and social factors, but effects are shown in conditions with purely organic origins too.
For example, in Parkinson’s disease, caused by damage to the basal ganglia of the brain, placebo effects can improve the debilitating tremor, with corresponding changes evident in imaging scans. Worsening i.e.,“nocebo” effects are possible too.
Placebo effects in Parkinson’s disease. The DBS (deep brain stimulator) is off; patient believes it’s on. A saline injection plus verbal suggestion of motor improvement leads to increased activity in the subthalamic nucleus (de la Fuente-Fernández R, et al. Science (2001) 293, 1164)
How to use placebo effects
Placebo effects depend on context and ritual, enacted by clinicians, and as such are an important part of therapeutic relationships that good clinicians work deliberately to create.
Andrew Weil puts it well, emphasising positive impact while also pointing to a “nuisance” effect (more on that later):
“I regard the placebo response as a pure example of healing elicited by the mind; far from being a nuisance, it is, potentially, the greatest therapeutic ally doctors can find in their efforts to mitigate disease. I believe further that the art of medicine is the selection of treatments and their presentation to patients in ways that increase their effectiveness through the activation of placebo responses.” Andrew Weil
Clinicians gain too.
A novel study (figure below) showed that when treating pain, areas of the doctor’s own brain implicated in expectancy for pain relief (e.g., the prefrontal cortex) and processing of reward are activated. These are the neural representations of reciprocal interactions between clinicians and patients, a hallmark of successful treatment correlated with the satisfaction that clinicians get from helping patients.
Not always safe?
Consumers might assume based on their easy availability and sale by reputable pharmacy groups that CAM products are safe. But there’s much less assurance of purity or safety than with prescription drugs. Many reports of CAM products contaminated, for example by metals, microbes and mycotoxins, suggest that regulatory processes are imperfect. Hardly surprising given the thousands of products to monitor.
| “Toxic element contamination was found in many supplements and pharmaceuticals…“ |
| Genuis SJ, et al. PLoS One. 2012;7(11):e49676 |
| “Many adverse events of herbal medicines can be attributed to the poor quality of the raw materials or the finished products….” |
| Zhang J et al. Complement Ther Med. 2012 20(1-2):100-6. |
| “These OTC products may be contaminated with excessive or banned pesticides, microbial contaminants, heavy metals, chemical toxins, and adulterated with orthodox drugs.” |
| Chan K. Chemosphere. 2003 Sep;52(9):1361-71 |
| “Patients relying on herbal products for therapeutic effects may expose themselves to either low doses of active constituents causing insufficient effects or alternatively take higher levels than expected, with the increased risk of toxicity or adverse effects, or be affected by the inadvertent inclusion of unexpected components with associated potential health risks.” |
| Ruparel P. Nat Prod Commun. 2011 May;6(5):733-44. |
Homeopathy is my favourite placebo
Homeopathy is my favourite kind of placebo medicine. When Samuel Hahneman (1755-1843) invented it, clinical trials didn’t exist to prove that the drugs or therapies of the day were efficacious. In many cases (e.g. the use of arsenic as a treatment) they were seriously toxic (cure worse than disease) but this hardly limited their use, given the lack of alternatives.
Hahneman’s innovative remedies were likely to be much safer, if made according to his creative formula, which involves multiple (10 to 50 or more) dilution steps and a lot of shaking (“succussion”). Even in fancy bottles, these medicines are essentially water, containing pharmacologically active substances only in infinitesimally small (zero or near-zero) amounts, labelled with Latin ingredient names to give them the right kind of mystique.
In South Africa, despite its lack of scientific basis, homeopathy has official status. The Allied Health Professions Council of South Africa (AHPCSA) is the statutory body that controls it along with aromatherapy, ayurveda, Chinese medicine and acupuncture, chiropractic, naturopathy, osteopathy, phytotherapy, reflexology, therapeutic aromatherapy, therapeutic reflexology and Unani Tibb. All modalities that harness placebo effects rather than pharmacologic ones?
Homeopathy in South Africa
A 2010 research project [4] surveyed 61 registered homeopaths and analysed commercial off-the-shelf homeopathic remedies.
| Ingredients of homeopathic remedies | |
| Name listed on remedy | Conventional Name |
| Acidum nitricum | Nitric acid |
| Alumina | Aluminium |
| Arsenicum album | Arsenic oxide |
| Atropa belladonna (Belladonna) Spag | Atropine |
| Bryonia alba Spag | White bryony |
| Calcarea fluorica | Calcium fluoride |
| Carbo animalis | Animal charcoal (Bones) |
| Carbo vegetabilis | Vegetable charcoal |
| Conium maculatum Spag | Poison hemlock |
| Hepar sulphuris calcareum | Calcium sulfide |
| Hydrastis canadensis Spag | Goldenseal |
| Lycopodium clavatum | Groundpine |
| Magnesium muriaticum | Magnesium chloride |
| Mercurius corrosivus | Mercuric chloride |
| Natrium muriaticum | Salt (sodium chloride) |
| Phytolacca decandra Spag | Pokeweed |
| Plumbum metallicum | Lead |
| Sepia officinalis | Cuttlefish |
| Silicea | Silicon oxides |
| Silicea | Silicon oxide |
| Strychnos nux-vomica (Nux vomica) Spag | Strychnine |
| Thuja occidentalis Spag | White cedar |
| Remedy A | Remedy B | Remedy C | |||
| Atropine | D10 | Nitric acid | D10 | Aluminium | D30 |
| Animal charcoal | D10 | Arsenic oxide | D10 | White bryony | D8 |
| Mercuric chloride | D10 | Animal charcoal | D10 | Calcium fluoride | D10 |
| Salt (sodium chloride) | D6 | Poison hemlock | D8 | Vegetable charcoal | D30 |
| Silicon oxide | D10 | Calcium sulfide | D10 | Groundpine | D30 |
| Sulphur | D30 | Goldenseal | D4 | Pokeweed | D3 |
| Alcohol | 20% | Magnesium chloride | D4 | Lead | D10 |
| Cuttlefish | D10 | Strychnine | D4 | ||
| Silicon oxides | D10 | Sulphur | D10 | ||
| White cedar | D28 | Alcohol | 20% | ||
| Alcohol | 20% | ||||
D30 is a measure of concentration, a product that has been successively diluted 30 times. After 30 dilution steps, the dilution factor is 1 in 1030. This is equivalent to 1 part of the substance in 1,000,000,000,000,000,000,000,000,000,000,000 parts of the diluent.
| Remedy A | Remedy B | Remedy C | |
| μg/L | μg/L | μg/L | |
| Magnesium | 94.19 | 1503.89 | 44.09 |
| Calcium | 1892.06 | 1416.60 | 1028.08 |
| Potassium | 343.83 | 552.01 | 600.12 |
| Aluminium | 20.21 | 8.42 | 77.32 |
| Chromium | 1.86 | 2.28 | 0.24 |
| Iron | 1.39 | 2.72 | 1.43 |
| Barium | 0.98 | 2.46 | 0.67 |
| Zinc | 0.74 | 2.29 | 0.74 |
| Arsenic | 0.63 | 0.16 | 0.18 |
| Selenium | 0.39 | 0.00 | 0.00 |
| Antimony | 0.29 | 0.14 | 0.02 |
| Mercury | 0.11 | 0.00 | 0.00 |
| Lead | 0.11 | 0.36 | 0.02 |
| Molybdenum | 0.10 | 0.10 | 0.08 |
| Nickel | 0.08 | 1.51 | 0.18 |
| Manganese | 0.07 | 1.00 | 0.00 |
| Cobalt | 0.01 | 0.05 | 0.01 |
| Copper | 0.00 | 0.59 | 0.00 |
| Cadmium | 0.00 | 0.03 | 0.01 |
The survey showed that many homeopaths believe their medicines are effective treatments for serious conditions like HIV (46%) and tuberculosis (35%), and for prevention of malaria (29%); 31% said homeopathy discourages people from getting immunised and 45% agreed that taking too much of a homeopathic medicine can harm you.
The possibility that these practitioners, based on such beliefs, might turn patients away from standard medical treatments, is a cause for concern. On the other hand, overdosing on a medicine which is just water seems unlikely, a point made by 10:23 campaigners (image below). The 20% alcohol could certainly get you high.
Supporters of the 10:23 campaign taking overdoses of homeopathic remedies to prove that homeopathy “has nothing in it”. (All survived)
The study’s final conclusion:
Placebos are important to modern medicine
While homeopaths and naturopaths may take full advantage of placebo effects, these are not phenomena operating only at the fringe; they’re central to the methods of evidence-based medicine (EBM). Placebo-controlled drug trials are how safety and efficacy are scientifically established.
The challenge for EBM is that placebo effects are built into overall treatment effects (figure below). For clinical triallists, including pharmaceutical companies trying to prove therapeutic drug effects, this is a nuisance. Trials are designed to separate the two phenomena, consuming huge resources in the effort to do so.
Placebo effects come with almost any medical treatment. The job of clinical trials is to discern drug (or other therapy) effect.
Placebo effects aren’t limited to drugs; they’re equally powerful in surgery, as shown in trials that compare sham procedures with the real thing.
An early example (1959) was published in the New England Journal of Medicine: ligation (tying off) of the internal mammary artery was thought to be an effective treatment for angina (caused by low blood flow to the heart muscle), but abandoned after the trial showed no difference between the sham and real surgeries. More recently, sham procedures have been compared with three of the commonest operations – in the ORBITA trial, percutaneous coronary interventions (‘stents’) (result: “even with severe coronary stenosis, exercise capacity and symptoms are not improved significantly compared with a placebo intervention”) and in two kinds of knee operation (cartilage operations, and for osteoarthritis) (outcomes no better than placebo surgery).
Along with placebo effects come the possibility of nocebo effects too, where negative expectations, including those we are required to disclose as part of informed consent processes, lead to worse outcomes and/or side effects.
The existence and intensity of placebo and nocebo effects vary depending on the information provided to patients, and how it is presented to them. These phenomena are crucial to the design and conduct of clinical trials, especially with the importance now assigned to outcomes reported directly by patients.
People’s susceptibility or receptiveness to placebo effects varies at least in part due to genetics. The “placebome” is the group of genome-related mediators that affect an individual’s response to placebo treatments. These are not assessed in most placebo-controlled clinical trials but maybe it’s time to do so.
The placebome-disease network (https://pubmed.ncbi.nlm.nih.gov/28570268/) shows how the placebo effect is linked to certain diseases. The placebome part of this network is closely related to brain signaling and brain proteins. The closer the placebome is to certain disease patterns in this network, the stronger the placebo effect is for those diseases. The placebome’s closeness to pathways affected by some drugs suggests that placebos and drugs can interact with each other. This information is useful for understanding how the placebo effect works at the molecular level. It can help in reducing the impact of the placebo effect in clinical trials and in creating treatments that intentionally use placebo effects.
Open label placebo trials
There’s a widespread belief that using placebos in clinical practice must involve deception and is therefore unethical. Yet a number of trials have shown positive effects of open label placebo. This is where a preparation with no pharmacologically active ingredient is given, with full disclosure, accompanied by information that the medicine is expected to work. Positive results have been reported in conditions such as irritable bowel syndrome, chronic low back pain, depression, ADHD and allergic rhinitis.
Even in anaesthesia
General anaesthesia renders people unconscious and unable to breathe without support. Not much room for mind-brain effects there?
When volunteers are given remifentanil, a potent opioid, the drug reduces the intensity of a standardised painful stimulus as you would expect but can also have less effect, or even be associated with a heightening of the pain, depending on suggestions offered by investigators.
In Cleveland, one of the professionals I loved working with was Pat, an excellent, experienced CRNA (certified registered nurse anesthetist). In the minutes before we injected our anaesthetic drugs Pat would tell each patient, in a kind but firm voice, that they would wake up after surgery free of pain, and not cough on their breathing tube as they did so. I humoured her, sceptical of any benefit from these utterances.
A 2007 study from New York showed that patients who received a 15 minute hypnosis session before breast cancer surgery needed less sedative medicine during the procedure than the control group not so exposed. Maybe Pat was right. In anaesthesia, in fact all of clinical medicine placebo and mind-brain effects have a role.
Verbal suggestions of harm e.g. when placing an intravenous cannula (“drip”) – “this will hurt” or “this will feel like a bee sting” – create expectations of harm and anxiety, activating neural circuitry. Avoiding words like hurt, pain and sting, and using language such as “you will feel a quick sensation as we start the process which will make you feel more comfortable” can help minimise nocebo responses, along with distraction, a confident tone, and validation of feelings.
Bottom Line
Placebo effects are complex and involve psychological, neurobiological, and social factors. Placebo effects are important and useful; professionals and patients need to appreciate both their beneficial role and limitations. Just don’t substitute a homeopathic, or other CAM “vaccine”, or antibiotic, for the real thing. Clinical trials need methods to cope with the variability of placebo responses.
“The challenge seems to be to integrate non-specific therapies into practice in an ethical way….. to increase the awareness of physicians that contextual healing factors are part of nearly every treatment ….and to help physicians to harness the ‘power of the placebo’,while remaining authentic and credible”. Michael Balint
For more on placebos
The Journal of Interdisciplinary Placebo Studies (JIPS) hosts a growing database of over 5,000 scientific articles covering placebo effects and mechanisms, including trials, reviews, and meta-analyses. You can subscribe to their monthly newsletter.
Linda Kantor is a psychologist and leading exponent and teacher of mindfulness meditation. Together, we have created a line of pure placebo medicines for various indications combined with condition-specific guided meditations. Look out for the product called “trust©” – because that is the basis for it.
[1]Historically, nearly twice as many applications were received than were approved but in December 2022, SAHPRA declared it had cleared the huge backlog of drugs (16,000) awaiting licensing. Hopefully this includes all the CAM products.
[2] Documentation for submission to SAHPRA typically includes: information on the product formulation, manufacturing process and quality control measures; evidence of safety and efficacy, which may be based on traditional use and homeopathic “provings”; labelling and package inserts that comply with regulatory requirements, along with fees and compliance with Good Manufacturing Practices (GMP). SAHPRA may inspect the facility to verify compliance and require a response to queries or requests for additional information. Once the product is licensed and on the market, the manufacturer must monitor its safety and efficacy and report adverse events.
[3] Interestingly, a declared placebo medicine which makes therapeutic claims backed by clinical trial evidence becomes eligible for a higher Schedule, even in the absence of any Active Pharmaceutical Ingredient (API). This adds costs and may be one reason why nobody sells actual “sugar pills”.
[4] Unpublished research, data available on request.