Dr. Z Recommends
On current topics that may be in the news or, more likely, are frequently brought up my clients, I offer the following evaluations and recommendations.
On current topics that may be in the news or, more likely, are frequently brought up my clients, I offer the following evaluations and recommendations.
Bottom Line: Proceed with caution and buy only from reputable manufacturers. Much research still needs to be done to determine whether CBD oil and related products have any lasting health benefits.
Pros: Some improvement has been documented for certain conditions, namely epilepsy in children and severe mental health issues such as psychosis.
Cons: Trials on numerous other disorders have yielded inconclusive results or no results. The product is being exploited by unscrupulous vendors who are making outlandish claims and charge exorbitant prices for a product that costs pennies to make. Buyer beware!
What is CBD Oil? And, Is It Safe?
Cannabidiol (CBD) oil is essentially a concentrated solvent extract made from cannabis flowers or leaves that is dissolved in an edible oil such as sunflower, hemp, or olive oil. Solvents used can vary from relatively innocuous organic solvents (ethanol, isopropyl alcohol) to more harmful ones (petroleum-ether, naphtha), or even supercritical fluids (butane, CO2). The exact conditions and solvents applied have a great impact on, for example, the taste, color, and viscosity of the final product (…) However, although research into the therapeutic effects of CBD is rapidly increasing, most current uses of CBD are not (yet) supported by clinical data (…) If CBD oil was used mainly by adult, well-informed, and reasonably healthy consumers, the impact of its widespread use would perhaps be quite acceptable and limited. However, this is not the case, as CBD is actively marketed for use by children (e.g., for Dravet syndrome, ADHD, autism), elderly people (Alzheimer’s disease, dementia, Parkinson’s disease), patients suffering from complex diseases (cancer, multiple sclerosis, chronic pain), and even pets (anxiety, appetite, sleep). Indiscriminate use of CBD may lead to various issues among these consumers. For example, CBD shows an exciting potential for treating epilepsy in children, but the long-term effects of highdose CBD on these children’s brain functions remain unclear, while there are strong clues that the endocannabinoid system is central in the proper neuronal development of the adolescent brain . In order to halt the unchecked advertising of CBD products, health authorities in various countries have begun sending official warning letters to stop producers and sellers from making unfounded health claims [24, 25] (…) However, the risks to be assessed about CBD products may not have much to do with the pure compound CBD itself, but more with the unknown composition and quality of the products offered. In particular, we should be looking into the presence of contaminants in these concentrated extracts, and into incorrect or even misleading labels for the cannabinoid content of products (…) For example, pesticides are frequently present in cannabis sold by Dutch coffee shops , but were also found in cannabis offered under state law in California  as well as medicinal cannabis from licensed producers in Canada . If any of these contaminants were present in hemp used for CBD extraction, they would likely end up in a concentrated form in the final oil. One contaminant specifically relevant to cannabis (CBD or THC) oils is the residual presence of toxic solvents used during the extraction procedure  (…) Almost overnight, CBD oils have become an interesting combination of popular holistic medicine, miracle cure, and a natural answer to the synthetic drugs dominating modern medicine. With CBD, patients receive the promise of being in control of their own ailments, and no longer feeling at the mercy of their treating physicians. This has turned out to be a particularly powerful message. Many patients use CBD oils freely for ailments both confirmed and self-diagnosed, and the rapid innovations with CBD products have actually been quite impressive. But while new CBD products keep entering the market virtually unchecked, effective regulatory control of these products has stayed far behind. As a result, unknown risks about long-term effects remain unaddressed, especially in vulnerable groups such as children, the elderly, and the chronically or terminally ill. (Med Cannabis Cannabinoids 2018;1:65–72, The Trouble with CBD Oil, Arno Hazekamp, April 11, 2018)
Effects on Autism Spectrum Disorders
At present, however, there are no convincing pre-clinical or clinical data showing efficacy and safety of cannabinoid treatment in Autism Spectrum Disorder patients. (Progress in Neuro-Psychopharmacology and Biological Psychiatry – Volume 89, 8 March 2019, Pages 90-96)
Effects on Epilepsy
In 2017, two randomized, placebo-controlled, clinical trials suggested that cannabidiol may be effective in the treatment of epilepsy, though conclusions about both seizure reduction and adverse effects are clouded by the large number of patients taking concomitant anti-seizure medications (such as valproic acid and clobazam) whose serum levels are often increased with the administration of cannabidiol. (Current Pediatrics Reports, March 2018, Volume 6, Issue 1, pp 26–29)
Since CBD, differently from THC is not considered an abuse drug and is at the same time legal but not regulated, this has caused the development of a market of CBD-based products for medical purpose, such as CBD oil, tinctures and vapors that has rapidly expanded, flourishing in a no man’s land with potential health dangers for patients and all end-users. Indeed, the lack of regulation of such products does not assure the patient about the quality of the product itself, the effective dosage of CBD that is fundamental for its therapeutic effectiveness, the purity and the absence of chemical or microbiological contaminations, thus raising critical public safety concerns. (Pharmacology & Therapeutics, 2017)
(P)hysicians have significant difficulty prescribing cannabinoids freely because of the paucity of sound scientific studies(…) The exact anti-epileptic mechanism of cannabidiol is currently not known, but it modulates a number of endogenous systems and may have a novel anti-convulsant effect. However, it has broad drug-drug interactions with several agents, including inducer and inhibitor of CYP3A4 or CYP2C19. Cannabidiol can cause liver enzyme elevation, especially when co-administered with valproate. (Pediatric Neurology, Available online 22 March 2019)
Effects Over Time
Further study will need to be conducted to determine the permanency of our patient’s positive behaviors and how long (the patient) will need to continue taking the CBD oil (…) Although CBD is considered generally safe,17 the long-term effects are yet to be studied. (The Permanente Journal/Perm J 2016 Fall;20(4):16-005)
Effects on Crohn’s Disease
In this study of moderately active Crohn’s disease, CBD was safe but had no beneficial effects. This could be due to lack of effect of CBD on Crohn’s disease, but could also be due to the small dose of CBD, the small number of patients in the study, or the lack of the necessary synergism with other cannabinoids. Further investigation is warranted. (Digestive Diseases and Sciences, June 2017, Volume 62, Issue 6, pp 1615–1620)
Effects on Sleep Behavior
Although some studies have demonstrated the potential effect of CBD on sleep behavior, research about the effects of CBD on the slow wave sleep (SWS) of humans with regular sleep is still lacking. The impact of CBD on sleep, possible side-effects or the advantages of lack of them, including objective measures through polysomnography, has not yet been investigated (…) We found no significant differences in polysomnography results following the administration of CBD and placebo to healthy volunteers. Likewise, there were no statistically significant changes in the subjective and cognitive measures collected during the two nights of polysomnographic exams. (Frontiers in Pharmacology, April 2018, Vol. 9, Article 315)
Effects on Psychosis (Schizophrenia)
Eight studies evaluated the clinical effect of CBD in psychosis. Five of these studies found a beneficial effect of CBD in reducing psychotic symptoms in schizophrenia (SKZ) (Zuardi et al. 1995; Leweke et al. 2012; Leweke, 2013; McGuire et al. 2018) and in Parkinson’s disease (Zuardi et al. 2009), while the others found only mild effects or no improvement over psychotic symptoms in patients with SKZ (Zuardi et al. 2006; Boggs et al. 2018) or in bipolar disorder (BD) patients experiencing a manic episode with psychotic features (Zuardi et al. 2010) (…) However, the findings presented in this literature overview must be considered in light of some limitations. First, there are still few randomised placebo-controlled clinical trials with small sample size. Second, CBD was administered in inconsistent dosage, formulation and timing of administration. Third, some studies tested CBD efficacy in adjunction to standard medications (Zuardi et al. 1995, 2009, 2010; Leweke et al. 2012; Boggs et al. 2018; McGuire et al. 2018), which may have therefore conditioned the results. Fourth, major considerations must be given to the lack of assessment of biological measures among the above mentioned studies, since only three studies evaluated biological measures, such as endocannabinoid (Leweke et al. 2012) or CBD plasma levels (McGuire et al. 2018) and cerebral blood flow changes (Crippa et al. 2011). (Epidemiology and Psychiatric Sciences (2018), 27, 327–335. © Cambridge University Press 2018 doi:10.1017/S2045796018000239)
Bottom Line: Fully-grown adults may use recreational marijuana without any noticeable benefits or side effects, other than a temporary brain impairment. Younger adults (under age 21) and adolescents, on the other hand, are incurring serious and documented risks of brain damage that are not worth taking and may cause cognitive damage that is irreversible in adulthood and even after they quit using. Current efforts to normalize cannabis use are being driven largely by a combination of grassroots activism, pharmacological ingenuity, and private profiteering, with a worrisome disregard for scientific evidence, gaps in our knowledge, or the possibility of unintended consequences [especially for young people].
Pros: No medical applications have been documented for street-level or commercially available recreational marijuana.
Cons: Far too many individuals report that they do not get the mellow, relaxed feeling from marijuana that they expected, and instead they experience paranoia, anxiety and even psychosis. This is due to the fact that today’s marijuana is delivered in much higher concentrations than ever before (+30% vs. 8-10%). The substance is addictive and leads to dependency to “feel normal.”
Effects of Marijuana On the Human Brain
We systematically review the empirical research published in the past decade (from January 2004 to February 2015) on acute and chronic effects of cannabis and cannabinoids and on persistence or recovery after abstinence. (…) Verbal learning and memory and attention are most consistently impaired by acute and chronic exposure to cannabis. Psychomotor function is most affected during acute intoxication, with some evidence for persistence in chronic users and after cessation of use. Impaired verbal memory, attention, and some executive functions may persist after prolonged abstinence, but persistence or recovery across all cognitive domains remains under researched. Associations between poorer performance and a range of cannabis use parameters, including a younger age of onset, are frequently reported. Little further evidence has emerged for the development of tolerance to the acutely impairing effects of cannabis. Evidence for potential protection from harmful effects by cannabidiol continues to increase but is not definitive. In light of increasing trends toward legalization of cannabis, the knowledge gained from this body of research needs to be incorporated into strategies to minimize harm. (Biological Psychiatry, 2016, 79 (1), 557-567)
Acute Adverse Effects of Marijuana
Acute adverse effects of cannabis use include anxiety and panic in naive users, and a probable increased risk of accidents if users drive while intoxicated (panel 1). Use during pregnancy could reduce birth weight, but does not seem to cause birth defects. Whether cannabis contributes to behavioral disorders in the offspring of women who smoked cannabis during pregnancy is uncertain. Chronic cannabis use can produce a dependence syndrome in as many as one in ten users. Regular users have a higher risk of chronic bronchitis and impaired respiratory function, and psychotic symptoms and disorders, most probably if they have a history of psychotic symptoms or a family history of these disorders. The most probable adverse psychosocial effect in adolescents who become regular users is impaired educational attainment. Adolescent regular cannabis users are more likely to use other illicit drugs, although the explanation of this association remains contested. Regular cannabis use in adolescence might also adversely affect mental health in young adults, with the strongest evidence for an increased risk of psychotic symptoms and disorders. (The Lancet, Vol 374 October 17, 2009)
Adverse Effects of Marijuana Use by Adolescents and Young Adults
Cannabis use during adolescence increases the risk of developing psychotic disorders later in life. However, the neurobiological processes underlying this relationship are unknown. This review reports the results of a literature search comprising various neurobiological disciplines, ultimately converging into a model that might explain the neurobiology of cannabis-induced schizophrenia. The article briefly reviews current insights into brain development during adolescence. In particular, the role of the excitatory neurotransmitter glutamate in experience-dependent maturation of specific cortical circuitries is examined. The review also covers recent hypotheses regarding disturbances in strengthening and pruning of synaptic connections in the prefrontal cortex, and the link with latent psychotic disorders. In the present model, cannabis-induced schizophrenia is considered to be a distortion of normal late postnatal brain maturation. Distortion of glutamatergic transmission during critical periods may disturb prefrontal neurocircuitry in specific brain areas. Our model postulates that adolescent exposure to D9-tetrahydrocannabinol (THC), the primary psychoactive substance in cannabis, transiently disturbs physiological control of the endogenous cannabinoid system over glutamate and GABA release. As a result, THC may adversely affect adolescent experience-dependent maturation of neural circuitries within prefrontal cortical areas. Depending on dose, exact time window and duration of exposure, this may ultimately lead to the development of psychosis or schizophrenia. The proposed model provides testable hypotheses which can be addressed in future studies, including animal experiments, reanalysis of existing epidemiological data, and prospective epidemiological studies in which the role of the dose–time–effect relationship should be central. (Progress in Neurobiology 92 (2010) 370–385)
Young Users Show Neuropsychological Decline From Childhood To Midlife
Recent reports show that fewer adolescents believe that regular cannabis use is harmful to health. Concomitantly, adolescents are initiating cannabis use at younger ages, and more adolescents are using cannabis on a daily basis. The purpose of the present study was to test the association between persistent cannabis use and neuropsychological decline and determine whether decline is concentrated among adolescent-onset cannabis users. Participants were members of the Dunedin Study, a prospective study of a birth cohort of 1,037 individuals followed from birth (1972/1973) to age 38 y. Cannabis use was ascertained in interviews at ages 18, 21, 26, 32, and 38 y. Neuropsychological testing was conducted at age 13 y, before initiation of cannabis use, and again at age 38 y, after a pattern of persistent cannabis use had developed. Persistent cannabis use was associated with neuropsychological decline broadly across domains of functioning, even after controlling for years of education. Informants also reported noticing more cognitive problems for persistent cannabis users. Impairment was concentrated among adolescent-onset cannabis users, with more persistent use associated with greater decline. Further, cessation of cannabis use did not fully restore neuropsychological functioning among adolescent-onset cannabis users. Findings are suggestive of a neurotoxic effect of cannabis on the adolescent brain and highlight the importance of prevention and policy efforts targeting adolescents. (Meier M H, Caspi A, Ambler A, et al. Persistent cannabis users show neuropsychological decline from childhood to midlife.Proc Natl Acad Sci USA. 2012;109(40):E2657-E2664.)
State of Knowledge About Marijuana
The human brain undergoes a maturational process during adolescence that includes reorganization, refinements and functional improvements. This is driven by changes in brain grey matter (GM) due to synaptic pruning (elimination of underutilized or unnecessary neural connections), and white matter (WM) due to myelination.
• These changes continue at least until the mid-20s and thus brain maturation is vulnerable during this time to stressors/insults.
• The endocannabinoid system plays a role in this brain maturation and thus exogenous cannabinoids from cannabis can affect this process directly in a negative way.
• Regular cannabis use in youth and young adults can affect aspects of cognition, including attention, memory, processing speed, visuospatial functioning and overall intelligence. Worse performance is related to earlier adolescent onset of use. Abstinence following regular use may improve some, but not all, of these cognitive domains.
• Early and regular use increases the risk of developing a primary psychotic illness in those individuals who are vulnerable. Vulnerability factors are not currently clear, but may include factors such as childhood trauma and genetics. In those young adults who have developed psychosis, continued cannabis use worsens long-term symptom and functional outcomes.
• Cannabis may increase the risk of depression and early regular use is associated with younger age of onset of symptoms of psychosis and of bipolar disorder.
• Cannabis with high tetrahydrocannabinol (THC) content (high potency) can result in significantly worse mental health and cognitive outcomes, including worsening of panic disorder and other anxiety disorders.
• Early age of use of cannabis increases the potential for adult dependence to cannabis.
• Cannabis may be associated with increased progression to other illicit drug use in the context of particular factors (e.g., high frequency and early age of use). (Canadian journal of psychiatry. Revue canadienne de psychiatrie · January 2018)
Effects of Heavy Marijuana Use
Heavy cannabis use has been frequently associated with increased rates of mental illness and cognitive impairment, particularly amongst adolescent users. However, the neurobiological processes that underlie these associations are still not well understood. In this review, we discuss the findings of studies examining the acute and chronic effects of cannabis use on the brain, with a particular focus on the impact of commencing use during adolescence. Accumulating evidence from both animal and human studies suggests that regular heavy use during this period is associated with more severe and persistent negative outcomes than use during adulthood, suggesting that the adolescent brain may be particularly vulnerable to the effects of cannabis exposure. As the endocannabinoid system plays an important role in brain development, it is plausible that prolonged use during adolescence results in a disruption in the normative neuromaturational processes that occur during this period. We identify synaptic pruning and white matter development as two processes that may be adversely impacted by cannabis exposure during adolescence. Potentially, alterations in these processes may underlie the cognitive and emotional deficits that have been associated with regular use commencing during adolescence. (Pharmacology & Therapeutics, Volume 148, April 2015, Pages 1-16)
Marijuana Is a Highly Profitable Business
Current efforts to normalize cannabis use are being driven largely by a combination of grassroots activism, pharmacological ingenuity, and private profiteering, with a worrisome disregard for scientific evidence, gaps in our knowledge,or the possibility of unintended consequences. Given the critical and wide-ranging role of the endocannabinoid system in the brain,81-83 the increasing prevalence of cannabis use and use disorders over the last decade and the increased THC concentration in cannabis plants, there is a need to clarify which aspects of cannabis exposure (eg, age at initiation, quantity used, frequency of use, duration of use, and potency of cannabis used) confer the greatest risk for the development of cannabis use disorder or for other adverse consequences (ie, cognitive deficits, lack of motivation, or psychosis). In addition, there are many unanswered questions more directly linked to the soundness of hastily implemented policies (…) (T)here is strong physiological and epidemiological evidence supporting a mechanistic link between cannabis use and schizophrenia. Tetrahydrocannabinol (particularly at high doses) can cause acute, transient, dose-dependent psychosis (schizophrenia-like positive and negative symptoms).51 In addition, prospective, longitudinal, epidemiological studies consistently report an association between cannabis use and schizophrenia in which cannabis use precedes psychosis52 independent of alcohol consumption53 and even after removing52,54 or controlling for55,56 those individuals who had used other drugs. (JAMA Psychiatry. 2016;73(3):292-297. doi:10.1001/jamapsychiatry.2015.3278 Published online February 3, 2016)
Effects of Marijuana Use During Pregnancy
Since the psychoactive ingredients of cannabis can cross the placenta and be secreted in the maternal milk (Hutchings et al., 1989; Jakubovic et al., 1977), cannabis use and abuse during pregnancy and lactation may have long-lasting neurobehavioral effects on the offspring. Second, cannabis use has increased in adolescents, whose developing brain might be particularly susceptible to social and environmental influences. Thus, cannabis exposure at this critical developmental age may lead to neurobehavioral alterations or induce neuropsychiatric disorders, such as schizophrenia, later in life. Third, the endocannabinoid system has been proposed as a novel therapeutic target for the treatment of some neuropsychiatric diseases (Piomelli et al., 2006; Vinod and Hungund, 2006), including neurodevelopmental disorders, such as ADHD. However, the potential therapeutic application of cannabinoid drugs in children requires a better knowledge of the effects of these compounds on the CNS of immature individuals. The studies reviewed here suggest that changes in the activity of the endocannabinoid system during stages of high neuronal plasticity, such as the perinatal and adolescent period, can have long-lasting behavioral consequences. (European Journal of Pharmacology 585 (2008) 441-452)
Long-term Epigenetic Damage by Marijuana Use
Extensive debates continue regarding marijuana (Cannabis), the most commonly used illicit substance in many countries worldwide. There has been an exponential increase of cannabis studies over the past two decades but the drug’s long-term effects still lack in-depth scientific data. The epigenome is a critical molecular machinery with the capacity to maintain persistent alterations of gene expression and behaviors induced by cannabinoids that have been observed across the individual’s lifespan and even into the subsequent generation. Though mechanistic investigations regarding the consequences of developmental cannabis exposure remain sparse, human and animal studies have begun to reveal specific epigenetic disruptions in the brain and the periphery (such as) long-term disturbances in epigenetic regulation in relation to prenatal, adolescent and parental germline cannabinoid exposure. Expanding knowledge about the protracted molecular memory could help to identify novel targets to develop preventive strategies and treatments for behaviors relevant to neuropsychiatric risks associated with developmental cannabis exposure.(Neuroscience & Biobehavioral Reviews · May 2017 DOI: 10.1016/j.neubiorev.2017.05.011)
More Effects on Adolescent and Pregnant Women
Marijuana abuse during pregnancy and adolescence represents a major health problem owing to its potential consequences on neural development. Prenatally cannabis-exposed children display cognitive deficits, suggesting that maternal consumption has interfered with the proper maturation of the brain. Several pharmacological effects of THC, the active principle of Cannabis sativa preparations such as hashish and marijuana, are mimicked by the endogenous eCBs, 2-AG and AEA. Adverse effect of prenatal exposure to marijuana. Marijuana is the most prevalent illicit substance abused by pregnant women, with an incidence of 2–6% (determined by interview or self-report) and as high as 11% by serum. The mean potency of marijuana preparations, in terms of D9-tetrahydrocannabinol content, has increased from 3.4% in 1993 to 8.8% in 2008, reaching 30% in some hashish preparations. Human marijuana consumption during pregnancy appears to have lasting effects on the child’s higher cognitive function. (Future Neurology (2011) 6(4), 459–480)
Effects of Marijuana on Brain Matter
The dose-dependent toxicity of the main psychoactive component of cannabis in brain regions rich in cannabinoid CB1 receptors is well known in animal studies. However, research in humans does not show common findings across studies regarding the brain regions that are affected after long-term exposure to cannabis. In the present study, we investigate (using Voxel-based Morphometry) gray matter changes in a group of regular cannabis smokers in comparison with a group of occasional smokers matched by the years of cannabis use. We provide evidence that regular cannabis use is associated with gray matter volume reduction in the medial temporal cortex, temporal pole, parahippocampal gyrus, insula, and orbitofrontal cortex; these regions are rich in cannabinoid CB1 receptors and functionally associated with motivational, emotional, and affective processing. Furthermore, these changes correlate with the frequency of cannabis use in the 3 months before inclusion in the study. The age of onset of drug use also influences the magnitude of these changes. Significant gray matter volume reduction could result either from heavy consumption unrelated to the age of onset or instead from recreational cannabis use initiated at an adolescent age. In contrast, the larger gray matter volume detected in the cerebellum of regular smokers without any correlation with the monthly consumption of cannabis may be related to developmental (ontogenic) processes that occur in adolescence. (Neuropsychopharmacology volume 39, pages 2041–2048 (2014)
Effects of Marijuana Smoke
The pathophysiological effects of marijuana smoke and its constituent cannabinoids were reported. Marijuana smoke is mutagenic in the Ames test and in tissue culture and cannabinoids inhibit biosynthesis of macromolecules. In animals, marijuana or tetrahydrocannabinol (THC), the intoxicating material it contains, produces symptoms of neurobehavioural toxicity, disrupts all phases of gonadal or reproductive function, and is fetotoxic. Smoking marijuana can lead to symptoms of airway obstruction as well as squamous metaplasia. Clinical manifestations of pathophysiology due to marijuana smoking are now being reported. These include: longterm impairment of memory in adolescents; prolonged impairment of psychomotor performance; a sixfold increase in the incidence of schizophrenia; cancer of mouth, jaw, tongue and lung in 19-30 year olds; fetotoxicity; and non- lymphoblastic leukaemia in children of marijuana-smoking mothers. (Medical Journal of Australia / Volume 156, Issue 7, 1992).
Bottom Line: Proceed with caution and realize that it may not work for you and any weight loss will likely not be permanent, unless you stay on it for the rest of your life. Much research still needs to be done to determine whether the keto diet has any lasting health benefits beyond temporary weight loss.
Pros: Dramatic weight loss has been documented in case of severely obese individuals. The diet is helpful in managing certain types of diabetes.
Cons: Randomized trials are sorely lacking. There is simply insufficient evidence that the diet is safe for the heart and the circulatory system. Cholesterol and arterial plaque remain a concern even for individuals who are on a strict keto diet.
What are ketogenic diets?
Ketogenic diets are characterized by a marked reduction in carbohydrates (usually to <50 g/day) and a relative increase in the proportions of protein and fat – usually extremely high percentages of fat because it is difficult to increase proteins beyond a point.
Standard ketogenic diet (SKD): This is a very low-carbohydrate with moderate-protein and high-fat diet. It typically contains 70 per cent fat, 20 per cent protein and only 10 per cent carbohydrates.
Cyclical ketogenic diet (CKD): This diet involves periods of higher-carbohydrates in between the ketogenic diet cycles, for example, five ketogenic days followed by two high-carbohydrate days as a cycle.
Targeted ketogenic diet (TKD): This diet permits adding additional carbohydrates around the periods of the intensive physical workout.
High-protein ketogenic diet (HPKD): This diet includes more protein and the ratio around 60 per cent fat, 35 per cent protein and five per cent carbohydrates but as can be seen, it is still a very high fat diet.
(…) The dictum, ‘Moderation is the key’ should be used, while following any long-term diet plan. While low carbohydrate ketogenic diet does, admittedly, show dramatic improvements in the short term, these can increase morbidity and mortality in the long run and are rarely sustainable. Instead of letting the pendulum of nutrients swing on either side, one must be vigilant of the balance and interplay of nutrients, and there should be a representation of all food groups on the plate (…) (I)t appears that it would be most prudent to have a diet with about 50 per cent carbohydrate (using complex carbs and whole grains such as brown rice or whole wheat) about 20-25 per cent protein (preferably from vegetable proteins such as legumes and pulses) and the remaining 25-30 per cent from healthy fats like monounsaturated fats (e.g. groundnut oil or mustard oil and nuts and seeds) along with plenty of green leafy vegetables. Such a diet may not immediately give dramatic results as far as weight reduction is concerned. However, it will be sustainable in the long term and will be less risky and certainly more healthy and also help prevent non-communicable diseases such as diabetes, cardiovascular disease and certain cancers. (Indian J Med Res. 2018 Sep; 148(3): 251–253. doi: 10.4103/ijmr.IJMR_1666_18: 10.4103/ijmr.IJMR_1666_18)
Keto Diet and Mental Disorders
Despite its long history in neurology, the role of keto diet (KD) in mental disorders is unclear. Half of the published studies are based on animal models of mental disorders with limited generalizability to the analog conditions in humans. The review lists some major limitations including the lack of measuring ketone levels in four studies and the issue of compliance to the rigid diet in humans. Currently, there is insufficient evidence for the use of KD in mental disorders, and it is not a recommended treatment option. Future research should include long-term, prospective, randomized, placebo-controlled crossover dietary trials to examine the effect of KD in various mental disorders. (Frontiers in Psychiatry, March 20, 2017)
High Fat vs. Low Fat Diets
In support of higher fat intake, severalmeta-analyses found slightly greater weight loss on high-fat rather than low-fat diets (9, 10), and preliminary data suggest the potential for excellent control of diabetes through carbohydrate restriction (11, 12). But versions of low-carbohydrate, high-fat diets have been around at least as early as the 1800s, with no clear evidence of superiority for long-term obesity treatment at present. And regardless of
body weight, high intakes of fat—especially from redmeat and dairy products—might increase risk for heart disease or cancer (…) Emerging evidence suggests that a ketogenic diet—a special type of low-carbohydrate diet with fat typically =70% of energy—may have unique therapeutic effects beyond those of less restrictive regimens (…) Clinical translation. Moderately low-carbohydrate diets entail relatively simple changes in diet, focused primarily on substituting high-fat foods for processed carbohydrates while allowing several daily servings of whole fruits, legumes, andminimally processed grains. A ketogenic diet may include various nutrient-dense whole foods such as nonstarchy vegetables, nuts, eggs, cheese, butter/cream, fish,meats, oils, and select fruits. Proper formulation of a ketogenic diet entails restriction of carbohydrate, adequate but not high intake of protein, and sufficient sodium to offset the natriuretic effect of ketosis and reduced insulinemia. Recent data amongmotivated patients suggest the possibility of good compliance and improved quality of life through 1 year (11), although safety has not been fully assessed in long-term trials (…) Macronutrient feeding studies have been too short and too small to distinguish transient from chronic effects; many behavioral trials have lacked the intensity to produce meaningful differences between dietary treatment groups; and observational studies can be affected by confounding, inability to distinguish cause and effect, and other methodological problems. Furthermore, despite promising preliminary data, few major studies of a ketogenic diet in the treatment of diabetes have been conducted. Additional questions related to sustainability for the individual (whether people can realistically remain on prescribed diets) and for the environment (the impacts of specific dietary patterns on natural resources and climate change) require more study. Given the enormous human and economic toll of diet-related disease, high-quality research into key controversies should be given priority. (Science 362, 764–770 (2018) 16 November 2018)
State of Knowledge About the Keto Diet
1. With a focus on nutrient quality, good health and low chronic disease risk can be achieved for many people on diets with a broad range of carbohydrate-to-fat ratios.
2. Replacement of saturated fat with naturally occurring unsaturated fats provides health benefits for the general population. Industrially produced trans fats are harmful and should be eliminated.The metabolism of saturated fat may differ on carbohydrate-restricted diets, an issue that requires study.
3. Replacement of highly processed carbohydrates (including refined grains, potato products, and free sugars) with unprocessed carbohydrates (nonstarchy vegetables, whole fruits, legumes, and whole or minimally processed grains) provides health benefits.
4. Biological factors appear to influence responses to diets of differing macronutrient composition. People with relatively normal insulin sensitivity and b cell function may do well on diets with a wide range of carbohydrate-to-fat ratios; those with insulin resistance, hypersecretion of insulin, or glucose intolerance may benefit from a lowercarbohydrate, higher-fat diet.
5. A ketogenic diet may confer particular metabolic benefits for some people with abnormal carbohydrate metabolism, a possibility that requires long-term study.
6. Well-formulated low-carbohydrate, high-fat diets do not require high intakes of protein or animal products. Reduced carbohydrate consumption can be achieved by substituting grains, starchy vegetables, and sugars with nonhydrogenated plant oils, nuts, seeds, avocado, and other high-fat plant foods.
7. There is broad agreement regarding the fundamental components of a healthful diet that can serve to inform policy, clinical management, and individual dietary choice. Nonetheless, important questions relevant to the epidemics of diet-related chronic disease remain. Greater investment in
nutrition research should assume a high priority. (Science 362, 764–770 (2018) 16 November 2018)
Keto Diet and Lipid Markers
Large randomized controlled trials of at least 6 months duration with carbohydrate restriction appear superior in improving lipid markers when compared with low-fat diets. Dietary guidelines should consider carbohydrate restriction as an alternative dietary strategy for the prevention/management of dyslipidemia for populations with cardiometabolic risk. (Nutrition Reviews, Volume 77, Issue 3, March 2019, Pages 161–180)
Keto Diet and Cardiovascular Health
Based on the available literature, KD may be associated with some improvements in some cardiovascular risk factors, such as obesity, type 2 diabetes and HDL cholesterol levels, but these effects are usually limited in time. As KD are often rich in fats, some negative effects could happen. Mainly in rodents, developments of NAFLD and insulin resistance were described. In humans, insulin resistance is also a potential negative effect, but some studies have shown improvements in insulin sensitivity. Nevertheless, many subjects contemplating such diets are overweight or obese at baseline, and even a moderate weight loss could be metabolically beneficial for them. However, it is mandatory to maintain body weight after weight loss, which is usually a major problem. More studies are therefore warranted to better assess the effects of long term use of KD on metabolic diseases and cardiovascular risk factors, but also to better define which dietary macronutrient composition is optimal. (Nutrients 2017, 9, 517; doi:10.3390/nu9050517)
Keto Diet and Physical Performance
In summary, our results reveal that a 6-week non-energy restricted KD had a slightly negative impact on physical performance including endurance capacity, maximum work load, and faster exhaustion. Furthermore, we noted numerous metabolic adaptations, including alterations in many biochemical parameters. The significant weight loss, evenly distributed between FM and FFM, comprised neither muscle mass nor function.We detected a mildly negative impact from this 6-week non-energy-restricted KD on physical performance (endurance capacity, peak power and faster exhaustion). Our findings lead us to assume that a KD does not impact physical fitness in a clinically relevant manner that would impair activities of daily living and aerobic training. However, a KD may be a matter of concern in competitive athletes. (Urbain et al. Nutrition & Metabolism (2017) 14:17 DOI 10.1186/s12986-017-0175-5)
Keto Diet and Kidney Damage
We reviewed the cardiovascular, metabolic, anesthetic, and postsurgical profiles in the literature and summarized technical issues of anesthesia and surgery along with long-term changes from published papers. Doubts with ketogenic diet were raised due to possible renal damage caused by significant excretion of nitrogen found in animal models, the effects of acidosis, and the concerns of increasing triglycerides and cholesterol levels. Though current literature supports the efficacy of very low carbohydrate keto-diets their potential negative effects on renal function and acidosis are debated. An increase in nitrogen excretion during protein metabolism in the postoperative period could lead to renal damage. (Minerva Gastroenetrologica & Dietologica, 10 March 2018)
Keto Diet and Alzheimer’s Disorder
The present study was undertaken to determine whether elevating ketones with diet affected cerebral bioenergetics and Alzheimer’s Disease biomarkers in cerebrospinal fluid (CSF) in adults at risk for AD due to amnestic mild cognitive impairment (MCI) and metabolic dysregulation (prediabetes) (…) Ketogenic diet intervention enhanced brain ketone utilization in MCI and prediabetes, and produced correlated increases in CSF total tau and Ab42. Future investigation is needed to examine the relationship of these effects to changes in cognition. (CLINICAL THERAPEUTICS: CLINICAL TRIALS — INNOVATIVE TRIALS, Podium Presentations: Wednesday, July 27, 2016)
Keto Diet and Type 2 Diabetes
In conclusion, Ketogenic diet has several benefits on the management of type two diabetes. These benefits include the reduction of HbA1c level, weight loss, and improvement of lipid profile, cardiac benefits, reversibility of nephropathy and even possible effect on reversing diabetic neuropathy and
retinopathy. Future studies should be conducted on a large population of patients to fully understand the mechanism of action between ketone bodies and the above benefits as well as the possible long-term disadvantages of applying such a diet regimen. (Obesity & Eating Disorders, ISSN 2471-8203 Vol.2 No.2:22 2016)
Keto Diet and Neurologic Disorders
As ketogenic diets are being utilized with increasing frequency for adult neurologic disorders, recognition and management of potential adverse effects and contraindications must be considered. The adverse effects most often reported by adults on ketogenic diets for the treatment of epilepsy are weight loss, gastrointestinal effects, and a transient increase in lipids. In clinical studies of KD use in other neurological disorders in adults, similar side effects have been reported although a true estimate of prevalence in these populations is difficult due to the small number of participants, often with lack of control groups for comparison, short duration of follow up, reliance on self-report of adverse effects in some studies, and heterogeneity in KD therapy applied [43, 143]. Gastrointestinal side effects can include constipation, diarrhea (typically with MCT supplementation), nausea, vomiting, and rarely pancreatitis (KD therapies are therefore contraindicated in acute pancreatitis). The side effects can improve with continued diet use and with minor adjustments, rarely necessitating pharmaceutical intervention or diet discontinuation. Strategies utilized by dietitians and nutritionists include recommending multiple small meals throughout the day; increasing fiber, sodium, and fluid intake; and daily exercise. When used, gradual introduction of MCT may reduce gastrointestinal side effects. Given that many adults with neurologic disorders are overweight or obese, weight loss may be a welcomed effect, and for those who are normal or underweight and wish to maintain or gain weight, regulation and monitoring of caloric intake is recommended. Anorexia is a contraindication to using KD therapies. (Neurotherapeutics. https://doi.org/10.1007/s13311-018-0666-8)
Adverse Effects of Keto Diets
Although very helpful in a variety of pathologies, ketogenic diets also have short- and long-term adverse effects, which are easily distinguishable. Short-term side effects include gastro intestinal problems, such as gastro-oesophageal reflux and constipation, acidosis , hypoglycaemia , dehydration, and lethargy . This group of effects are normally transient and easily managed . On the other hand, long-term side effects include hyperlipidaemia (although with some controversy [6,7]), hypercholesterolaemia , nephrolithiasis  and cardiomyopathy  (Fig. 5). According to a review of 27 papers describing the adverse effects of the ketogenic diet , vomiting and increased serum lipid levels seem to be the most common. In a study including 52 epileptic children treated with the classic ketogenic diet, five patients experienced serious adverse effects . These events, although not very frequent, can deter patients from complying with a long-term diet. Additionally, a diet high in cholesterol can lead to premature heart disease . These findings show that although the diet may be useful in lessening seizure severity and occurrence, there are many adverse effects that need to be carefully monitored. Additionally, young patients must be monitored carefully to ensure they are receiving the appropriate nutrient balance. Often, patients find it difficult to maintain a diet within the restrictions of the classic ketogenic diet, with its 4 : 1 fat:carbohydrate ratio . Although these adverse effects rarely lead to a cessation of the diet, they need to be recognized in due time . (Eur J Clinical Investigations 2016; 46 (3): 285–298)