A new perspective on the endogenous opioid system and its immune-neuro-psychological implications: From mental disorders to immune-related diseases and cancer. We will revisit the opioid system from an immune-neuro-psychological perspective, where complex interactions between the brain and the immune system, text and context take place in order to address an important evolutionary question: Are we safe? What does safety mean in the light of evolution? Not only does the evolutionary viewpoint reframe our understanding of this system, but also brings together the search for “safety and security” and pleasure. Matching our evolutionary goals: avoidance of suffering, searching for pleasure and energy conservation. Human cultural and technological development have gone through a tremendous breakthrough in the last couple of centuries, and as a consequence the so-called Anthropocene is testing our capacity for adaptation by causing an extreme amount of changes in a short period of time. Endogenous opioid peptides are highly context-dependent and are released in response to “natural reward stimuli”, yet modern-day natural stimuli are anything but normal. Social defeat, chronic social or economic stress, along with a sum of environmental cues such as chemicals, toxins, sedentary lifestyle or sleep deprivation does not only influence our physiology, but also our interpretation of the environment. This affects the opioid balance, which in turn increases the reactivity of our immune and neurological responses by making a “non-dangerous signal” dangerous. This mismatch leads to a chronic misbalance of this system, where susceptible people might develop multiple chronic pathologies. The opioid system therefore offers us new promising intermittent receptor interventions as immunomodulators in multiple immune-related diseases, chronic pain, malignant tumours, as well as alleviating symptoms of several mental disorders.

Mental health clinicians usually see their primary responsibility and goal as making their patients as emotionally and physically comfortable as possible, and often this is exactly the right clinical path to pursue. But this lecture will add nuance to this standard of clinical care by describing how humans evolved to require certain types of adaptive stressors to function optimally, not just physically, but also emotionally. From this perspective, the replacement of these types of stressors with the more chronic and diffuse psychological and physical stressors in the modern world goes a long way toward explaining the ongoing increase in depression and anxiety that plague our time in history. Recognition of this situation is widespread and undergirds recommendations that we should all reduce our stress. This talk takes a different tack and explores ways in which judiciously exposing our patients to certain types of adaptive stressors may provide novel therapeutic benefits. The talk demonstrates this idea by focusing on two very different, highly novel, adaptive stressor-based treatments for depression: psychedelics and whole body hyperthermia. In addition to discussing evidence supporting the therapeutic benefits of these treatments, this talk will explore the mechanisms by which these treatments may work, including acute immune responses and the causal capacity of transformational (but often stressful) conscious experiences.

The role of mitochondria in homeostatic adaptation – a new perspective Mitochondria are cellular organelles existing in eukaryotic cells to support and improve their energy production. As human cells, mostly depending on their specific function, have different energetic requirements their amount of mitochondria differs, which eventuates in differences concerning the ability to produce ATP: the more mitochondria – the higher the ATP production. Dysfunctional mitochondria or low amounts of these organelles can be responsible for several kinds of chronic diseases – whereby the term ‚mitochondriopathy‘ often is used. Research has shown that mitochondria are not only energy supporters, but also play an emerging role in intracellular communication. Under different circumstances they produce signals that have influence on cell metabolism and cell-cell communication. When our body has to alter homeostatic regulation, gets under stress or upregulates immunological activity changes in mitochondrial signalling occur. This allocates a new role to mitochondria as an own signal-system releasing substances called mitokines. Thus mitochondria can be seen as an additional system not only having influence on health and disease, but also behavior. Finally, recent research has shown that this communicational system not only works with mitokines, but also with complex mitochondrial structures: extracellular mitochondria. We are not alone.

There is definitely a relation between (LDL) cholesterol and coronary atherosclerotic disease (CAD). Cholesterol-ester accumulation in the vessel wall is a major factor in the formation of an ‘unstable plaque’ that is at the root of a myocardial infarction. There is also definitely a relation between cholesterol lowering with statins and lower CAD risk. But all of these well-established facts are not evidence of cholesterol as the primary CAD cause. There is even- well-established evidence that some drugs and nutrients increase (LDL) cholesterol while lowering CAD risk (SGLT2i, ketogenic diet, fish oil), and also of the opposite (hormone replacement therapy). That CAD is an inflammatory disease was first suggested in 1856. Targeting of the pro-inflammatory cytokine IL-1beta has convincingly proven causality. A major discovery by Hotamisligil was that inflammation and metabolism are intimately related. It made clear that an unhealthy lifestyle gives rise to (low grade) inflammation via danger signals (LAMPS), and that the ensuing change of cholesterol metabolism is secondary to a primary inflammatory culprit. Acute inflammation not only changes cholesterol metabolism, for all good reasons, but drives adjustment of virtually all hormonal axes. The resulting ‘allostatic condition’ is meant for the short term but becomes a danger when chronic. The chronic counterpart is known as the ‘metabolic syndrome’ and by other names like ‘insulin resistance syndrome’ and ‘inflammaging’. It is widespread in the population and was mistaken for ‘homo sapiens physiology’. It thereby became the basis of many well-intended dietary recommendations for genuinely healthy people that were issued by respectable organizations. Examples are: lower intake of saturated fat, cholesterol and sodium, and replacement of saturated fat by polyunsaturated fat, notably linoleic acid. Misinterpretation of what was originally meant with ‘Evidence Based Medicine’ subsequently saddled us with too low recommendations for nutrients like fish oil, selenium and too high for calcium, to name just a few. These introduced additional disbalances, like a low magnesium and omega-3/omega 6 status. By showing that inflammation deliberately deposits cholesterol in our vessels, this presentation makes an attempt to find our genuine physiology as an equilibrium between pro-inflammatory and anti-inflammatory factors in our lifestyle. A disbalanced inflammatory state is probably at the basis of many chronic degenerative diseases, for instance also those of the brain. Only by intervention high in the pathophysiological cascade, will we be fully successful in both their primary and secondary prevention. The basic problem is that we still do not fully understand what Darwin has meant with ‘adaptation to the conditions of existence’, which in 2011 became the basis of what is nowadays widely regarded as the best definition of ‘health’.

Can you help me to get rid of my pain?” is still one of the most frequently asked questions in healthcare. It’s not only disabling for the individual, but also leaves practitioners with big question marks, because in many cases they don’t have a good treatment strategy. The many articles written in the past decennia describe a myriad of mostly psychological and neuro endocrinological pathways. And although these pathways give a good insight to the different mechanisms involved in chronic pain. They didn’t help to reduce the burden of chronic pain in the Western society, where still 20% of the people are suffering from chronic pain. Why is chronic pain in 2023 still a stubborn condition? Are we missing the bigger picture? Martijn will take a deep dive into this matter. He will describe the role of the immune system, perinatal imprinting and the role of the microbiome. With the aim of providing a clinical PNI explanation of chronic pain. And thereby new treatment options for the future.

Chronic Fatigue Syndrome (CFS) is a serious debilitating condition that imposes a burden of illness on millions of people around the world. Somewhere between 896.000 and 9.8 million Europeans are estimated to have this disorder which is characterized by profound fatigue and symptoms associated with autonomic, immunological, neuroendocrinological and psychological manifestations including pain, post-exertional malaise and sleep disturbances. Both the central nervous system and the immune system underlie this complex condition. The immune and nervous systems' interplay should be viewed as the consequence of interactions among social, demographic, economic, and ecological factors that are characteristic of today's human culture. CFS is characterized by both social and infectious factors that can cause chronic responses by boosting the brain and immune system's activity, resulting in exhaustion and maladaptation of the organism. In this talk we will review from a psychoneuroimmunological perspective the state of the art regarding this pathology, show the complex interaction between the different risk factors and the main mechanisms of action and how they condition the relationship.