In summary

How Does CBD Oil Help with Weight Loss?

  • Various studies have proven CBD’s effectiveness in mitigating the symptoms of seizures, cancer, chronic pain, inflammation, depression, and anxiety(1). However, recent studies(2) have also revealed its ability to promote weight loss.
  • A study revealed that CBD possessed anti-obesity properties as it was effective in blocking CB1 receptors(3). The blocking of CB1 receptors is known to reduce body weight and food intake(4).
  • Research published in the Molecular and Cellular Biochemistry scientific journal also showed CBD’s promising potential in combating obesity by promoting the ‘fat browning’ process(5).
    This process includes converting white fat cells (which store energy in fat) to brown fat cells.
    Brown fat cells are a valuable target for promoting weight loss due to its ability to burn excess calories(6).
  • However, research on CBD’s effectiveness as an aid to weight loss and appetite suppressant abilities are limited, with most of the research conducted on either mice or rat subjects.
  • Further research is needed to support CBD’s capacity to help individuals lose weight and suppress overeating.
The full article

Best CBD Oils For Weight Loss

Editor's Pick

Spruce 750mg Lab Grade CBD Oil

Specifically formulated to be more palatable to CBD users
Spruce 750mg Lab Grade CBD Oil Bottle
  • Overall Clinical Score
    99%
    Editor's Pick
  • Clinical Scores
    Value
    Quality
    Strength
    Customer Service
    Lab Testing Transparency
    Effectiveness
    Perfect for...New CBD users
  • Summary

    Each bottle of the 750mg CBD oil tincture contains 25mg of CBD per dropper full. The oil is peppermint flavor to mask any unpleasant tastes related to CBD.

    Pro's
    Cons's
     Mid-strength  No other flavors
     Natural peppermint flavor
     Made from 100% organic and natural ingredients
  • Features
    Discount pricing available? 20% Off Coupon Code: CBDCLINICALS
    Source
    Source of Hemp
    Kentucky, USA & North Carolina, USA
    Form Oil Tincture
    Ingredients Organic Hemp Seed Oil, Full Spectrum CBD Oil
    Type
    Type of CBD
    Full Spectrum
    Extraction
    Extraction Method
    Moonshine extraction method
    How to take it Under tongue
    Potency
    Potency - CBD Per Bottle
    750 mg per bottle
    Carrier Oil Organic Hemp Seed Oil
    Concentration
    CBD Concentration Per Serving
    25mg of CBD per dropper full (1ml)
    Drug Test Contains 0.3% THC but there is a chance you may test positive for marijuana
    Flavours Peppermint
    Price Range $89 ($75.65 for subscriptions, 15% discount from regular price)
    $/mg CBD
    Price ($/mg)
    $0.12/mg ($0.10/mg with subscription)
    Shipping
    Shipping/Time to delivery
    2-4 business days (first class USPS)
    Lab Tests
    Lab Testing Transparency
    Third Party Lab Tested post formulation for safety and potency, available on website
    Contaminants Organic, Non-GMO, no pesticides, no herbicides, no solvents or chemical fertilizers, No preservatives or sweeteners
    Allergens Vegan, Gluten free
    Refund policy Within 30 days
    Recommended for New CBD users
    Countries served USA only (all 50 states)
Check Latest Prices
Best Organic

NuLeaf Naturals 900mg Full Spectrum Hemp CBD Oil

Perfect for anyone who are looking for CBD products that promote a healthy body and mind.
NuLeaf Naturals 900mg Full Spectrum Hemp CBD Oil
  • Overall Clinical Score
    99%
    Best Organic
  • Clinical Scores
    Value
    Quality
    Strength
    Customer Service
    Lab Testing Transparency
    Effectiveness
    Perfect for...Health-conscious persons
  • Summary

    Natural remedy for various illnesses. NuLeaf Naturals’ CBD oil is a whole-plant extract containing a full spectrum of naturally occurring synergistic cannabinoids and terpenes.

    Pro's
    Cons's
     Pure CBD hemp  No other flavors
     All natural
     Approximately 300 drops total
  • Features
    Discount pricing available? 20% Off Coupon Code: CBDCLINICALS20
    Source
    Source of Hemp
    Colorado, USA
    Form Oil Tincture
    Ingredients Full Spectrum Hemp Extract, Organic Virgin Hemp Seed Oil
    Type
    Type of CBD
    Full Spectrum CBD
    Extraction
    Extraction Method
    CO2 Method
    How to take it Under the tongue for approximately 30 seconds before swallowing
    Potency
    Potency - CBD Per Bottle
    900mg per bottle
    Carrier Oil Organic Hemp Oil
    Concentration
    CBD Concentration Per Serving
    60mg per dropper full (1ml)
    Drug Test Contains 0.3% THC but there is a chance you may test positive for marijuana
    Flavours Natural
    Price Range $99 - $434
    $/mg CBD
    Price ($/mg)
    $0.08 - $0.13
    Shipping
    Shipping/Time to delivery
    2-3 Days via USPS
    Lab Tests
    Lab Testing Transparency
    Third Party Lab Tested post formulation for safety and potency, available on website
    Contaminants No additives or preservatives, Non-GMO, NO herbicides, pesticides, or chemical fertilizers
    Allergens Not specified
    Refund policy Within 30 days
    Recommended for Health-conscious persons
    Countries served USA (all 50 states) and over 40 countries including Australia, Azerbaijan, Beliza, Bosnia & Herzegovina, Brazil, Chile, China, Croatia, Czech Republic, Estonia, France, Hong Kong, Hungary, Ireland, Israel, Japan, Latvia, Lebanon, Lithuania, Macao, Malaysia, Malta, Netherlands, New Zealand, Oman, Paraguay, Poland, Portugal, Saudi Arabia, Serbia, Singapore, South Korea, Sweden, Switzerland, United Arab Emirates, United Kingdom, Uruguay, and many more.
Check Latest Prices
Best Customer Service

Sabaidee Super Good Vibes CBD Oil

4x the strength of a regular cbd oil
Sabaidee Super Good Vibes CBD Oil
  • Overall Clinical Score
    99%
    Best Customer Service
  • Clinical Scores
    Value
    Quality
    Strength
    Customer Service
    Lab Testing Transparency
    Effectiveness
    Perfect for...Patients who are looking for serious CBD oil support
  • Summary

    Super Good Vibes CBD Oil provides the purest and highest quality Cannabidiol (CBD) on the market as well as other high quality phytocannabinoids, terpenes, vitamins, omega fatty acids, trace minerals, and other beneficial for your health elements, which all work together to provide benefits.

    Pro's
    Cons's
     Extra strong  No other flavors
     Significant benefits with just a few drops
     100% Natural ingredients
  • Features
    Discount pricing available? 15% Off Coupon Code: CBDCLINICALS15
    Source
    Source of Hemp
    Colorado, USA
    Form Oil Tincture
    Ingredients Cannabidiol (CBD), Coconut Medium-chain triglycerides (MCT) Oil, Peppermint oil
    Type
    Type of CBD
    Broad Spectrum
    Extraction
    Extraction Method
    CO2-extraction
    How to take it Using 1-3 servings per day as needed is a good start to determine how much you need
    Potency
    Potency - CBD Per Bottle
    1000 mg per bottle
    Carrier Oil Coconut MCT Oil
    Concentration
    CBD Concentration Per Serving
    33.5 mg per dropper (1ml)
    Drug Test Contains 0.3% THC but there is a chance you may test positive for marijuana
    Flavours Peppermint
    Price Range Single Bottle - $119.95, 2-Pack - $109.97 each, 3-Pack - $98.31 each, 6-Pack - $79.99 each
    $/mg CBD
    Price ($/mg)
    Single bottle - $0.010, 2-Pack - $0.011, 3-Pack - $0.009, 6-Pack - $0.007
    Shipping
    Shipping/Time to delivery
    3-5 Business days
    Lab Tests
    Lab Testing Transparency
    Third Party Lab Tested post formulation for safety and potency, available on website
    Contaminants Contaminant-free
    Allergens Vegan and Gluten-free
    Refund policy Within 30 days
    Recommended for Patients who are looking for serious CBD oil support
    Countries served USA only (all 50 states)
Check Latest Prices
Natural Alternative

cbdMD CBD Oil Tinctures

Uses USA hemp that is grown on non-GMO farms, and is both vegan and gluten-free
cbdMD CBD Oil Tinctures Products
  • Overall Clinical Score
    99%
    Natural Alternative
  • Clinical Scores
    Value
    Quality
    Strength
    Customer Service
    Lab Testing Transparency
    Effectiveness
    Perfect for...CBD users with different needs
  • Summary

    cbdMD’s CBD oil tinctures are made using only CBD sourced from medical hemp and MCT oil as a carrier oil. Tinctures are offered in orange, mint, natural, and berry flavors. Safe for daily use, the oil tinctures are packaged with a built-in rubber dropper to adjust CBD dosage easily. The packaging is made to be easy to transport and discreet to use.

    Pro's
    Cons's
     Plenty of concentrations to choose from for all people with various kinds of needs  cbdMD uses MCT as its carrier oil so individuals who are allergic with coconuts should consider other brand options
     Has vegan, organic, and gluten-free ingredients
     Affordable pricing
     Affordable pricing
  • Features
    Discount pricing available? 15% Off Coupon Code: cbdMD15
    Source
    Source of Hemp
    Kentucky, USA
    Form Oil Tincture
    Ingredients Cannabidiol (CBD), MCT Oil, and Flavoring
    Type
    Type of CBD
    Broad Spectrum
    Extraction
    Extraction Method
    CO2 extraction method
    How to take it Under tongue
    Potency
    Potency - CBD Per Bottle
    300 mg - 7500 mg / 30 ml bottle, 1000 mg - 1500 mg / 60 ml bottle
    Carrier Oil Organic Coconut MCT Oil
    Concentration
    CBD Concentration Per Serving
    30 ml: 300 mg - 10 mg per dropper (1ml), 750 mg - 25 mg per dropper (1ml), 1500 mg - 50 mg per dropper (1ml), 3000 mg - 100 mg per dropper (1ml), 5000 mg - 166.6 mg per dropper (1ml), 7500 mg - 250 mg per dropper (1ml), 60 ml: 1000 mg - 16.6 mg per dropper (1ml), 1500 mg - 25 mg per dropper (1ml)
    Drug Test Containing less than 0.3% THC, there are still trace amounts
    Flavours Natural, Berry, Orange and Mint
    Price Range 30 ml Bottles: $29.99 for 300 mg, $69.99 for 750 mg, $99.99 for 1500 mg, $149.99 for 3000 mg, $239.99 for 5000 mg, $339.99 for 7500 mg 60 ml Bottles: $74.99 for 1000 mg, $99.99 for 1500 mg
    $/mg CBD
    Price ($/mg)
    30 ml - $0.05 - $0.10, 60 ml - $0.06 - $0.07
    Shipping
    Shipping/Time to delivery
    2-5 Business days (via Fedex)
    Lab Tests
    Lab Testing Transparency
    Third Party Lab Tested post formulation for safety and potency, available on website
    Contaminants 100% organic, non-GMO, and vegan-certified
    Allergens Vegan, Gluten free
    Refund policy Within 30 days
    Recommended for CBD users with different needs
    Countries served USA only (all 50 states)
Check Latest Prices

Why People Are Turning to CBD Oil for Weight Loss

Although many recognize CBD for its anti-seizure, anti-inflammatory, pain-relieving, neuroprotective, anti-anxiety, and antidepressant properties(7), recent studies have also suggested its promising potential in aiding individuals who need to lose weight and excess body fat.

One of the growing public health concerns leading to a need for weight loss is obesity and the accompanying metabolic disorders.

Obesity is a disease that occurs when the human body incurs an excessive amount of fat.

One way to know if an individual has become obese is if their body mass index (BMI) increases to 30 or higher. However, this method has not always been reliable as BMI cannot correctly measure the amount of body fat one has.

Many factors can contribute to obesity, from genetics to imbalances in metabolism and hormones. Diet also plays a big part in the development of obesity. 

When individuals consume too many calories and fail to burn these through exercise and normal daily activities, the body begins storing excess calories as fat.

Obesity should not be reduced to a mere cosmetic issue. 

Obesity, when left untreated, can lead to other severe medical conditions such as diabetes, heart disease, high blood pressure, and even cancer(8).

Weight loss is foremost the best remedy for obesity. The change to a healthy diet and an increase in physical activity should help obese individuals lose weight.

Studies also suggest that CBD oil may help in combating obesity by promoting weight loss.

One significant study investigated how the administration of cannabinoids, like CBD, could affect the appetite of rat subjects(9).

In the study, it was stated that tetrahydrocannabinol (THC), another famous cannabinoid, could increase appetite and food consumption in animals.

However, the researchers noted that few studies have verified if other cannabinoids, like CBD, had the same effects.

Together with the cannabinol (CBN), the researchers administered CBD to adult male rat subjects.

Results showed that while CBN increased the rats’ food consumption, CBD was able to reduce it significantly.

Researchers noted CBD’s possible anti-obesity effects but suggested that further studies were needed.

Another critical study published by the Molecular and Cellular Biochemistry scientific journal found that CBD had the potential to prevent obesity by promoting the “fat browning” process(10).

Brown fat, or brown adipose tissue, is a type of fat used to produce heat. When activated, it burns calories.

On the other hand, white fat, or white adipose tissue, stores energy and is more prevalent in adults.

The fat browning process occurs when the usual white fat cells (stored energy) in fatty tissue are converted into fat brown cells.

Brown fat is seen as a valuable target for promoting weight loss and a potential remedy for obesity and diabetes, as it burns excess calories(11).

The researchers also discovered that CBD was also able to advance the breakdown of adipocytes (fat cells) and its generation process by lessening the expression of proteins involved in it.

Another study found CBD to reduce rat subjects’ body weight gain due to CB2 receptors(12).

The research cited the role of the endocannabinoid system (ECS) in regulating food intake and energy balance. 

The ECS is vital in activating CBD’s therapeutic effects on the human body’s metabolism, which is responsible for converting food to energy.

The rat subjects were given CBD injections twice a day for 14 days. The researchers found that CBD was able to significantly reduce the rats’ body weight gain, with the higher dose being more effective.

Research has also linked a worsening metabolic syndrome (high blood pressure and blood sugar, excess body fat around the waist, and unstable cholesterol levels) to the development of hepatosteatosis or non-alcoholic fatty liver disease (NAFLD) in individuals with obesity(13).

The same study also discovered that individuals with NAFLD were prone to develop insulin resistance and heart conditions.

NAFLD develops when fat amasses in the liver of individuals who consume little to no alcohol, and causes inflammation. NAFLD is also referred to as fatty liver(14).

Available treatments for NAFLD are few, which prompted researchers to investigate cannabinoids, like CBD, as a potential alternative remedy.

In a 2015 study, researchers used CBD to improve insulin sensitivity and its effects on the levels of lipid or cholesterol in the body(15).

They found that CBD, along with another cannabinoid called tetrahydrocannabivarin (THCV), was able to reduce cholesterol levels in obese mice and zebrafish.,

This finding suggested that CBD could inhibit the development of NAFLD.

Both the cannabinoids were also able to lessen the buildup of triglycerides within the liver, one of the main components of natural fats and oil. 

It also improved the subjects’ resistance to insulin.

The researchers concluded that CBD’s properties posed a potential new treatment for obesity and metabolic diseases such as NAFLD.

Because it interacts with the endocannabinoid system, CBD, along with THCV, was also found to lower cholesterol and blood sugar levels in mice with type 2 diabetes(16).

Researchers concluded that cannabinoids, like CBD, had promising potential in controlling blood sugar levels of patients with type 2 diabetes.

Meanwhile, another study administered CBD treatment to female mice that were not obese yet prone to diabetes for five days a week for a total of four weeks(17).

The researchers stopped administering CBD treatment after this period. 

By the time the subjects were 24 weeks old, they had found that CBD was able to reduce the development of diabetes in the mice significantly.

Also, one significant study concluded that CBD had the potential to alleviate the symptoms of insulin resistance, type 2 diabetes, and the metabolic syndromes associated with it(18).

However, some study results have contradicted evidence pointing to CBD’s anti-obesity properties.

A 2014 research, published in the official journal of the Polish Physiological Society, examined the effects of CBD on rat subjects put on a high-fat sugar diet(19).

Researchers cited the consumption of fats and sugars as one of the leading causes of obesity in humans. They investigated whether CBD could impact the food intake and body weight of the rat subjects.

When injected with CBD, the rats put on a high-fat diet developed an increase in body weight, despite their decreased food intake.

Meanwhile, the rat subjects given a free choice diet experienced no notable changes in body weight or food consumption.

Another study also examined the effects of CBD and other cannabinoids on the food intake of mice subjects(20).

They found that the administration of THC was able to increase the mice’s food consumption. At the same time, CBD did not affect food intake or activity.

However, another study explains that this result could be due to the low dosage of CBD administered to the mice(21).

The Cannabis sativa plant (where CBD and THC come from) was also known to cause appetite stimulation in its users(22), a phenomenon referred to as munchies.

One study found that 786 adult Inuits who used cannabis had a significantly lower chance of developing obesity(23).

Despite all this, research investigating the effects of CBD on appetite, weight, and metabolism is few, with the majority being animal studies.

Most of the information supporting CBD’s effectiveness in weight loss and appetite suppression is also anecdotal.

Most of the positive feedback is from individuals who have self-administered CBD oil as part of their daily regimen to achieve weight loss.

However, CBD is not a miracle cure for obesity, diabetes, heart disease, or any health conditions related to it.

Individuals should consult with health professionals if they wish to pursue CBD as an aid in weight loss.

Nevertheless, the anti-obesity and anti-diabetes effects of cannabinoids, including CBD, should be pursued.

These cannabinoids possess potential as an alternative weight loss aid, as evidenced by research.

How CBD Oil Works for Weight Loss

Various studies have attributed CBD’s weight loss and appetite suppressant effects to its special relationship with the endocannabinoid system (ECS).

The ECS plays a crucial role in regulating various bodily processes, including metabolism, appetite, and body weight regulation(24).

In particular, the ECS plays an essential role in amassing fat used for energy(25).

When the ECS becomes unbalanced or overactive, it can promote fat accumulation and even advance cardiovascular risks that lead to type 1 and type 2 diabetes.

To explain, the ECS is composed of three main components: cannabinoid receptors, endocannabinoids, and the enzymes that allow for its breakdown and synthesis.

CB1 and CB2 are the two primary receptors of the ECS.

CB1 receptors exist mostly in the brain and nervous system. However, they also exist in tissues and the endocrine gland. In contrast, most CB2 receptors are located in the immune system.

CB1 receptors play a crucial role in regulating appetite, metabolism, and body weight(26).

Specifically, blocking CB1 receptors help reduce body weight and food intake.

Meanwhile, stimulating CB2 receptors limit inflammatory responses, produce anti-obesity effects through appetite suppressant actions, and limit body weight gain(27).

Receptors are also responsible for the previously mentioned fat browning process, where white adipose tissues (white fat cells) are transformed into brown adipose tissues or brown fat cells.

Fat brown cells are a potential target for promoting weight loss in obese patients.

On the other hand, endocannabinoids (endogenous cannabinoids) are neurotransmitters that act as signals for the body to take action.

When they bind with either CB1 or CB2 receptors, specific effects are activated, depending on which receptor is triggered.

CBD or cannabidiol can also bind with CB1 or CB2 receptors since it is a phytocannabinoid.

While endocannabinoids originate from the body (hence the term ‘endogenous’), phytocannabinoids (phyto meaning from the plant) are cannabinoids naturally found in the Cannabis sativa plant.

Since CB1 receptors also exist in tissues and the endocrine gland, CBD’s interaction with these receptors can help reduce appetite and reduce overeating problems experienced by certain individuals.

Studies imply that CBD can block CB1 receptors, which is the reason for its anti-obesity effect(28).

On the other hand, a study that administered CBD to rats found CBD’s interaction with CB2 receptors to reduce the subjects’ body weight(29).

Researchers concluded that CB2 receptors played a crucial role in body weight regulation.  However, further studies should be conducted to support this evidence.

CBD is only one of the hundreds of phytocannabinoids naturally occurring in the Cannabis sativa plant.

Another one is THC or tetrahydrocannabinol, which is popular for its psychoactive properties that induce a euphoric “high” effect in its users.

CBD, on the other hand, is non-psychoactive because it comes from the hemp plant, one of the varieties of the Cannabis sativa plant.

Industrial hemp plants contain less than 0.3% THC. Hemp extracts like CBD oil and other hemp products are used for their numerous health benefits.

The Pros and Cons of CBD Oil for Weight Loss

Pros

  • CBD oil is considered safe and non-toxic for both humans and animals. Studies found CBD to contain little to no adverse effects(30).
  • Chronic use and intake of high doses of CBD appear to be well-tolerated by humans(31).
  • CBD oil has been given generally positive feedback by various individuals, health professionals, and health organizations, including WHO(32).
  • CBD is non-psychoactive, meaning it cannot give its users a euphoric high, unlike THC.
  • The director of the National Institute on Drug Abuse (NIDA) Nora Volkow claims that CBD is non-addictive(33) and that it is safe for daily use.
  • Due to CBD’s popularity in the United States, various CBD products for weight loss are available on the market. There are CBD tinctures, oil drops, gummies, capsules, and soft gels from which users can freely choose.
  • The 2018 Farm Bill allowed for industrial hemp farming and the production of hemp products derived from it. However, restrictions still apply.
    Industrial hemp plants must contain less than 0.3% THC, and cannabis products and compounds are still regulated by the U.S. Food and Drug Administration (FDA)(34).

Cons

  • CB1 receptors, when activated, can enhance appetite and food intake.
    Meanwhile, blocking CB1 receptors can suppress appetite. However, this action was also seen to enact adverse psychiatric side effects(35).
    CBD blocks CB1 receptors, which explains its anti-obesity effects(36). However, due to the previously mentioned adverse psychiatric effects, further caution is needed when using CBD oil for weight loss.
  • Limited evidence supports the effectiveness of CBD in promoting weight loss and as an appetite suppressant. Most of the available research were animal studies.
  • CBD has shown no remarkable adverse effects on various human and animal studies. However, some notable side effects may include drowsiness, dry mouth, diarrhea, and fatigue(37).
  • Certain CBD products contained labeling inaccuracies, with some products containing more CBD, while others lesser amounts than stated(38).

How CBD Oil Compares to Alternative Options for Weight Loss

Common natural options for losing weight include Ayurvedic medicine, essential oils, and natural weight loss supplements.

Ayurvedic medicine, or Ayurveda, is an ancient Indian medical system that emphasizes a natural and holistic approach to promoting physical and mental health(39).

Ayurvedic treatment includes the use of plants, minerals, diet, exercise, massage, pressure point treatment, and lifestyle changes to bring balance to mind, body, and spirit.

Evidence backing the effectiveness of Ayurvedic medicine in Western medical journals are few. However, like CBD oil, many individuals have used Ayurveda as a natural means to lose weight.

Ayurveda uses various plant extracts and herbs to promote overall health and well-being. Similar to CBD oil, essential oils from plant extracts have also been used to aid weight loss.

One study reviewed various literature investigating the effectiveness of essential oils as anti-obesity agents (40).

The researchers reviewed existing literature on essential oils from the year 2000 to 2015. They found that only one study specifically used essential oils to combat obesity.

However, the lone study’s data was not enough to support the claim that essential oils were effective in reducing fat accumulation in obesity.

Many dietary weight loss supplements also include plant extract as ingredients.

The U.S. National Institutes of Health Office of Dietary Supplements (ODS) published a fact sheet about dietary weight loss supplements.

The fact sheet revealed that common weight loss supplements contained African mango, bitter orange, caffeine, raspberry ketone, green tea, and green coffee bean extract(41).

However, in the same fact sheet, the ODS states that evidence supporting dietary supplements’ abilities to reduce body weight and promote weight loss is inconclusive at best.

The ODS still recommends a healthy diet and an increase in physical activity as the best ways to lose weight.

Like the previously mentioned natural weight loss options, CBD oil also works best when combined with a healthy diet, lessened intake of calories, and physical activities.

How to Choose the Best CBD Oil for Weight Loss

Users looking to use CBD for weight loss should know what to look for when selecting CBD products.

Consider the following when choosing CBD products for weight loss:

  • CBD products are labeled as either full-spectrum CBD, broad-spectrum, or CBD isolate.

Full-spectrum CBD contains the majority of the active cannabinoids found within the hemp plant, including terpenes and flavonoids. It also contains natural ingredients and compounds such as Omega-3 and Omega-6 fatty acids. When used, all of these components combine to produce the famed entourage effect.

Broad-spectrum CBD oil is essentially the same. However, it is marketed as being THC free as it contains less than 0.3% THC.

Meanwhile, CBD isolates contain pure CBD oil. These CBD products are suitable for those suffering from allergies to other components found in hemp extracts.

Many recommend full-spectrum CBD as it is the most potent and produces maximum effectiveness. However, it is essential to consult a health professional regarding the use of full-spectrum CBD oil.

  • Be aware of the exact legal provisions surrounding the purchasing and use of CBD oil.

The 2018 Farm Bill has allowed for the selling and distribution of CBD products in various states.

However, it is safer to check the laws of the state where the product is going to be purchased from and used.

  • Prioritize buying from sellers, and CBD brands that have organic, non-GMO CBD products as these are indicative of high quality. 
  • Buy CBD products from only legitimate sellers. The majority of companies cultivate hemp from their farms or simply purchase from licensed industrial hemp producers. Users should know how their CBD oil was manufactured and packaged.
  • Check the certifications of CBD brands and sellers. CBD products must have certification codes, while companies must have a certificate of analysis (COA).
  • CBD brands and sellers must also have good manufacturing processes (cGMP) and third-party lab certificates of analysis for all batches of CBD oil produced.
  • Check CBD product reviews and customer feedback for each CBD product. Consider these as testimonials to the products’ performance.
  • Lastly, users should first consult with their health professionals before using CBD as an appetite suppressant or weight loss aid. 

Weight gain and overeating may be symptoms of more significant diseases, to which CBD is not a verified treatment or cure. 

It is up to the physician’s discretion on whether or not they are going to prescribe CBD as an additional remedy.

Best CBD Oils For Weight Loss

Editor's Pick

Spruce 750mg Lab Grade CBD Oil

Specifically formulated to be more palatable to CBD users
Spruce 750mg Lab Grade CBD Oil Bottle
  • Overall Clinical Score
    99%
    Editor's Pick
  • Clinical Scores
    Value
    Quality
    Strength
    Customer Service
    Lab Testing Transparency
    Effectiveness
    Perfect for...New CBD users
  • Summary

    Each bottle of the 750mg CBD oil tincture contains 25mg of CBD per dropper full. The oil is peppermint flavor to mask any unpleasant tastes related to CBD.

    Pro's
    Cons's
     Mid-strength  No other flavors
     Natural peppermint flavor
     Made from 100% organic and natural ingredients
  • Features
    Discount pricing available? 20% Off Coupon Code: CBDCLINICALS
    Source
    Source of Hemp
    Kentucky, USA & North Carolina, USA
    Form Oil Tincture
    Ingredients Organic Hemp Seed Oil, Full Spectrum CBD Oil
    Type
    Type of CBD
    Full Spectrum
    Extraction
    Extraction Method
    Moonshine extraction method
    How to take it Under tongue
    Potency
    Potency - CBD Per Bottle
    750 mg per bottle
    Carrier Oil Organic Hemp Seed Oil
    Concentration
    CBD Concentration Per Serving
    25mg of CBD per dropper full (1ml)
    Drug Test Contains 0.3% THC but there is a chance you may test positive for marijuana
    Flavours Peppermint
    Price Range $89 ($75.65 for subscriptions, 15% discount from regular price)
    $/mg CBD
    Price ($/mg)
    $0.12/mg ($0.10/mg with subscription)
    Shipping
    Shipping/Time to delivery
    2-4 business days (first class USPS)
    Lab Tests
    Lab Testing Transparency
    Third Party Lab Tested post formulation for safety and potency, available on website
    Contaminants Organic, Non-GMO, no pesticides, no herbicides, no solvents or chemical fertilizers, No preservatives or sweeteners
    Allergens Vegan, Gluten free
    Refund policy Within 30 days
    Recommended for New CBD users
    Countries served USA only (all 50 states)
Check Latest Prices
Best Organic

NuLeaf Naturals 900mg Full Spectrum Hemp CBD Oil

Perfect for anyone who are looking for CBD products that promote a healthy body and mind.
NuLeaf Naturals 900mg Full Spectrum Hemp CBD Oil
  • Overall Clinical Score
    99%
    Best Organic
  • Clinical Scores
    Value
    Quality
    Strength
    Customer Service
    Lab Testing Transparency
    Effectiveness
    Perfect for...Health-conscious persons
  • Summary

    Natural remedy for various illnesses. NuLeaf Naturals’ CBD oil is a whole-plant extract containing a full spectrum of naturally occurring synergistic cannabinoids and terpenes.

    Pro's
    Cons's
     Pure CBD hemp  No other flavors
     All natural
     Approximately 300 drops total
  • Features
    Discount pricing available? 20% Off Coupon Code: CBDCLINICALS20
    Source
    Source of Hemp
    Colorado, USA
    Form Oil Tincture
    Ingredients Full Spectrum Hemp Extract, Organic Virgin Hemp Seed Oil
    Type
    Type of CBD
    Full Spectrum CBD
    Extraction
    Extraction Method
    CO2 Method
    How to take it Under the tongue for approximately 30 seconds before swallowing
    Potency
    Potency - CBD Per Bottle
    900mg per bottle
    Carrier Oil Organic Hemp Oil
    Concentration
    CBD Concentration Per Serving
    60mg per dropper full (1ml)
    Drug Test Contains 0.3% THC but there is a chance you may test positive for marijuana
    Flavours Natural
    Price Range $99 - $434
    $/mg CBD
    Price ($/mg)
    $0.08 - $0.13
    Shipping
    Shipping/Time to delivery
    2-3 Days via USPS
    Lab Tests
    Lab Testing Transparency
    Third Party Lab Tested post formulation for safety and potency, available on website
    Contaminants No additives or preservatives, Non-GMO, NO herbicides, pesticides, or chemical fertilizers
    Allergens Not specified
    Refund policy Within 30 days
    Recommended for Health-conscious persons
    Countries served USA (all 50 states) and over 40 countries including Australia, Azerbaijan, Beliza, Bosnia & Herzegovina, Brazil, Chile, China, Croatia, Czech Republic, Estonia, France, Hong Kong, Hungary, Ireland, Israel, Japan, Latvia, Lebanon, Lithuania, Macao, Malaysia, Malta, Netherlands, New Zealand, Oman, Paraguay, Poland, Portugal, Saudi Arabia, Serbia, Singapore, South Korea, Sweden, Switzerland, United Arab Emirates, United Kingdom, Uruguay, and many more.
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Sabaidee Super Good Vibes CBD Oil

4x the strength of a regular cbd oil
Sabaidee Super Good Vibes CBD Oil
  • Overall Clinical Score
    99%
    Best Customer Service
  • Clinical Scores
    Value
    Quality
    Strength
    Customer Service
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    Effectiveness
    Perfect for...Patients who are looking for serious CBD oil support
  • Summary

    Super Good Vibes CBD Oil provides the purest and highest quality Cannabidiol (CBD) on the market as well as other high quality phytocannabinoids, terpenes, vitamins, omega fatty acids, trace minerals, and other beneficial for your health elements, which all work together to provide benefits.

    Pro's
    Cons's
     Extra strong  No other flavors
     Significant benefits with just a few drops
     100% Natural ingredients
  • Features
    Discount pricing available? 15% Off Coupon Code: CBDCLINICALS15
    Source
    Source of Hemp
    Colorado, USA
    Form Oil Tincture
    Ingredients Cannabidiol (CBD), Coconut Medium-chain triglycerides (MCT) Oil, Peppermint oil
    Type
    Type of CBD
    Broad Spectrum
    Extraction
    Extraction Method
    CO2-extraction
    How to take it Using 1-3 servings per day as needed is a good start to determine how much you need
    Potency
    Potency - CBD Per Bottle
    1000 mg per bottle
    Carrier Oil Coconut MCT Oil
    Concentration
    CBD Concentration Per Serving
    33.5 mg per dropper (1ml)
    Drug Test Contains 0.3% THC but there is a chance you may test positive for marijuana
    Flavours Peppermint
    Price Range Single Bottle - $119.95, 2-Pack - $109.97 each, 3-Pack - $98.31 each, 6-Pack - $79.99 each
    $/mg CBD
    Price ($/mg)
    Single bottle - $0.010, 2-Pack - $0.011, 3-Pack - $0.009, 6-Pack - $0.007
    Shipping
    Shipping/Time to delivery
    3-5 Business days
    Lab Tests
    Lab Testing Transparency
    Third Party Lab Tested post formulation for safety and potency, available on website
    Contaminants Contaminant-free
    Allergens Vegan and Gluten-free
    Refund policy Within 30 days
    Recommended for Patients who are looking for serious CBD oil support
    Countries served USA only (all 50 states)
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Natural Alternative

cbdMD CBD Oil Tinctures

Uses USA hemp that is grown on non-GMO farms, and is both vegan and gluten-free
cbdMD CBD Oil Tinctures Products
  • Overall Clinical Score
    99%
    Natural Alternative
  • Clinical Scores
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    Perfect for...CBD users with different needs
  • Summary

    cbdMD’s CBD oil tinctures are made using only CBD sourced from medical hemp and MCT oil as a carrier oil. Tinctures are offered in orange, mint, natural, and berry flavors. Safe for daily use, the oil tinctures are packaged with a built-in rubber dropper to adjust CBD dosage easily. The packaging is made to be easy to transport and discreet to use.

    Pro's
    Cons's
     Plenty of concentrations to choose from for all people with various kinds of needs  cbdMD uses MCT as its carrier oil so individuals who are allergic with coconuts should consider other brand options
     Has vegan, organic, and gluten-free ingredients
     Affordable pricing
     Affordable pricing
  • Features
    Discount pricing available? 15% Off Coupon Code: cbdMD15
    Source
    Source of Hemp
    Kentucky, USA
    Form Oil Tincture
    Ingredients Cannabidiol (CBD), MCT Oil, and Flavoring
    Type
    Type of CBD
    Broad Spectrum
    Extraction
    Extraction Method
    CO2 extraction method
    How to take it Under tongue
    Potency
    Potency - CBD Per Bottle
    300 mg - 7500 mg / 30 ml bottle, 1000 mg - 1500 mg / 60 ml bottle
    Carrier Oil Organic Coconut MCT Oil
    Concentration
    CBD Concentration Per Serving
    30 ml: 300 mg - 10 mg per dropper (1ml), 750 mg - 25 mg per dropper (1ml), 1500 mg - 50 mg per dropper (1ml), 3000 mg - 100 mg per dropper (1ml), 5000 mg - 166.6 mg per dropper (1ml), 7500 mg - 250 mg per dropper (1ml), 60 ml: 1000 mg - 16.6 mg per dropper (1ml), 1500 mg - 25 mg per dropper (1ml)
    Drug Test Containing less than 0.3% THC, there are still trace amounts
    Flavours Natural, Berry, Orange and Mint
    Price Range 30 ml Bottles: $29.99 for 300 mg, $69.99 for 750 mg, $99.99 for 1500 mg, $149.99 for 3000 mg, $239.99 for 5000 mg, $339.99 for 7500 mg 60 ml Bottles: $74.99 for 1000 mg, $99.99 for 1500 mg
    $/mg CBD
    Price ($/mg)
    30 ml - $0.05 - $0.10, 60 ml - $0.06 - $0.07
    Shipping
    Shipping/Time to delivery
    2-5 Business days (via Fedex)
    Lab Tests
    Lab Testing Transparency
    Third Party Lab Tested post formulation for safety and potency, available on website
    Contaminants 100% organic, non-GMO, and vegan-certified
    Allergens Vegan, Gluten free
    Refund policy Within 30 days
    Recommended for CBD users with different needs
    Countries served USA only (all 50 states)
Check Latest Prices

CBD Dosage for Weight Loss

There is yet to be a standardized and approved dosage chart for CBD use for weight loss.

Users are encouraged to first seek advice from medical professionals if they wish to use CBD oil to help lose weight.

However, the general rule for CBD dosage is to start with small initial doses and gradually increase in incremental amounts until the desired effect manifests.

Non-profit organization Project CBD states in an article that a prolonged, low dose therapy may be advantageous for those managing chronic symptoms and preventing the recurrence of disease(42).

When in doubt, follow the dosing instructions as provided by the manufacturer of the CBD product purchased and consult with your physician.

Since no standardized dosage chart is available, CBD brands provide their dosage standard and charts.

Therefore, the safest route is to follow the provided dosage as per the product’s instructions.

How to Take CBD Oil for Weight Loss

There are many ways to administer CBD oil for weight loss. 

Although topical CBD products are available, most CBD products for weight loss are taken by mouth.

CBD oil tincture dominates the market. Various oil drops and hemp extracts are applied sublingually (under the tongue) and swallowed after a few seconds.

Certain brands have flavored CBD oil products for those who do not enjoy the natural, earthy taste of hemp extracts.

CBD oil can also be dropped and mixed into food and drinks if the usual sublingual route is not preferred.

Select CBD oil products can also be repurposed for vaping. However, CBD vape juice is also available for this specialized method of administration.

Many users also claim that inhaling CBD through vape is more fast-acting than sublingual administration.

However, few studies have investigated the possible health impact of vaping CBD products.

One study investigated the effects of inhaling vaporized CBD to rat subjects, due to the prevalence of CBD vape products on the market(43). 

The researchers administered CBD to rats by letting the subjects inhale the vapor produced by an e-cigarette.

The researchers found that CBD lowered the subjects’ body temperature, inducing hypothermia. Inhaling CBD through vapor also produced dependency effects in the rats.

Non-profit organization Consumer Reports also found that several CBD vape users were hospitalized because of vitamin E acetate(44).

Vitamin E acetate is a chemical used in diluting oils for vape products.

Meanwhile, one study published in the Canadian journal of respiratory therapy stated that the vaporization of cannabis was able to reduce the delivery of toxic byproducts that exist in cannabis smoke(45).

The study mentioned that the vaporization of cannabis was less likely to be harmful than smoking.

However, it also noted that research on the long term effects of cannabis vaping had yet to be published, making it difficult to draw conclusions.

Researchers from Johns Hopkins Medicine also emphasized the importance of dosage when vaping cannabis products(46).

CBD products for weight loss also come in the form of capsules, gummies, and soft gels. 

It is a convenient way to take CBD, as it is in tablet or chewable forms. 

Some individuals also prefer these products since it is easier to follow the dosing instructions.

CBD brands that offer these types of products instruct on taking one to two capsules a day.

Keep in mind that CBD is by no means a cure for obesity, diabetes, or any metabolic diseases that may cause one to overeat or gain excess body fat.

Users can take CBD as help for weight loss. However, individuals should first consult with a physician before self-administering for any signs or symptoms of medical conditions.

Conclusion

Various studies have documented the anti-seizure, anti-inflammatory, pain-relieving, anti-anxiety, and antidepressant effects of CBD.

However, individuals are also turning to CBD oil as an aid for weight loss.

Various studies have shown evidence for CBD’s anti-obesity and anti-diabetes properties. However, much more research is further needed to validate these findings.

There is no known harm in using CBD oil as an aid for weight loss.

However, it is not going to cure or treat obesity, diabetes, or any metabolic disorders that accompany the former.

Users should seek advice from a health professional for any symptoms of overeating, excess fat, or bodyweight gain as these may be indicative of a severe disease.


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  12. Ignatowska-Jankowska B, Jankowski MM, Swiergiel AH. Cannabidiol decreases body weight gain in rats: involvement of CB2 receptors. Neurosci Lett. 2011;490(1):82‐84. doi:10.1016/j.neulet.2010.12.031
  13. Silvestri, C., Paris, D., Martella, A., Melck, D., Guadagnino, I., Cawthorne, M., Motta, A., & Di Marzo, V. (2015). Two non-psychoactive cannabinoids reduce intracellular lipid levels and inhibit hepatosteatosis. Journal of hepatology, 62(6), 1382–1390. https://doi.org/10.1016/j.jhep.2015.01.001
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  16. Jadoon, K. A., Ratcliffe, S. H., Barrett, D. A., Thomas, E. L., Stott, C., Bell, J. D., O’Sullivan, S. E., & Tan, G. D. (2016). Efficacy and Safety of Cannabidiol and Tetrahydrocannabivarin on Glycemic and Lipid Parameters in Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Pilot Study. Diabetes care, 39(10), 1777–1786. https://doi.org/10.2337/dc16-0650
  17. Weiss, L., Zeira, M., Reich, S., Slavin, S., Raz, I., Mechoulam, R., & Gallily, R. (2008). Cannabidiol arrests onset of autoimmune diabetes in NOD mice. Neuropharmacology, 54(1), 244–249. https://doi.org/10.1016/j.neuropharm.2007.06.029
  18. Bielawiec, P., Harasim-Symbor, E., & Chabowski, A. (2020). Phytocannabinoids: Useful Drugs for the Treatment of Obesity? Special Focus on Cannabidiol. Frontiers in endocrinology, 11, 114. https://doi.org/10.3389/fendo.2020.00114
  19. Wierucka-Rybak, M., Wolak, M., & Bojanowska, E. (2014). The effects of leptin in combination with a cannabinoid receptor 1 antagonist, AM 251, or cannabidiol on food intake and body weight in rats fed a high-fat or a free-choice high sugar diet. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society, 65(4), 487–496.
  20. Wiley, J. L., Burston, J. J., Leggett, D. C., Alekseeva, O. O., Razdan, R. K., Mahadevan, A., & Martin, B. R. (2005). CB1 cannabinoid receptor-mediated modulation of food intake in mice. British journal of pharmacology, 145(3), 293–300. https://doi.org/10.1038/sj.bjp.0706157
  21. Bielawiec, P., Harasim-Symbor, E., & Chabowski, A. (2020). Phytocannabinoids: Useful Drugs for the Treatment of Obesity? Special Focus on Cannabidiol. Frontiers in endocrinology, 11, 114. https://doi.org/10.3389/fendo.2020.00114
  22. Ward, S. J., & Dykstra, L. A. (2005). The role of CB1 receptors in sweet versus fat reinforcement: effect of CB1 receptor deletion, CB1 receptor antagonism (SR141716A) and CB1 receptor agonism (CP-55940). Behavioural pharmacology, 16(5-6), 381–388. https://doi.org/10.1097/00008877-200509000-00010
  23. The Inuits also had lower BMI (body mass index) and lower body fat. Ngueta, G., Bélanger, R. E., Laouan-Sidi, E. A., & Lucas, M. (2015). Cannabis use in relation to obesity and insulin resistance in the Inuit population. Obesity (Silver Spring, Md.), 23(2), 290–295. https://doi.org/10.1002/oby.20973
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  28. Bielawiec, P., Harasim-Symbor, E., & Chabowski, A. (2020). Phytocannabinoids: Useful Drugs for the Treatment of Obesity? Special Focus on Cannabidiol. Frontiers in endocrinology, 11, 114. https://doi.org/10.3389/fendo.2020.00114
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  45. Loflin, M., & Earleywine, M. (2015). No smoke, no fire: What the initial literature suggests regarding vapourized cannabis and respiratory risk. Canadian journal of respiratory therapy : CJRT = Revue canadienne de la therapie respiratoire : RCTR, 51(1), 7–9.
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TOWARD EUROPEAN GUIDELINES FOR PKU: HOW TO SPEAK A COMMON LANGUAGE? 

Annemiek van Wegberg, Msc,1 François Maillot, MD, PhD,2 and Francjan van Spronsen, MD, PhD Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; and CHRU de Tours, Université François Rabelais, INSERM U1069, Tours, France

 

ABSTRACT

Background: Because phenylketonuria (PKU; OMIM 261600) is a rare disease, international collaboration is needed to collect enough patient data to determine outcome and prognosis, and to establish international guidelines, which are currently being developed. This necessitates the use of a common language.   Objective: The aim of this study was to examine whether consensus exists about the concepts of “compliance,” “off diet,” and “lost to followup.”   Methods: A survey of 10 multiplechoice questions was conducted among 68 professionals attending a workshop on the development of European guidelines for PKU management during the 5th European Phenylketonuria Group Symposium in 2013. Consensus was considered to exist if an answer was given by the majority (>50%) of responders. Results: Fiftythree percent of the participants considered ‟>75% of requested number of blood samples” as optimal compliance. Sixty percent reported ‟<50% of requested number of blood samples” as poor compliance. Fiftysix percent of the participants considered ‟>75% of requested number of outpatients visits” as optimal compliance. For the other 5 questions regarding compliance, no consensus was realized. Sixty percent of the responders defined the combination of “patient does not take a protein substitute” and “is not in good metabolic control” as “off diet.”  There was no consensus for the definition of “lost to followup.”

 

Conclusions: Consensus was clearly lacking regarding the surveyed concepts, with only 4 of the 10 questions achieving consensus. A score table is proposed for the definition of poor, fair, and good compliance, independent of age and sex. Other concepts, such as the definition of the severity of phenylalanine hydroxylase deficiency, need to be determined.

 

INTRODUCTION

Phenylketonuria (PKU, OMIM 261600) is a rare disease; therefore, centers and countries have to cooperate to collect enough data from their patients to determine outcome and prognosis, and to establish guidelines. However, such cooperation necessitates the use of common definitions in a comparable way. There is a need for consistent terminology in PKU care to compare results and develop guidelines.1,2We investigated the possibility of consensus about concepts of “compliance” (or lack of it), “off diet,” and “lost to follow up” to be able to speak the same language while European guidelines are being developed for PKU.

 

METHODS

In 2008, a meeting on the concept of “diet for life” was initiated. Two months in advance of that meeting, the 10 participants (dieticians, pediatricians, and a psychologist experienced with PKU treatment and research) received an openended survey on their use and interpretation of definitions of “compliance,” “off diet,” and “lost to followup.” The results of the survey were discussed during the meeting to ensure there was no misunderstanding about the questions and possible answers. Based on their input, a multiplechoice questionnaire was developed that was tallied with voting machines during the workshops on European guidelines at the 5th European Phenylketonuria Group Symposium in March 2013. The consensus workshop was 1 of 4 different workshops and was run twice. The target audience for the symposium was professionals working in the field of pediatric and adult inherited metabolic disorders, either as health care professionals or researchers, all over the world. The survey included 10 multiplechoice questions about the concepts of “compliance,” “off  diet,” and “lost to followup.” Eight of these questions regarded compliance with metabolic control (phenylalanine [Phe] concentrations), frequency of blood sampling, use of protein substitutes, and frequency of outpatient visits. All questions were developed to be independent of age or sex and independent of the national or centerbased guidelines the participants followed. Each question had 3 to 5 possible answers.   Consensus was considered to exist if an answer was given by the majority (>50%) of responders. Statistics were descriptive due to the aim and nature of the study.

 

RESULTS

A total of 84 professionals participated in the workshop. Of these, 54 were physicians (64%), 14 were dieticians (17%), 8 were industry related (10%), and 8 had another profession (researcher, patients organization) or their profession was unknown. The 16 participants of the last groups mentioned were excluded from the analysis. Participating and treating professionals originated from centers in Belgium, Brazil, Canada, Germany, Estonia, France, Israel, Italy, Latvia, Kazakhstan, Poland, Portugal, Romania, Saudi Arabia, Slovakia, Spain, the Netherlands, Turkey, and United Kingdom, with about 80% hailing from European countries. The PKU experience of the participants ranged from <5 to >20 years.  The present survey showed consensus for 4 of the 10 questions. Figure 1 presents the 8 questions on compliance, along with the corresponding responses. Fiftythree percent of responders considered  ‟>75% of requested number of blood samples” as optimal compliance. Sixty percent reported  ‟<50% of requested number of blood samples” as poor compliance. Fiftysix percent of the participants considered  ‟>75% of requested number of outpatients visits” as optimal compliance. For the other 5 questions regarding compliance, no consensus was realized.   Fortyfour percent of the responders reported ‟>75% of phenylalanine concentrations in target range” as optimal compliance. Thirtyone percent considered ‟<25% of the phenylalanine concentrations in target range” to be poor compliance, followed by 29% of participants reporting ‟<50% of phenylalanine in target range” and 28% of participants reporting  ‟mean of Phe concentrations clearly out of target range.” Fortyseven percent of responders reported ‟100% of requested amounts” as optimal compliance. Fortythree percent considered ‟<66% of requested amounts” to be poor compliance. Forty seven percent considered ‟<50% of requested number of outpatients visits” to be poor compliance. Figure 2 presents responses to the questions on “off  diet” and “lost to followup.” Sixty percent of participants defined the combination of “patients does not take a protein substitute”    and “is not in good metabolic control” as “off  diet.” In contrast, there was no consensus for the definition of “lost to followup”, as the answers were almost evenly distributed.

 

DISCUSSION

The aim of this study was to determine whether consensus exists on definitions of some commonly used concepts in the daytoday care of patients with PKU. Using a common language will facilitate the quality of patient care and collaboration with regard both to research and to defining international guidelines. This applies to all health care areas, not just PKU.38 To achieve our goal, we developed a multiplechoice survey that was conducted during 1 of the 4 workshops having a representative number of participants.   Consensus was achieved on only 4 of the 10 questions, which means there was a lack of consensus on 6 questions. On 2 questions, consensus was almost reached, with 47% of the participants in agreement (Figure 1, E and H). No clear consensus exists with regard to metabolic control, perhaps because there was no simple choice. An additional reason for lack of consensus might be the different use of classification (mean of Phe concentrations and a percentage of target range) in different centers. For the use of protein substitutes, the difference between the 2 largest groups was 10% (Figure 1F). Participants had to choose between 100% or >80% as optimal use. Although optimal should be close to 100%, this might have been viewed as unrealistic. Another reason for lack of consensus on this issue might be that it is difficult to control. On the one hand, everyone agrees about the importance of taking protein substitutes at the right amount and at the right time, but we also know that this is very hard to monitor, requiring new biochemical measures for more optimal oversight. It should be stressed that we did not discuss the given answers by participants to achieve consensus. It is very possible that consensus could have been reached by real discussion.   To further simplify the use of the definition of compliance, we developed a simple structured score, giving a maximum of 2 points for good compliance with regard to  ‟frequency of blood sampling,”  ‟use of a protein substitute,” and  ‟frequency of outpatient visit” (Table). As the authors unanimously believed that metabolic control was most important, it was granted double the points of the other issues, amounting to a total maximum score of 10. When compliance was poor,

no points were granted; fair compliance was given half of the maximal points. Fair compliance was judged applicable when compliance was neither good nor poor. Because we only found consensus for 3 of the 8 questions, we arbitrarily based the cutoff points on the answers given by the majority of the participants.   The other issues of “off diet” and “lost to followup” had different responses with regard to consensus. “Off diet” was clearly defined as “not taking a protein substitute and being out of metabolic control.” However, there was no consensus with regard to the definition of “lost to followup.” Most of the group did not answer this question, perhaps because it was too complicated or unclear. The same applied to 2 questions on compliance that >10% of the participants did not answer (Figure 1, A and F). This is a first proposal toward definitions of the concepts of “compliance,” “off diet,” and “lost to followup” that are used in the routine care of patients with PKU. Defining other concepts might be helpful, considering for example the definition of the severity of PAH deficiency. Blau et al showed that the definitions reported for moderate and mild PKU and mild hyperphenylalaninemia (HPA) varied considerably not only between countries, but also between centers within a country, so there appears to be a need for a common definition for classificaTIon.9 This is important, as the decision on treatment also depends on the definition of mild HPA

and mild PKU. Van Spronsen added that untreated Phe concentrations in blood have lost their power to successfully define various severities of phenylalanine hydroxylase deficiency―because of neonatal screening, patients now begin treatment before untreated Phe concentrations have achieved their full potential concentraTIon.2 The development of guidelines will need at least some consensus on such issues so that good clinical practice, sound (international) research, and international guidelines can be realized. Therefore, one of the aims of future meetings on guidelines should also be to achieve consensus about concepts like these.

 

Table. Compliance Score in Patients With Phenylketonuria, Independent of Age and Sex

 

Parameter Poor Fair Good
Metabolic control   <25% of Phe levels in  target range  25%‐75% of Phe levels in target range>75% of Phe levels in  target range
Score024
Frequency of blood  sampling<50% of requested  number of blood samples  50%‐75% of requested number of blood samples>75% of requested number of blood samples
Score012
Protein substitute <67% of requested amounts at requested times67%‐100% of requested amounts at requested times100% of requested amounts at requested times
Score012
Frequency of outpatient visits<50% of requested number of outpatient visits50%‐75% of requested number of outpatient visits>75% of requested number of outpatient visits
Score012
Total compliance score<5 5‐7 7‐10

REFERENCES:

  1. van Spronsen FJ, Burgard P. The truth of treating paTIents with phenylketonuria after childhood: the need for a new guideline. J Inherit Metab Dis. 2008;31:673679.
  2. van Spronsen FJ. Phenylketonuria management from an European perspective: a commentary. Mol Genet Metab. 2010;100:107110.
  3. Rose JS, Fisch BJ, Hogan WR, et al. Common medical terminology comes of age, Part one: standard language improves healthcare quality. J Healthc Inf Manag. 2001;15:307‐318.
  4. Rodriguez‐Roisin R. Toward a consensus definition for COPD exacerbations.Chest.2000;117:398S‐401S.
  5. Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010;51:1069‐1077. 
  6. Taylor DR, Bateman ED, Boulet LP, et al. A new perspecTIve on concepts of asthma severity and control. Eur Respir J. 2008;32:545‐554.
  7. AnTInori A, Coenen T, Costagiola D, et al; European Late Presenter Consensus Working Group. Late presentaTIon of HIV infection: a consensus definiTIon. HIV Med. 2011;12:61‐64. 
  8. Glad SB, Aarseth JH, Nyland H, et al. Benign multiple sclerosis: a need for a consensus. Acta Neurol Scand Suppl. 2010;190:44‐50.  

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TASTE PERCEPTION AND SENSORY SENSITIVITY: RELATIONSHIP TO FEEDING PROBLEMS IN BOYS WITH BARTH SYNDROME

Stacey Reynolds, PhD, OTR/L1; Consuelo M. Kreider, PhD, OTR/L2; Lauren E. Meeley, MS, OTR/L1 and Roxanna M. Bendixen, PhD, OTR/L3; Department of Occupational Therapy, 1 Virginia Commonwealth University, Richmond, Virginia; 2 University of Florida, Gainesville, Florida; and 3 University of Pittsburgh, Pittsburgh, Pennsylvania

ABSTRACT

Background: Feeding problems are common in boys with Barth syndrome and may contribute to the population’s propensity for growth delay and muscle weakness.  

Objectives: The purpose of this study was to quantify and describe feeding issues in Barth syndrome and examine altered taste perception and sensory sensitivity as contributing factors.

Methods: A cross-sectional, 2‐group comparison design was used to examine feeding preferences and behaviors, chemical taste perception, and sensory sensitivities in 50 boys aged 4 to 17 years with (n = 24) and without (n = 26) Barth. Taste perception was measured using chemical test strips saturated with phenylthiocarbamide (PTC) and sodium benzoate (NaB). Feeding problems were documented by parents using a food inventory, and sensory sensitivities were recorded using the Short Sensory Profile. Results: Boys with Barth differed significantly from typical peers with regard to problem feeding behaviors. Food refusal and food selectivity were identified as being present in ~50% of the sample, while 70.8% had identified problems related to gagging or swallowing foods. About half of all Barth families noted that their child’s eating habits did not match the family’s and that separate meals were often prepared. About 50% of the boys demonstrated probable or definite differences in taste/smell sensitivity, which was significantly higher than in controls. On tests of chemical taste perception, boys with Barth were significantly more likely to be supertasters to PTC  (P < .05) and nontasters to NaB (P < .01). Taster status did not directly relate to the presence of feeding problems; however, taste/smell sensitivity did significantly relate to food selectivity by type and texture.

Conclusions: Feeding problems were found in at least 50% to 70% of these boys with Barth syndrome, and were  often present before 6 months of age. Differences in taste perception may influence dietary choices in boys with Barth, particularly their craving of salty foods. Taste/smell sensitivity also appears to influence food selectivity and therefore may be important to consider in this population, particularly in light of dietary influences on cardiac function, energy consumption, and overall growth.   

INTRODUCTION

Barth syndrome is a rare X‐linked genetic disorder with  ~150 living cases and 500 known cases identified in the Barth Syndrome Registry.1 It is a potentially fatal disease caused by mutation of the tafazzin (TAZ) gene on chromosome Xq28, resulting in a loss of function in the protein product tafazzin, a transacylase. The alteration in tafazzin activity results in remolding of cardiolipin in mitochondrial membranes. Structural and functional changes in mitochondrial integrity are believed to be primarily responsible for the Barth phenotype, characterized by core features of cardiomyopathy, skeletal myopathy, and neutropenia.2Other common features of the disorder include feeding problems, exercise intolerance, and delays in growth, gross motor milestones, and puberty. Of these characteristics, the issue of feeding problems has received little attention in the literature, although it is commonly discussed among those familiar with the disorder.   Anecdotally, many parents report that, in infancy, their child with Barth had difficulty transitioning to solid foods and gagged frequently during mealtimes or even in the presence of food. In a report documenting 4 cases of Barth in the Czech Republic, feeding problems were present in 3 of the boys at the time of their initial referral at 3 to 4 months of age.3 Data from the Barth Syndrome Registry suggest that approximately a third of boys with Barth require a nasogastric or gastrostomy tube for feeding at some point.4 These feeding problems have the potential to contribute not only to growth delay and muscle weakness, but also may add to family stress, with parents concerned about their child’s nutritional intake and troublesome mealtime behaviors.   Unfortunately, feeding problems and mealtime behaviors in boys with Barth syndrome do not appear to resolve atier infancy. In a study published in 2012, our team used qualitative methods to examine feeding issues in boys with Barth aged 4 to 17 years.5 These boys were reported to have a restricted repertoire of foods they would eat, with many continuing to exhibit an abnormally sensitive gag reflex. Interestingly, boys with Barth were also identified as having very strong taste preferences, with most boys preferring foods that were very salty, cheesy, or spicy. The study concluded that atypical taste/smell and tactile sensitivities may heavily contribute to feeding problems in the Barth population, and that this was an area in need of further research.   The purpose of the present study was to (1) quantify and compare the presence of atypical feeding behaviors in boys with and without Barth syndrome, (2) quantify and compare chemical taste perception and other sensory sensitivities in boys with and without Barth, and (3) examine the relationship between problematic feeding behaviors, taste perception, and sensory sensitivities in boys with Barth. Our primary hypothesis was that boys with Barth would be more likely to be classified as “supertasters” with regard to bitter chemical taste sensitivity, and secondly, that taste perception would influence food refusal and food selectivity. Taster Perception and Food Selection Taste perception is based on the chemical sensitivity of receptors located on the tongue; genetic variation in taste‐receptor sensitivity generates unique perceptions of certain tastes.6 It has been shown that, at least to some extent, taste perception influences food preferences and, along with environmental influences, may contribute to dietary choices.6,7 The most well‐ studied chemical taste receptor gene is TAS2R38, which encodes for bitter receptors detecting the thiourea compounds phenyltiocarbamide (PTC) and 6‐n‐ propylthiouracil (PROP). While there is a natural range in which these bitter compounds are detected, individuals who perceive PTC/PROP to be intensely bitter have sometimes been termed “supertasters.”8 Over the past 2 decades, research has suggested that individuals who have a higher sensitivity for these bitter compounds may report less liking of vegetables and consume fewer vegetables overall 7,9,10; they also may consume less fruits compared with low‐sensitivity tasters.11 Alternatively,

nontasters, those who least taste the bitterness in PROP, have reported consuming more alcohol and have a greater preference for high‐fat and sweet foods.12   Markedly less studied than bitter taste, salty‐taste perception has been examined and found to have a relationship to perception of bitter tastes. Perceived bitterness of PROP has been associated with a higher perceived intensity of aqueous salt samples13 and perceived saltiness in foods.14 PROP supertasters, in one study, were shown to be most sensitive to sodium changes in chicken broth, and disliked broths with the highest sodium concentraTIon.14 While PROP supertasters did show frequent high‐sodium food intake, researchers suggested that in the contemporary salt‐rich American diet, supertasters may find foods to be sufficiently salty, while nontasters may seek to increase the stimulus intensity to achieve desired levels of saltiness.  Given the potential influence of taster status (eg, supertaster vs nontaster) on dietary food choices, these phenotypic behaviors may be important to consider with relation to Barth syndrome, particularly in light of dietary influences on cardiac function, energy consumption, and immunologic functions.   Sensory Sensitivities and Feeding Behaviors In populations with childhood genetic disorders, no studies to date have correlated sensory sensitivity with problematic feeding behaviors, such as food selectivity. However, studies on typical children have associated selective eating with sensory sensitivity in tactile and taste/smell domains. In a study by Farrow and Coulthard,15  taste/smell and tactile sensitivities were associated with a child’s lower consumption of fruits and vegetables, and with higher food neophobia.16 Our previous research found that ~50% of children with Barth syndrome had a probable or definite difference in taste/ smell sensiTIvity.5 Therefore, taste/smell sensitivity could account for the food selectivity seen in this population.

METHODS

Design

A cross-sectional, descriptive, 2‐group comparison design was used. All procedures were approved by the universities’ internal review boards prior to subject recruitment. Consent and assent procedures    were completed for all participants. 

Subjects

Twenty‐five males with a diagnosis of Barth syndrome between the ages of 3 and 17 years were recruited at the Barth Syndrome Foundation Conference held in St. Petersburg, Florida, in June 2012.  A convenience sample of 25 typical boys ages 3 to 17 years with no known medical (eg, heart condition, cancer), genetic (eg, fragile X or Angelman syndrome) or psychological diagnoses (eg, autism, bipolar) were recruited from community centers, schools, and youth groups in an urban university setting. All boys and their caregivers demonstrated the proficiency in English needed to follow instructions and complete written forms.

Tools

Food Inventory  

Parents of boys with Barth syndrome and control subjects were asked to complete a 4‐part food inventory questionnaire. The first section asked questions about unusual or problem behaviors associated with food intake or food preference. In response to each behavior or symptom listed, parents responded “yes” or “no”; if parents responded “yes,” they were asked to write details about the behavior, including age of onset. The second section of the questionnaire asked parents to provide information about the frequency that specific foods were eaten by the child and if those foods were eaten by the family. Drinking and meal patterns were queried in the third section, which included questions such as “Does your child often complain of being thirsty?”, “Do your child’s food habits match the family’s?”, and “How would you describe your child’s appetite?” Similar to the first section, parents were asked to provide written details about unusual behaviors. In the fourth section, parents were asked to complete a checklist about whether or not the child was able to eat specific food consistencies (eg, smooth or creamy foods, chewy foods); response options included that the child “can eat” the food, “won’t eat” the food, or “has never tried” the food.   

Evaluation of Taste Perception

To measure taster perception, subjects were asked to rate responsiveness to PTC and sodium benzoate (NaB, a salty compound) using standardized test strips (Indigo Instruments, Tonawanda, NY). All boys with Barth were tested over a period of 3 days at the Barth Syndrome Foundation Conference. Boys were accompanied by parents to a conference room in the hotel and completed all testing procedures with minimal distractions. Testing of control boys was conducted at a location convenient for families, which included the family home, the child’s school, or a community center. In all cases, researchers attempted to limit outside distractions during taste testing.   The taste‐test protocol was administered in the same way to both Barth and control groups. Procedures for the taste test were first explained to the child and family, and questions were answered. Procedures began by asking the children to rinse their mouth with room‐temperature water and spit the water into a disposable cup. Next, the PTC strip was placed lengthwise onto the child’s tongue; the child was then asked to close his mouth and let the strip rest on his tongue for 10 seconds. After removing the strip, the child was asked to rate the taste by pointing his finger along a visual analog scale ranging from “no taste” to “intensely bitter or revolting.” Subjects then repeated the water‐rinsing procedure at least one time, or until they reported no aftertastes of the test strip. The entire taste‐test procedure was repeated for the NaB test strips. Taste test answers were marked on the visual analog scale and were later converted to a scale score ranging from 1 to 5, using an overlay sheet with the numeric scale. Children with scores ranging from 1 to 1.5 were categorized as nontasters, scores of 1.6 to 4.4 were categorized as moderate tasters, and scores of 4.5 to 5 were categorized as supertasters.   Short Sensory Profile The Short Sensory Profile (SSP) is a 38‐item questionnaire that examines a child’s behavioral reactions to various sensory situations found in everyday life.17 Parents completed the SSP for all participants, ranking each behavior on a frequency scale ranging from “always” (child always responds in this manner) to “never” (child never responds in this manner). For the purposes of this study, only section scores related to taste/smell sensitivity and tactile sensitivity were included, as these were the sections most relevant to feeding. For each section, the child’s raw score was recorded and then classified into 1 of 3 categories: typical performance (at or above 1 standard deviation [SD] below the mean), probable difference (between 1 and 2 SDs below the mean), and definite difference (more than 2 SDs below the mean).   

Statistical Analysis

All data were entered into the SPSS 21 statistical analysis program. The first 2 study objectives involved comparison of boys with and without Barth syndrome. Descriptive statistics were initially run for both groups. Pearson  χ2 tests were used to compare boys with and without Barth for all categorical dependent variables (food inventory, taste perception, taste status). A one‐ way analysis of variance was conducted to compare mean scores (continuous raw scores) on the SSP for boys with and without Barth. Parental written responses from the food inventory were transcribed into a separate word processing document; specific trends (eg, number of times gag reported) were counted and are reported as descriptive data. The third objective of the study was to test whether taste perception and/or behavioral report of taste/smell sensitivity are related to the presence of atypical food behaviors in boys with Barth syndrome. A Pearson  Χ2 test was used to examine the relationship between taster status (nontaster, moderate taster, and supertaster) and the presence of salient problem behaviors. A similar analysis was run to examine the relationship between categories of taste/smell performance (typical, probable difference, and definite difference) and the presence of salient problem behaviors. The alpha level for all statistical tests was set at 0.05.

RESULTS

Sample Characteristics

Of the 25 boys with Barth syndrome recruited for this study, only one child (a 3‐year‐old) was unable to complete the protocol. The remaining 24 boys in the Barth sample ranged in age from 4 to 17 years with a mean (SD) age of 9.92 (4.3) years. Owing to an aggressive sample strategy, data were collected on 26 typical boys instead of the targeted 25. Because our target N was 50 for the study, it was decided that all data would be included in the final analysis. Boys in the typical sample ranged in age from 5 to 17 years, with a mean age of 11.7 (3.6) years. Although the mean age for the Barth sample was lower than that of the control group, these differences were not significant (P = .106). Of the boys in the Barth group, 28% were born prematurely, compared with only 3.8% of boys in the control group. Food allergies were more common in the control group, as were seasonal allergies. Presence of attention deficit hyperactivity disorder (ADHD), learning disabilities, and asthma were similar between groups. A full description of group characteristics can be found in Table 1.  

Food Behaviors and Preferences

A 2×2 Pearson  χ2 test of independence was used to examine the relationship between Barth syndrome and behaviors listed on the food inventory. The grouping variable was diagnostic group (Barth, control), and the outcome variable was presence of feeding behavior (yes, no). The relationship between all examined variables was significant (Table 2).  

Very few children in the control population were noted to have problem behaviors related to feeding or eating.

Table 1. Participants Diagnostics Characteristics (N  =  24)

Never, % Previous, % Current, %
Barth Control Barth Control Barth Control
ADHD87.580.8 – 12.519.2
Learning disability95.8100 –  – 4.2
Asthma95.892.3 –  – 4.27.7
Food allergies95.880 –  – 4.220
Seasonal allergies70.865.48.3 – 20.834.6
Diabetes95.8100 –  – 4.2 – 
Hearing impairment95.71004.3 –  –  – 
Reflux87.596.24.23.88.3 – 
Nasogastric intubation66.710033.30 – 
Nasal cannula87.510012.50 – 
Gastrostomy tube95.81004.20 – 

Three respondents noted that their typical child refused to eat fish, while 2 reported that their child would not eat mashed potatoes. One child in the control group was noted to have a strong aversion to green vegetables, while another had a strong preference for cereal and pasta. Only one 5‐ year‐old child in the control group was noted to have problems with dysphagia (ie, problems swallowing and gagging in response to food), whereby the child would immediately cough and spit out any food he didn’t like. In contrast, dysphagia was the most prevalent behavior noted in the Barth population (70.8 %). Eight caregivers reported that these problems were present at birth or during early infancy. While 12 of the 17 caregivers indicated problems with hypersensitive gag (elicited by actual foods and food smells), 3 respondents noted problems with the actual mechanisms of swallowing. Half of the Barth population (50%) were also reported to engage in food refusal behaviors, defined as refusing all or most food. Of the 12 caregivers, 7 noted that food refusal started at birth or during infancy. Two caregivers noted that their child outgrew this behavior; one family noted the behavior improved with time. Selectivity based on food type (eating only a narrow variety of foods) also began for most boys with Barth syndrome in infancy around the time they began to eat solid foods. Of the 13 boys with Barth (54.2%) who were reported to have food selectivity by type, 4 were identified as having a strong preference for salty foods and 3 were reported to strongly prefer cheese or dairy items. Food selectivity by texture was defined as only certain textures or refusing to eat certain textures. Nine respondents noted that problems tolerating food textures started at birth or when their child was first introduced to solid food. When more specific information was gathered about aversion to food textures, parents identified mashed table foods (eg, mashed potatoes) and soups with pieces of meat or vegetables as the foods their children with Barth wouldn’t eat or have never tried (Table 3).

Unusual food preferences and behaviors were also present in about a third of the Barth sample. Unusual food preferences was defined as eating only certain brands of foods, refusing to eat a preferred food if it was not a specific temperature, or needing a certain cup or preferred utensil to eat. Unusual feeding behaviors were defined as other behaviors or attitudes regarding eating or drinking that the parent or caregiver believed were atypical. Only 4 families provided a written response for these items. Two families noted temperature preferences, with one of these families indicating that their child was very specific about the temperature of his bottle. One additional family reported that their child required the use of separate utensils for each food eaten during the meal, and foods could not touch on the plate. Two respondents noted that their child ate very small meals or “grazed” throughout the day as opposed to eating at mealtimes. This is commensurate with the finding that nearly a quarter of boys with Barth (23.8%) in our sample have a small appetite.   When asked about whether their child’s food habits and preferences matched the family’s, more than half of Barth families (56.5%) reported “no.” Similarly, about half of Barth families acknowledged that it was common for caregivers to prepare a separate meal for their child because he would not eat the family meal.  

Table 2. Food Behaviors and χ2 Analysis

Barth, % yesControl, % yesχ2 Value df (n = ) P Value
Food refusal 5015.46.8721 (50) .009 *
Selectivity by texture 5015.46.8721 (50) .009*
Selectivity by type 54.211.510.4221 (50) .001*
Dysphagia or gag 70.83.824.0361 (50) <.001*
Unusual food preferences 37.53.88.8341 (50) .003*
Unusual food behaviors 33.37.75.1281 (50) .024*
Complain of being thirsty 30.409.232 1 (49) .002*
Poor appetite 23.83.84.1571 (50) .041*
Eating habits match the family43.584.69.115 1 (50) .003*
Requires separate meals 58.323.16.464 1 (50) .011*

EVALUATION OF PLASMA SUBSTANCE P AND BETA‐ENDORPHIN LEVELS IN CHILDREN WITH PRADER‐WILLI SYNDROME M.G. Butler, MD, PhD1, T. A. Nelson, BS1, D.J. Driscoll, MD, PhD2, A.M. Manzardo, PhD11

Departments of Psychiatry & Behavioral Sciences and Pediatrics, University of Kansas Medical Center, Kansas City, KS, USA 2 Department of Pediatrics and Center for Epigenetics, University of Florida Medical Center, Gainesville, FL, USA

ABSTRACT

Background: Prader‐Willi syndrome (PWS) is a rare obesity‐related genetic disorder often caused by a deletion of the chromosome 15q11‐q13 region inherited from the father or by maternal disomy 15. Growth hormone deficiency with short stature, hypogonadism, cognitive and behavioral problems, analgesia, decreased gastric motility and decreased ability to vomit with hyperphagia are common in PWS leading to severe obesity in early childhood, if not controlled. Substance P (SP) and beta‐endorphin (BE) are neuropepTIdes involved with centrally and peripherally mediated pain perception, emotional regulation, and gastric motility impacting nausea, emesis and feeding patterns.   

Objective:  The goal of this study was to investigate potential mechanisms for PWS symptom development for pain, emotion and gastric motility and plasma levels of substance P and beta‐endorphin between PWS and unrelated unaffected children.  

Methodology: Plasma samples were collected from 23 Caucasian children with PWS and 18 unrelated, unaffected siblings with an average age of 8.2 ±2.0 years and age range of 5 to 11 years following an overnight fast and neuropeptide substance P and beta‐endorphin levels were assessed using Multiplex sandwich immunoassays using the Luminex magnetic‐bead based plaƞorm. Linear regression analysis was carried out on log‐transformed values adjusted for age, sex, and body mass index (BMI).   Results: The mean plasma SP (57 ± 23 pg/ml) and BE (592 ± 200 pg/ml) levels in PWS were significantly higher than SP (35 ± 20 pg/ml, F=10.5, P<0.01) and BE (402 ± 162 pg/ml, F=10.8, P<0.01) levels found in unrelated, unaffected siblings suggesting a previously uncharacterized neuroendocrine pathophysiology in PWS.   Conclusions: The increased BE and SP plasma levels relative to unrelated, unaffected siblings may contribute to hyperphagia, abnormal pain sensation and adrenal insufficiency seen in PWS. Increases in SP levels may be modulated by central and/or peripheral actions of BE on opioid, GABA or POMC precursors and may reflect loss of feedback inhibitory control. Further studies are needed to confirm and elucidate the biochemical basis for observed disturbances in neuropeptide levels seen in our study and may impact on the development and persistence of symptoms commonly seen in PWS. 

INTRODUCTION

Prader‐Willi syndrome (PWS) is a rare disorder due to errors in genomic imprinting most often from a de novo paternal chromosome 15q11‐q13 deletion seen in about 70% of cases, maternal disomy 15 (both 15s from the mother) in about 25% of cases or a small percentage of cases caused by imprinting defects. An initial finding in PWS is decreased fetal activity followed by severe infantile hypotonia1,2 with most babies exhibiting feeding difficulties with diminished swallowing and sucking reflexes. These symptoms resolve slowly in early childhood with the development of overeating and hyperphagia leading to severe obesity and corresponding comorbidities, if not controlled. Other symptoms of PWS include hypogenitalism/hypogonadism; cognitive im‐ pairment (average IQ of 65); temper tantrums, obsessive compulsive disorder, and skin picking; abnormal temperature regulation; analgesia; decreased gastric motility and growth hormone deficiency leading to short stature and small hands and feet.1,3 Central adrenal insufficiency is also reported in about 10% of cases.4 Enamel hypoplasia and dry, sticky saliva are common. PWS occurs in about 1 in 10,000 live births.1 While PWS was first described by Prader et al. in 19565, the mechanism(s) of symptom development and persistence have not yet been elucidated fully. Although dozens of genes have been localized to the 15q11‐q13 region, the definitive genetic disturbances and causative pathophysiology in this rare obesity‐related disorder have escaped characterization. In addition, there is a paucity of laboratory evaluations of neuro‐related peptides that may contribute to PWS.   Beta‐endorphin (BE) is a 31 amino acid peptide which is primarily synthesized and stored in the anterior pituitary gland. It is one of ten pepTIdes produced from processing of proopiomelanocorTIn (POMC) by prohormone convertases.6 Additional products of POMC are adrenocorticotropic hormone (ACTH);    N‐terminal peptide of proopiomelanocorTIn (pro‐γ‐MSH);  α‐,  β‐, and  γ‐ melanotropin; corticotrophin‐like intermediate peptide; β‐  and γ‐lipotropin; and [Met]‐enkephalin. Mutations of the POMC gene which is located on chromosome 2 are associated with onset of early childhood obesity, adrenal insufficiency, and changes in pigmentation (e.g., red hair); all of which can be seen in PWS.7 BE is stored in the hypothalamus and anterior pituitary gland and released in response to corTIcotropin releasing hormone secreTIon aFTer stress. Gene expression studies from human lymphoblast cells from PWS subjects and whole brain specimens from a PWS mouse model show POMC gene disturbances (e.g., 34 fold increase in the PWS mouse model compared to normal littermates).8,9    BE functions as an opioid receptor agonist producing strong analgesic effects, also a common finding in PWS and acts on the central nervous system (CNS) to produce overeating in rats.10 Substance P (SP), an 11 amino acid peptide derived from the preprotachykinin‐A gene and secreted by enterochromaffin cells, is a member of the tachykinin neuropeptide family.   It functions as a neurotransmitter and neuromodulator.11 This neuropeptide is associated with a variety of effects including neurogenic inflammation, stimulation of cell growth, vasodilation, pain perception, gastric motility and regulation of mood disorders, stress, anxiety, reinforcement, respiratory rhythm and nausea/emesis. It also plays a role in neurotoxicity and neurogenesis,12‐16 many of these features are present in PWS.    In addition, exposure of mouse adipocytes to SP can produce altered regulation in adiposity and adipocytokine profiles.   SP is also thought to function in transmission of pain signals with elevated levels associated with hyperalgesia. Therefore, a goal for this study was to explore whether substance P and beta‐ endorphin, both neuropeptides that modulate adiposity and function with complementary effects on pain perception, may contribute to the constellation of symptoms seen in PWS by comparing plasma levels in a cohort of PWS and control children.

METHODS

Subjects

Twenty‐three American Caucasian children (13 males, 10 females) were diagnosed with PWS and confirmed by genetic testing with 15 having a paternal chromosome 15q11 –q13 deletion and 8 showing maternal uniparental disomy 15 with an average age of 8.2 ± 2.0 years and age range of 5 to 11 years. Eighteen American Caucasian children and 18 (10 males, 8 females) were unaffected, unrelated siblings having an average age of 8.2 ± 2.3 years within an age range of 5 to 11 years.    These children were recruited from a large, ongoing, mutiI‐site rare disease consortium on PWS.    Consent forms were approved by the local Human Subjects CommiƩee and signed.    All children with PWS were receiving growth hormone, but were otherwise healthy. On an average less than ten percent of individuals with PWS present with adrenal gland insufficiency4 or thyroid problems.17 Peripheral blood was collected in anTI‐coagulant EDTA tubes in the morning following a supervised overnight fast and plasma separated immediately then stored at  ‐ 80°C until used. Height (cm) and weight (kg) were also rouTInely obtained on each subject and body mass index (BMI) calculated using a wall mounted stadiometer and calibrated electronic weight balance, respectively, in the clinical seƫng.  The average BMI ± SD for the 23 children diagnosed with PWS was 20.7 ± 5.0 while the average BMI ± SD for the 18 unaffected, unrelated siblings was 18.2 ± 2.3. AddiTIonal information including PWS genetic subtype, age, gender, weight, height, BMI and BMI‐z score and total body fat percentage by dual‐energy x‐ray absorptiometry in relationship to selected plasma chemokine levels on each participant within this study cohort have previously been reported.18 Demographic, subject description and neuropeptide data are shown in Table 1.  

BETA‐ENDORPHIN AND SUBSTANCE P ASSAYS BE and SP levels were determined from plasma samples using the Milliplex Human Neuropeptide Kit (Millipore; Billerica, MA) and multiplex sandwich immunoassays following established protocols.19 Blood plasma (25ul) combined with Milliplex quality control standards were mixed with assay buffer and pre‐mixed antibody‐coupled magneTIc beads followed by overnight incubation at 4°C. Incubation was carried out using a micro‐titer plate shaker at 300 RPM.    The biological samples were then washed on the following day and incubated for 1 hour at room temperature in the presence of secondary detecTIon anTIbodies. Another series of washes were carried out then followed by the addition of a fluorescent Streptavidin‐Phycoerythrin detecTIon soluTIon. The enTIre mixture was incubated at room temperature for 30 minutes. Each sample was run in duplicate. The plate was then read on the Luminex 200TM instrument (Luminex Molecular Diagnostic; Toronto, ON) based on magnetic‐ bead technology aFTer sheath fluid was added to each sample then incubated.    The level of magnetic field separates the beads. BE and SP levels were analyzed in both PWS and control plasma specimens using the Luminex 200TM v2.3 software with indicated minimal detectable concentration levels in pg/ml for each analyze. Plasma BE and SP concentrations were calculated using a standard curve derived from the reference BE and SP concentration standards supplied by the manufacturer. The inter‐assay coefficient of variation for both BE and SP was < 20% and the intra‐assay coefficient of variation was < 15%.    Plasma samples were analyzed using numbers and blinded as to gender and control versus PWS status during each assay run.   

STATISTICAL ANALYSIS

Data were presented as mean ± standard deviation for raw and/or log‐transformed BE and SP levels by diagnosis (PWS or unrelated siblings), gender and PWS subtype. Pearson correlation and one‐way analysis of variance (ANOVA) was used to test for significant differences in age, gender, BMI and diagnosis using log‐transformed BE and SP levels (Table 1). Final linear regression analysis with Bonferroni correcTIon was controlled for the effects of age, gender and BMI.    Laboratory data falling below the detection limits were replaced with values at one half of the minimum detection level for the respective neuropeptide as reported in previous studies.19‐21 Log‐ transformed data met the necessary statistical criteria for assumption of normality by showing equal variance and near linear residual plots. Findings with p‐values of <0.05 were considered significant. Statistical analyses including descriptive statistics were generated using SAS statistical analysis software version 9.4 (SAS Inc., Cary, NC).   

RESULTS

There was no significant difference in age, or BMI between PWS and unaffected, unrelated sibling groups (Table 1). There was also no significant difference in SP or BE levels between male and female subjects or between PWS deletion or uniparental maternal disomy 15 genetic subtypes (Table 1) or relevant correlations between plasma SP or BE levels with age, sex or body fat content. Plasma SP levels were significantly higher in PWS children (mean = 57.0 pg/ml) compared with unaffected, unrelated siblings (mean = 34.8 pg/ml) for log‐transformed SP levels controlled for age, sex and BMI (F=4.3, P<0.01, Figure 1).   The range of SP plasma levels in children with PWS was 8‐ 95 pg/ml and 8‐83 pg/ml for unaffected, unrelated siblings. Plasma BE levels were also significantly higher in PWS children (mean = 592 pg/ml) compared with unaffected, unrelated siblings (mean = 402 pg/ml) for log‐ transformed BE levels controlled for age, sex and BMI (F=6.5, P<0.001, Figure 2).  The range of plasma BE levels in PWS children was 261‐998 pg/ml and 188‐705 pg/ml in the unaffected, unrelated siblings. Mean plasma BE levels were also determined for PWS genetic subtypes and subject subgroups with data shown in Figure 2. Box and whisker plot of log transformed plasma BE and SP levels are shown in Figure 3.   

Table 1: Summary of Substance P and Beta-endorphin Levels

Prader‐Willi syndrome (n = 23)Unrelated Siblings (n = 18)F‐value P‐value
Age (yrs) 8.2 ± 2.08.2 ± 2.3 0.010.92
BMI (kg/m2) 20.7 ± 5.0 18.2 ± 3.3 3.10.08
Substance P (pg/ml) 57.0 ± 23.1 34.8 ± 20.0 10.5< 0.01
Beta-endorphin (pg/ml) 592 ± 200 402 ± 162 10.8< 0.01
Male (N=23) Female (N=18)
Substance P (pg/ml) 47.8 ± 24.7 46.5 ± 24.40.030.86
Beta-endorphin (pg/ml) 495 ± 197 526 ± 221 0.20.64
Deletion (N=15) UPD (N=8)
Substance P (pg/ml) 52.5 ± 24.1 65.6 ± 19.91.70.2
Beta-endorphin (pg/ml) 555 ± 199 662 ± 197 1.50.23

Analysis carried out using uncontrolled analysis of variance by diagnostic subgroup, gender or PWS genetic subtype.

UPD=uniparental maternal disomy 15

DISCUSSION   

Children with PWS presented with statistically significant elevations in morning fasting plasma levels in both BE and SP compared to age and gender matched unaffected, unrelated siblings. Notable overlap exists between the actions of BE and SP and common features seen in PWS including increased pain threshold, hyperphagia (over‐eating) and decreased gastric motility which may reflect a mechanism for pathogenicity observed in PWS. We focus our discussion on the complex regulatory interplay between BE and SP associated neuroendocrine pathways and their possible link to selective features seen in PWS. Disturbances to POMC Influencing BE Prohormone convertase enzymes function in the processing of POMC to yield BE and nine other proteins and precursor molecules. Disturbances in prohormone convertase enzyme function and subsequent disruptions in POMC gene expression may produce abnormal levels of proteins, which can result in phenotypically detectable symptoms. In 1994, Gabreël et al.22 described a subset of patients with PWS possessing altered immunoreactivity of pituitary polypeptide 7B2 [also called secretory granule neuroendocrine protein 1 (SGNE1)], a neuroendocrine chaperone that interacts with prohormone convertase 2 and is encoded on the human chromosome region 15q13 ‐q14, distal to the PWS 15q11‐q13 chromosome region.23 In those patients, the function of polypeptide 7B2 in the supraoptic nucleus and paraventricular nucleus was severely depressed or completely eliminated.22 A follow‐ up study confirmed that patients with PWS lacking polypeptide 7B2 immunoreactivity possessed slightly diminished prohormone convertase 1 immunoreactivity and demonstrated no prohormone convertase immunoreacTIvity.24    Thus, at least a portion of patients with PWS are susceptible to changes in POMC levels and function, which could disturb BE levels. While polypeptide 7B2 mutations are unlikely to explain entirely the development and persistence of the symptoms seen in PWS, prior studies have shown associations between POMC disturbances and phenotypic manifestations common to PWS, such as early‐onset obesity, adrenal insufficiency, and light pigmentaTIon.25‐28 In addition, Bittel et al.8 reported elevations in POMC gene expression in whole brain specimens of the PWS imprinting center deletion neonatal mice indicating an important genetic factor for survival of these mice.  This may affect eating behavior regulating energy homeostasis. Also, POMC knockout mice have also been shown to develop obesity.  Analgesia BE is present in CNS neurons and in the peripheral nervous system, where it acts as an opioid receptor agonist.10 In the peripheral nervous system, BE binds to pre‐  and post‐synaptic nerve terminals of the primary afferent neurons, peripheral sensory nerve fibers, and dorsal root ganglia; attachment to pre‐synaptic terminals is more common than post‐synapTIc.29 Binding of BE to opioid receptors in the peripheral nervous system leads to a reduction of SP levels.29,30 SP coexists with glutamate in primary afferents that respond to painful stimuli and is thought to participate in the transmission of pain signals to the CNS.13,31 Therefore, decreased SP levels following BE binding to opioid receptors may produce an analgesic state as SP, in contrast to BE, functions to enhance pain sensation. Indeed, mice lacking the neurokinin 1 receptor [NK1R or tachykinin receptor 1 (TACR1)] for SP demonstrated statistically significant decreases in hot‐plate latency (45% reduction) and tail‐flick latency (70% reduction) following cold water swims, which produces a non‐ opiate, NMDA‐dependent analgesia.13    Conversely, elevated levels of SP should be associated with increased pain perception, i.e. hyperalgesia, in patients with PWS. In our PWS cohort, there was significant elevation of SP coupled with a history of decreased pain sensation or analgesia common in PWS indicating a potential loss of SP function in the CNS.   In the CNS, BE binds to opioid receptors at the pre‐ and post‐synaptic nerve terminals of the amygdala, rostral ventral medulla, periaqueductal gray matter, and mesencephalic reticular formation; like in the peripheral nervous system, pre‐synaptic binding predominates.32 Instead of reducing SP levels, the binding of BE to CNS receptors leads to inhibition of GABA release, which causes excess production of dopamine and downstream analgesia.32   The antinociceptive effect of BE in the CNS was first tested by Loh et al.33, whose team injected 1 µl of BE into rats and 5 µl of BE into mice intracerebral. The results of BE injection were a two‐fold increase in latency to the hot‐plate and tail‐flick response tests in mice; elimination of writing response following intraperitoneal acetic acid injection for as little as 25 minutes in mice; and significant decrease in shaking response following cold water immersion in rats.33    Quantification of BE potency has shown that its analgesic effect is 18‐33  times stronger than morphine33 suggesting that persistently elevated BE levels in PWS might contribute to lack of pain perception. Simultaneous elevation of SP and BE levels may indicate a complex interaction and potential disruption of neuropeptide function in PWS, specifically the role of these neuropeptides in determining the levels of analgesia. However, our study did not contain measures on pain threshold in the study participants to permit correlation analysis with plasma neuropeptide levels but decreased pain sensation is a common finding in PWS.34 Obesity Studies on both neuropeptides (BE and SP) have been associated with abnormal regulation of adiposity or overeating in animal models. The effects of SP on preadipocytes and mature adipocytes in mouse cells tested by Miegueu et al.35 and when treated with SP demonstrated decreased fatty acid uptake and storage; increased lipolysis; significantly reduced expression of differentiation‐related transcription factors peroxisome proliferator‐activated receptor gamma – 2 (PPARγ2) and CCAAT/enhancer binding protein, alpha (CEBPα) as well as fatty acid binding protein 4 (FABP4) and diacylglycerol O‐acyltransferase‐1.   Significantly elevated CD36 (thrombospondin receptor) expression, increased secretion of complement component C3, monocyte chemoattractant protein‐1 (MCP‐1), and keratinocyte‐derived chemokine, and downregulation of insulin receptor substrate‐1, insulin responsive glucose transporter (SLC2A4), adiponectin mRNA expression, and insulin‐mediated action were also noted.34 Observed alterations to transcription factors led to exploration into the effects of SP on preadipocyte differentiation, which was decreased by SP exposure.35 In our children with PWS, abnormal elevations of SP were detected that may have contributed to dysregulaTIon of adiposity, although further experiments would be required to determine if their adipocytokine profiles match those detected by Miegueu et al.35   BE levels may also be involved in the development and persistence of obese states. For example, genetically obese (ob/ob) mice showed a 14‐fold elevation in corticotropin levels reported by Edwardson and Hough.36   Beloff‐Chain et al.37 also detected an increase in corticotropin‐like intermediate peptide levels. Elevations in both corticotropin and corTIcotropin‐like intermediate peptide are significant as both neuropeptides share a common precursor with BE. Corticotropin and BE are both released concomitantly in vivo and in vitro from rat pituitary glands, but the synthesis and/or degeneration of these neuropeptides may be uncoupled.6,38 Functionally, injection of BE into the rat brain is associated with overeaTIng39 and conversely, administration of naloxone, an opiate antagonist, in ob/ob mice and fa/fa rats yielded a significant reduction of food intake without affecting lean littermates.    The pituitaries of the obese mice contained twice as much BE as well.38 Therefore, elevated BE levels in PWS exaggerate neuropeptide effects contributing to overeating. Although hyperphagia is a cardinal feature in PWS, our study did not include hyperphagia measurement data such as diet records or PWS nutritional phases40 to judge the level of overeating or hyperphagia in relationship to the neuropepTIde levels in the PWS children.     Adrenal Insufficiency Regulation of the hypothalamic corticotropin releasing hormone neurons in rats was tested in 1988 by Calogero et al.41 parTIcularly the effects of corticotropin releasing hormone, glucocorticoids, and products of POMC processing – corticotropin, BE,  α‐melanocyte‐stimulating hormone, corticotropin‐like intermediate peptide, β‐lipotropin, and dexamethasone.    POMC products generate inhibitory effects on corticotropin, dexamethasone and BE,  α‐ melanocyte‐stimulating hormone, and corticotropin‐like intermediate peptide with BE as the strongest inhibitor of the three.41 The results of the Calogero et al. study implied the existence of several complicated negative feedback loops indicating the potential effect that elevated BE levels may have on adrenal function in individuals with PWS. A limitation of our study included the lack of information about the adrenal insufficiency status in each individual PWS child in our cohort and comparison with individual neuropeptide levels. However, an average of only 10 percent of children with PWS are reported to have adrenal insufficiency.

CONCLUSIONS

BE and SP act in complicated facilitatory and inhibitory pathways, sometimes antagonistically, and may contribute to common features seen in PWS, particularly obesity/overeating, abnormal pain sensation, and adrenal insufficiency. However, a limitation of our study included the lack of markers for hyperphagia, pain sensation and adrenal insufficiency with the prior two features considered common in individuals with PWS. Experiments on mouse adipocytes demonstrated that persistent SP exposure can produce altered regulation of adiposity and adipocytokine profiles, whereas BE can act in the CNS to produce overeating in rats; blocking opiate receptors with naloxone significantly reduced food intake in obese mice and rats. SP is also thought to function in transmission of pain signals, and elevated levels may be associated with hyperalgesia. Conversely, BE binding to opioid receptors in the peripheral nervous system leads to reduced SP levels, decreasing pain perception; centrally, BE binding causes a reduction of GABA release that produces analgesia. Lastly, disturbances to POMC, the precursor molecule to BE, are associated with early‐ onset obesity, light pigmentation, and adrenal insufficiency; high levels of BE found in PWS children in our study compared with unaffected, unrelated siblings may produce feedback inhibition of serotonin‐stimulated release of corticotropin  releasing hormone. Hence, children with PWS in our study presented with significantly elevated plasma levels of BE and SP compared to age and gender matched unaffected, unrelated siblings. Elevations of BE levels may be partly explained by the work of Gabreël et al.22,24, who found that altered 7B2 immunoreactivity in a group of patients with PWS was associated with reduced or eliminated prohormone convertase 2 function, but this is unlikely to encompass all patients with PWS and supported by POMC gene expression in human PWS subjects and PWS mouse models.8,9    A paradoxical elevation of SP also complicates interpretation of the role of these neuropeptides in PWS pathophysiology. While more work must be done to determine if BE and SP are functioning properly in the central and peripheral nervous system, the functions of BE coalesce with the constellation of symptoms often seen in PWS, particularly in decreasing pain perception, producing overeating, and inhibiting release of corticotropin releasing hormone. If SP is involved in PWS symptom development, it may be in modifying adipocytokine profiles, but SP otherwise seems unable to function properly in the central nervous system of PWS. Our study describes a preliminary approach to examine differences in plasma neuropeptide levels in children with and without PWS, future studies should include objective measures of hyperphagia, pain sensation and adrenal insufficiency in relationship to the plasma concentration levels for these neuropeptides.

CONFLICT OF INTEREST

None of the authors have any commercial or other associations that might pose a conflict in connection with the submitted manuscript. FUNDING Partial funding support was received from the Angelman, Reft and Prader‐Willi Syndrome Consortium (U54 HD06122) which is a part of the National Institute of health (NIH) Rare Disease Clinical Research Network (RDCRN) supported through collaboration between the NIH Office of Rare Disease Research (ORDR) at the National Center of Advancing Translational Science (NCATS) and the National Institute of Child Health and Human Development (NICHD).    NICHD grant number HD02528 is also acknowledged. The content is solely the responsibility of the authors and does not necessarily represent the office views of the National Institutes of Health.

ACKNOWLEDGEMENTS

We thank Carla Meister for preparation of the manuscript and Carlos Sulsona for technical assistance.

CochraneCorner     

Enzyme Replacement Therapy for Anderson‐Fabry Disease* Regina P. El Dib, PhD1; Paulo Nascimento, MD, PhD2; and Gregory M. Pastores, MD3, Botucatu Medical School, Universidade Estadual Paulista, Botucatu, Brazil; 2 Anesthesiology Department, Botucatu Medical School, Universidade Estadual Paulista, Botucatu, Brazil; and 3 Neurogentics Laboratory, New York University School of Medicine, New York, New York

*Published in the Cochrane Database of Systematic Reviews. 2013;(2):CD006663. doi:

 

Anderson‐Fabry disease (AFD) is an X‐linked recessive multisystemic disorder caused by a deficiency of the lysosomal enzyme alpha–galactosidase A (AGAL). The incidence of AFD is estimated to be 1 in 117,000 live births for males1; however, recent newborn screening surveys suggest that the incidence may be much higher, up to 1 in 3100.2 Although most reports have focused on symptomatic male patients, females with AFD can develop disease‐related problems.3 Clinically, AFD is characterized by major renal, cardiac, and cere‐brovascular complications consequent to the progressive deposition of an incompletely metabolized substrate, globotriaosylceramide (Gb3), in multiple cell types, and by the attendant mechanisms of TIssue injury that remain to be more fully defined. Renal and cardiac failure are prominent sources of morbidity and likely account for the reduced survival among affected males and females (in whom median age of death is 50–57 years and 70–72 years, respectively). Enzyme replacement therapy (ERT), the first specific treatment for AFD, consists of regular intravenous infusion of a recombinant enzyme formulation. Two forms of recombinant AGAL exist: agalsidasealfa (Replagal®, Shire Human Genetic Therapies, Cambridge, Massachusetts) and agalsidase beta (Fabrazyme®, Genzyme Corporation, Cambridge, Massachusetts). Agalsidasealfa is generated by the acTIvaTIon of the AGAL gene in a continuous human cell line, whereas agalsidase beta is produced in a Chinese hamster ovary mammalian cell expression system, transduced with the human AGAL sequence. A sizable percentage of people receiving ERT for AFD have seroconverted (ie, developed antibodies)— the frequency of developing anTIbodies against agalsidasealfa and agalsidase beta has been reported to be 55% and 83%, respectively, of individuals treated.4,5 Recent studies have shown that the presence of antibodies may influence Gb3 storage in skin capillaries and Gb3 excretion in urine, but no relationship between antibody formation and plasma Gb3 levels or clinical outcome has been established thus far.6 We examined randomized and quasirandomized controlled trials to evaluate the effectiveness and safety of ERT compared with placebo, other interventions, or no interventions for treating AFD. Changes in Gb3 concentraTIon in plasma and TIssue (ie, endothelial cells), death, and pain (acroparesthesia and Fabry crises) were our primary outcomes. We identified 6 studies (n=223) comparing either agalsidasealfa or beta with placebo or each other; however, the methodologic quality of these studies was largely poor.   Two trials compared agalsidasealfa with placebo and reported on Gb3 concentration in plasma and  tissue; aggregate results were nonsignificant. One study reported pain scores, with a significant improvement at up to 3, 5, and 6 months for patients receiving treatment. A significant difference was observed in pain‐related quality of life after 5 months and up to 6 months , but at no other time points. Neither study reported deaths. One of the 3 trials comparing agalsidase beta with placebo reported on Gb3 concentration in plasma and tissue, and showed significant improvement in kidney, heart, and composite results (renal, cardiac, and cerebrovascular complications and death) (Figure). No significant difference was found between groups for death; none of the studies reported on pain. Only one trial compared agalsidasealfa to agalsidase beta. There was no significant difference between groups for any serious or other adverse events. This review highlights the need for continued research on the use of ERT for AFD.

 

REFERENCES

  1. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999;281:249‐254.
  2. Spada M, Pagliardini S, Yasuda M, et al. High incidence of later‐onset Fabry disease revealed by newborn screening. Am J Hum Genet. 2006;79:31‐40.
  3. Wilcox WR, Oliveira JP, Hopkin RJ, et al. Females with Fabry disease frequently have major organ involvement: lessons from the Fabry Registry. Molec Genet Metab. 2008;93:112‐128.
  4. Eng CM, Guffon N, Wilcox WR, et al; International   Collaborative Fabry Disease Study Group. Safety and efficacy of recombinant human alpha‐galactosidase A— replacement therapy in Fabry’s disease. N Engl J Med. 2001;345:9‐16.
  5. Schiffmann R, Kopp JB, Austin HA, et al. Enzyme re‐ placement therapy in Fabry disease: a randomized con‐ trolled trial. JAMA. 2001;285:2743‐2749.
  6. Hollak CE, Linthorst GE. Immune response to enzyme replacement therapy in Fabry disease: impact on clinical outcome? Molec Genet Metab. 2009;96:1‐3.

Figure. Agalsidase Beta vs Placebo: Microvascular Endothelial Deposits of Gb3   Abbreviations: Gb3, globotriaosylceramide; SD, standard deviation.

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An Open Access Journal

The Lysosomal Disease Network’s 10th Annual WORLDSymposiumâ„¢ 2014

By: Rare Disorders

Monday February 10, 2014 – Friday, February 14, 2014

The Lysosomal Disease Network’s 10th Annual WORLDSymposium™

 2014

This symposium is designed for basic, translational and clinical researchers, patient advocacy groups, clinicians, and all others who are interested in learning more about the latest discoveries in the management and treatment of lysosomal diseases, and the clinical investigation of these advances.  This meeting will help researchers and clinicians to better manage and understand diagnostic options for patients with lysosomal diseases; to identify areas requiring additional basic and clinical research, public policy and regulatory attention; and to identify and explore the latest findings in the natural history of lysosomal diseases.

Co-Presented by the Lysosomal Disease Network and the National Institutes of Health Office of Rare Diseases Research–National Center for Advancing Translational Science (NCATS),the National Institute of Neurological Disorders and Stroke (NINDS), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

www.lysosomaldiseasenetwork.org

Held at: Manchester Grand Hyatt San Diego

One Market Place

San Diego, CA 92101 USA

Cut-off date: Friday, January 10, 2014 – After the cut-off date, room rates may be available at prevailing rates.

A block of sleeping rooms is available at a discounted rate of $239 single, $239 double; plus taxes. Please make your reservation directly with the hotel prior to the cut-off date and refer to the course by name (Lysosomal Disease Network’s 10th Annual WORLD Symposium™  2014 to receive the discounted rate. Reservations will be accepted on space and rate availability.

Amphetamines

Main Risks and Target Organs

Acute central nervous system stimulation, cardiotoxicity causing tachycardia, arrhythmias, hypertension and cardiovascular collapse.  High risk of dependency and abuse.

Summary of Clinical Effects

Cardiovascular – Palpitation, chest pain, tachycardia, arrhythmias and hypertension are common; cardiovascular collapse can occur in severe poisoning.  Myocardial ischaemia, infarction and ventricular dysfunction are described.

Central Nervous System (CNS) – Stimulation of CNS, tremor, restlessness, agitation, insomnia, increased motor activity, headache, convulsions, coma and hyperreflexia are described.

Stroke and cerebral vasculitis have been observed. Gastrointestinal – Vomiting, diarrhoea and cramps may occur. Acute transient ischaemic colitis has occurred with chronic         methamphetamine abuse.

Genitourinary – Increased bladder sphincter tone may cause dysuria, hesitancy and acute urinary retention.  Renal failure can occur secondary to dehydration or rhabdomyolysis. Renal ischaemia may be noted.

Dermatologic – Skin is usually pale and diaphoretic, but mucous membranes appear dry.

Endocrine – Transient hyperthyroxinaemia may be noted.

Metabolism – Increased metabolic and muscular activity may result in hyperventilation and hyperthermia.  Weight loss is common with chronic use.

Fluid/Electrolyte – Hypo- and hyperkalaemia have been reported.  Dehydration is common.

Musculoskeletal – Fasciculations and rigidity may be noted. Rhabdomyolysis is an important consequence of severe amphetamine poisoning.

Psychiatric – Agitation, confusion, mood elevation, increased wakefulness, talkativeness, irritability and panic attacks are typical.  Chronic abuse can cause delusions and paranoia.

A withdrawal syndrome occurs after abrupt cessation following chronic use.

Diagnosis

The diagnosis of acute amphetamine poisoning is made on the history of exposure or abuse, and the characteristic features of CNS and cardiovascular stimulation. The presence of amphetamines in urine or blood can support the diagnosis but is not helpful in management.  Whilst some patients show signs of toxicity at blood concentrations of 20 µg/L, chronic abusers of amphetamine have been known to have blood concentration of up to 3000 µg/L.

First Aid Measures and Management Principles

Management of amphetamine and its complications is essentially supportive. The initial priority is stabilisation of the airway, breathing and circulation.  Monitoring of pulse, blood pressure, oxygenation, core temperature and cardiac rhythm should instituted. Supplemental oxygen should be administered. Specific supportive care measures that may be necessary include:  maintenance of hydration, control of seizures, relief of agitation, control of hyperthermia, control of hypertension, management of rhabdomyolysis. Decontamination with oral activated charcoal is appropriate if the patient is conscious. There are no suitable methods of enhancing elimination of amphetamine and no specific antidotes.

Contraindications include anorexia, insomnia, psychopathic personality disorders, suicidal tendencies, Gilles de la Tourette syndrome and other disorders, hyperthyroidism, narrow angle glaucoma, diabetes mellitis and cardiovascular diseases such as angina, hypertension and arrythmias (Dollery, 1991; Reynolds, 1996). Amphetamine interacts with several other drugs (see 7.6).

Routes of Exposure

Oral – Readily absorbed from the gastro-intestinal tract and buccal mucosa.  It Is resistant to metabolism by monoamine oxidase.

Inhalation – Amphetamine is rapidly absorbed by inhalation and is abused by this route (Brust, 1993).

Parenteral – Frequent route of entry in abuse situations.

Kinetics of Amphetamine

Absorption by route of exposure – Amphetamine is rapidly absorbed after oral ingestion. Peak plasma levels occur within 1 to 3 hours, varying with the degree of physical activity and the amount of food in the stomach.  Absorption is usually complete by 4 to 6 hours. Sustained release preparations are available as resin-bound, rather than soluble, salts. These compounds display reduced peak blood levels compared with standard amphetamine preparations, but the total amount absorbed and time to peak levels remain similar (Dollery, 1991).

Distribution by route of exposure – Amphetamines are concentrated in the kidney, lungs, cerebrospinal fluid and brain.  They are highly lipid soluble and readily cross the blood-brain barrier. Protein binding and volume of distribution varies widely, but the average volume of distribution is 5 L/kg body weight (Dollery, 1991).

Biological Half-Life by Route of Exposure

Under normal conditions, about 30% of amphetamine is excreted unchanged in the urine but this excretion is highly variable and is dependent on urinary pH. When the urinary pH is acidic (pH 5.5 to 6.0), elimination is predominantly by urinary excretion with approximately 60% of a dose of amphetamine being excreted unchanged by the kidney within 48 hours.  When the urinary pH is alkaline (pH 7.5 to 8.0), elimination is predominantly by deamination (less than 7% excreted unchanged in the urine); the half-life ranging from 16 to 31 hours (Ellenhorn, 1997).

Metabolism

The major metabolic pathway for amphetamine involves deamination by cytochrome P450 to para-hydroxyamphetamine and phenylacetone; this latter compound is subsequently oxidised to benzoic acid and excreted as glucuronide or glycine (hippuric acid) conjugate.  Smaller amounts of amphetamine are converted to norephedrine by oxidation. Hydroxylation produces an active metabolite, O-hyroxynorephedrine, which acts as a false neurotransmitter and may account for some drug effect, especially in chronic users (Dollery, 1991).”

Elimination and excretion

Normally 5 to 30% of a therapeutic dose of amphetamine is excreted unchanged in the urine by 24 hours, but the actual amount of urinary excretion and metabolism is highly pH dependent (Dollery, 1991).

Toxicodynamics

Amphetamine appears to exert most or all of its effect in the CNS by causing release of biogenic amines, especially norepinephrine and dopamine, from storage sites in nerve terminals. It may also slow down catecholamine metabolism by inhibiting monoamine  oxidase (Hardman et al., 1997).” (edited)

Teratogenicity

The use of amphetamine for medical indications does not pose a significant risk to the fetus for congenital anomalies (Briggs, 1990).  Amphetamines generally do not appear to be human teratogens. Mild withdrawal symptoms may be observed in the newborn, but the few studies of infant follow-up have not shown long-term sequelae, although more studies of this  nature are needed. Illicit maternal use or abuse of amphetamine presents a significant risk to the foetus and newborn, including intrauterine growth retardation, premature delivery and the potential for increased maternal, fetal and neonatal morbidity.

These poor outcomes are probably multifactorial in origin, involving multiple drug use, life-styles and poor maternal health.  However, cerebral injuries occurring in newborns exposed in utero appear to be directly related to the vasoconstrictive properties of amphetamines.  Ericksson et al. (1989) followed 65 children whose mothers were addicted to amphetamine during pregnancy, at least during the first trimester. Intelligence, psychological function, growth, and physical health were all within the normal range at eight years, but those children exposed throughout pregnancy tended to be more aggressive.”

Interactions with Other Drugs

Acetazolamide – administration may increase serum concentration of amphetamine.

Alcohol – may increase serum concentration of amphetamine.

Ascorbic acid -lowering urinary pH, may enhance amphetamine excretion

Furazolidone – amphetamines may induce a hypertensive response in patients taking furazolidone.

Guanethidine – amphetamine inhibits the antihypertensive response to guanethidine.

Haloperidol – limited evidence indicates that haloperidol may inhibit the effects of amphetamine but the clinical importance of this interaction is not established.

Lithium carbonate – isolated case reports indicate that lithium may inhibit the effects of amphetamine.

Monoamine oxidase inhibitor – severe hypertensive reactions have followed the administration of amphetamines to patients taking monoamine oxidase inhibitors.

Noradrenaline – amphetamine abuse may enhance the pressor response to noradrenaline.

Phenothiazines – amphetamine may inhibit the antipsychotic effect of phenothiazines, and phenothiazines may inhibit the anorectic effect of amphetamines.

Sodium bicarbonate – large doses of sodium bicarbonateinhibit the elimination of amphetamine, thus increasing the amphetamine effect.

Tobacco smoking – amphetamine appears to induce dose-related increases in cigarette smoking.

Tricyclic antidepressants – theoretically increases the effect of amphetamine, but clinical evidence is lacking. (Stockley, 1994; Dollery, 1991)

Overall Interpretation of All Toxicological Analyses and Toxicological Investigations

Sample collection: Creatinine, urea, and electrolyte measurement are important to establish whether renal impairment or hyperkalaemia is present.  Measurements of serum creatine kinase, aspartate transaminase and myoglobin can help to establish if there is rhabdomyolysis, and myoglobin can be detected in urine.

Liver function tests are relevant, since hepatitis can occur. A full blood count and coagulation studies can be helpful, with measurement of fibrinogen and of fibrin degradation products, in establishing a diagnosis of disseminated intravascular coagulation.

Biomedical Analysis

Temperature, blood pressure, and pulse rate should be monitored frequently.  A temperature above 40°C, and marked hypertension and tachycardia are seen in severe poisoning. An electrocardiogram can be useful in detecting myocardial ischaemia or arrhythmia.  Electrocardiographic monitoring can be helpful in patients with arrhythmia.

Toxicological analysis

Urine or serum analysis for amphetamine can help to confirm exposure, but cannot be used to establish poisoning, because of difference in individual tolerance to amphetamines.

Clinical Effects

Acute Poisoning Through Ingestion

Effects are most marked on the central nervous system, cardiovascular system, and muscles.  The triad of hyperactivity, hyperpyrexia, and hypertension is characteristic of acute amphetamine overdosage. Agitation, confusion, headache, delirium, and hallucination, can be followed by coma, intracranial haemorrhage, stroke, and death. Chest pain, palpitation, hypertension, tachycardia, atrial and ventricular arrhythmia, and myocardial infarction can occur.

Muscle contraction, bruxism (jaw-grinding), trismus (jaw clenching), fasciculation, rhabdomyolysis, are seen leading to renal failure; and flushing, sweating, and hyperpyrexia can all occur.  Hyperpyrexia can cause disseminated intravascular coagulation. (Brust, 1993; Derlet et al., 1989)

Acute Poisoning ThroughInhalation

The clinical effects are similar to those after ingestion, but occur more rapidly (Brust, 1993).

Acute Poisoning Through Parenteral exposure

Intravenous injection is a common mode of administration of amphetamine by abusers.  The euphoria produced is more intense, leading to a “rush” or “flash” which is compared to sexual orgasm  (Brust, 1993). Other clinical effects are similar to those observed after ingestion, but occur more rapidly.

Acute Poisoning Through Ingestion

Tolerance to the euphoric effects and CNS stimulation induced by amphetamine develops rapidly, leading abusers to use larger and larger amounts to attain and sustain the desired affect. Habitual use or chronic abuse usually results in toxic psychosis classically characterised by paranoia, delusions and hallucinations, which are usually visual, tactile or olfactory in nature, in contrast to the typical auditory hallucinations of schizophrenia.

The individual may act on the delusions, resulting in bizarre violent behaviour, hostility and aggression, sometimes leading to suicidal or homicidal actions. Dyskinesia, compulsive behaviour and impaired performance are common in chronic abusers.  The chronic abuser presents as a restless, garrulous, tremulous individual who is suspicious and anxious.

Course, Prognosis, and Cause of Death

Symptoms and signs give a clinical guide to the severity of intoxication as follows (Espelin and Done, 1968):

Mild toxicity – restlessness, irritability, insomnia, tremor, hyperreflexia, sweating, dilated pupils, flushing;

Moderate toxicity – hyperactivity, confusion, hypertension, tachypnoea, tachycardia, mild fever, sweating;

Severe toxicity – delirium, mania, self-injury, marked hypertension, tachycardia, arrhythmia, hyperpyrexia, convulsion, coma, circulatory collapse.

Death can be due to intracranial haemorrhage, acute heart failure or arrhythmia, hyperpyrexia, rhabdomyolysis and consequent hyperkalaemia or renal failure, and to violence related to the psychiatric effects (Kalant & Kalant, 1975).

Systematic Description of Clinical Effects

Cardiovascular symptoms of acute poisoning include palpitation and chest pain.  Tachycardia and hypertension are common. One third of patients reported by Derlet et al. (1989) had a blood pressure greater than 140/90 mmHg, and nearly two-thirds had a pulse rate above 100 beats per minute. Severe poisoning can cause acute myocardial ischaemia, myocardial infarction (Carson et al., 1987; Packe et al., 1990), and left ventricular failure (Kalant &  Kalant, 1975). These probably result from vasospasm, perhaps at sites of existing atherosclerosis. In at least one case, thrombus was demonstrated initially (Bashour, 1994).

Chronic oral amphetamine abuse can cause a chronic cardiomyopathy; an acute cardiomyopathy has also been described (Call et al., 1982). Hypertensive stroke is a well-recognised complication  of amphetamine poisoning (see 9.4.3). Intra-arterial injection of amphetamine can cause severe burning pain, vasospasm, and gangrene (Birkhahn & Heifetz, 1973).

Pulmonary fibrosis, right ventricular hypertrophy and pulmonary hypertension are frequently found at post-mortem examination. Pulmonary function tests usually are normal except for the carbon monoxide diffusing capacity.  Respiratory complications are sometimes caused by fillers or adulterants used in injections by chronic users. These can cause multiple microemboli to the lung, which can lead to restrictive lung disease. Pneumomediastinum has been reported after amphetamine   inhalation (Brust, 1993).

For the central nervous system (CNS),  main symptoms include agitation, confusion, delirium, hallucinations, dizziness, dyskinesia, hyperactivity, muscle fasciculation and rigidity, rigors, tics, tremors, seizures and coma. Both occlusive and haemorrhagic strokes have been reported after abuse of amphetamines. Twenty-one of 73 drug-using young persons with stroke had taken amphetamine (Kaku & Lowenstein, 1990), of whom six had documented intracerebral haemorrhage and two had subarachnoid haemorrhage.  Patients with underlying arteriovenous malformations may be at particular risk (Selmi et al., 1995).

Stroke can occur after oral, intravenous, or nasal administration.  Severe headache beginning within minutes of ingestion of amphetamine is usually the first symptom.  In more than half the cases, hypertension which is sometimes extreme, accompanies other symptoms. A Cerebral vasculitis has also been observed (Brust, 1993). Dystonia and dyskinesia can occur, even with therapeutic dosages (Mattson & Calverley, 1968). Psychiatric effects, particularly euphoria and excitement, are the motives for abuse. Paranoia and a psychiatric syndrome indistinguishable from schizophrenia are sequelae of chronic use ( Hall et al., 1988; Flaum & Schultz, 1996; Johnson & Milner, 1966).

In the autonomic nervous system, stimulation of alpha-adrenergic receptors produces mydriasis, increased metabolic rate, diaphoresis, increased sphincter tone, peripheral vasoconstriction and decreased gastrointestinal motility can occur. Stimulation of ß-adrenergic receptors produces increased heart rate and contractility, increased automaticity and dilatation of bronchioles.

For skeletal and smooth muscle, myalgia, muscle tenderness, muscle contractions, and rhabdomyolysis, leading to fever, circulatory collapse, and myoglobinuric renal failure, can occur with amphetamines can occur.  (Kendrick et al., 1977).

Common gastrointestinal symptoms include nausea, vomiting, diarrhoea, and abdominal cramps.  Anorexia may be severe. Epigastric pain and haematemesis have been described after intravenous amphetamine use.  A case of ischaemic colitis with normal mesenteric arteriography in a patient taking dexamphetamine has been described (Beyer et al., 1991). Hepatitis and fatal acute hepatic necrosis have been described (Kalant & Kalant, 1975).                           Renal failure, secondary to dehydration or rhabdomyolysis may be observed.

Increased bladder sphincter tone may cause dysuria, hesitancy and acute urinary retention.  This effect may be a direct result of peripheral alpha-agonist activity.Spontaneous rupture of the bladder has been described in a young woman who took alcohol and an amphetamine-containing diet tablet (Schwartz, 1981).

Transient hyperthyroxinaemia may result from heavy amphetamine use (Morley et al., 1980). Skin is usually pale and diaphoretic, but mucous membranes appear dry.  Chronic users may display skin lesion, abscesses, ulcers, cellulitis or necrotising angiitis due to physical insult to skin, or dermatologic signs of dietary deficiencies, e.g. cheilosis, purpura. Mydriasis may be noted on the eye, ear, nose, and throat. Diffuse hair loss may be noted. Chronic users may display signs of dietary deficiencies. Disseminated intravascular coagulation is an important consequence of severe poisoning ( Kendrick et al., 1980). Idiopathic thrombocytopenic purpura may occur. For fluid and electrolyte disturbance, increased metabolic and muscular activity may result in dehydration.

Special Risks on Pregnancy

Eriksson et al. (1989) followed 65 children whose mother were addicted to amphetamine during pregnancy, at least during the first trimester. Intelligence, psychological function, growth, and physical health were all within the normal range at  eight years, but those exposed throughout pregnancy tended to be more aggressive. A case report describes a normal female infant born to mother who took up to 180 mg/day of dexamphetamine for narcolepsy throughout pregnancy (Briggs et al., 1975).

Special Risks on Breast-feeding

Amphetamine is passed into breast milk and measurable amounts can be detected in breast-fed infant’s urine.  Therefore lactating mothers are advised not to take or use amphetamine.

Amphetamine Withdrawal Syndrome

Abrupt discontinuance following chronic use is characterised by apathy, depression, lethargy, anxiety and sleep disturbances.  Myalgias, abdominal pain, voracious appetite and a profound depression with suicidal tendencies may complicate the immediate post-withdrawal period and peak in 2 to 3 days.  To relieve these symptoms, the user will often return to use more amphetamine, often at increasing doses due to the tolerance which is readily established. Thus a cycle of use-withdrawal-use is established (Kramer et al., 1967; Hart & Wallace, 1975).  Physical effects are not life threatening but can lead to a stuporose state (Tuma, 1993); the associated depression can lead to suicide. It may take up to eight weeks for suppressed REM (rapid eye movement ) sleep to return to normal (Brust 1993).

When the intravenous dosage is increased too rapidly the individual develops a peculiar condition referred to as “overamped”: in which he or she is conscious but unable  to speak or move. Elevated blood pressure, temperature and pulse as well as chest distress occurs in this setting. Death from overdose in tolerant individuals is infrequent.

Management

General supportive measures should be used.  These should include stabilisation of the airway, breathing, and  circulation; relief of agitation, adequate hydration, and control of core temperature.  Convulsions, hyperthermia, and rhabdomyolysis may require specific treatment. Activated charcoal may be helpful for decontamination after oral ingestion.  Ipecacuanha is contra-indicated because of its stimulant properties. There are no effective methods of enhancing elimination and no antidote. Agitation and convulsion can be treated with diazepam.  If agitation is severe, then chlorpromazine may have specific advantages over other major tranquillisers ( Espelin & Done, 1968; Klawans, 1968). Parenteral dosages of 0.5 to 2 milligrams per kilogram have been used in Infants ( Espelin & Done, 1968). Severe hyperthermia (core temperature greater than 40°C) requires forced cooling by fans, tepid sponging or other means, and may also require the administration of diazepam or dantrolene or both agents in order to eliminate muscle activity.

Rhabdomyolysis associated with muscle overactivity can cause hyperkalaemia or renal failure, and should be treated conventionally.  Dialysis may be needed if renal failure supervenes. Acute severe hypertension (diastolic blood pressure greater than 100 mmHg) can be controlled by infusion of sodium nitroprusside by continuous intravenous infusion at an initial rate of 3 mcg/kg/min, titrated to achieve the desired response. Patients who are addicted to amphetamines may develop withdrawal syndrome described in 9.5.

Life Supportive Procedures and Symptomatic/Specific Treatment

Treatment is supportive. Administration of supplemental oxygen, establishment of intravenous access and monitoring of vital signs including core temperature, and cardiac rhythm are recommended. The following may be necessary according to clinical indication: maintenance adequate airway and ventilation, rehydration with intravenous fluids, control of seizures, control of agitation with benzodiazepines, control of severe hypertension (diastolic blood pressure greater than 110 mmHg), control of hyperthermia, treatment of hyperkalaemia, and cardiac intensive care for ischaemia or arrhythmia. No regime of oral decontamination has been demonstrated to improve outcome.  Ipecacuanha is contra-indicated. Oral activated charcoal may be helpful following oral overdosage. Forced acid diuresis has been abandoned as a decontamination procedure. Neither haemodialysis nor charcoal haemoperfusion is likely to be of benefit. There is no antidote to amphetamine poisoning in adults or children.

There are differences between dexamphetamine and related compounds such as 3,4-methylenedeoxymetamphetamine (“ecstacy”); for example, hyperthermia appears to be more of a problem with the latter, and this may be because of the association between use and frenetic physical activity (“rave” dancing) (Henry et al., 1992). In the past, energetic gastric decontamination procedures were suggested (Espelin & Done, 1968).  There is no evidence that such procedures improve outcome in amphetamine poisoning, and they are potentially hazardous. Oral activated charcoal is probably the safest option for decontamination, but is only likely to bind drug in the stomach if a substantial oral dose of amphetamine has been taken, and the charcoal is given within an hour or two of ingestion. If should only administered to patients in whom swallowing and gag reflexes are intact.  In drug smugglers who have swallowed supposedly inert packages of amphetamines (“stuffers” or “packers”), and who develop symptoms because of leakage from the packages, then repeated doses of oral activated charcoal with a cathartic are likely to be worthwhile.

Forced acid diuresis has now been abandoned as an elimination treatment, because it is intrinsically difficult and potentially dangerous. Treatment of agitation in amphetamine poisoning is required when a patient is a danger to himself or herself, or to others.  Because poisoning is associated with sympathetic overactivity, and chlorpromazine has alpha-adrenoreceptor antagonist actions, chlorpromazine has been recommended as the sedative treatment of choice (see 10.1). There is no study to demonstrate that chlorpromazine is in fact superior to benzodiazepine.

Case Reports

Ingestion of 2.2g (28mg/kg) in a 21 year old man resulted in severe toxicity (Ginsberg et.al., 1970).

An 18 month old male infant ingested an unknown amount of amphetamine, subsequently detected in the urine.  He had a history of restlessness and vomiting for 10 hours and was admitted to hospital with mild fever (38°C), pulse rate of 140 per minute and a respiratory rate of 34 per minute.  He looked acutely unwell, hyperactive and combative and had normal pupils with a bi-lateral light reflex. Some irregular flushing was found over the skin of the trunk. He was given diazepam 10mg intravenously, 10% chloral hydrate 10ml rectally and haloperidol 20mg intravenously.  After a sleep of 20 hours normal activity resumed and the patient was clinically well and discharged (Soong et.al., 1991).

A 20-month-old male infant was admitted to hospital with a history of being too restless, hyperactive and agitated to be manageable for several hours, and had not responded to 10mg diazepam given intravenously in a local medical clinic.  He had dilated pupils, doll’s eyes and normal discs. Generalised hypperreflexia and a mild clonus were noted, but no focal neurological abnormalities could be found. Hisvital signs were – blood pressure 130/90 mmHg, pulse rate 150/min, respiratory rate 46/min and normal temperature.  The clinical status remained unchanged for a further 18 hours and the patient then calmed down to sleep for 20 hours. Subsequently the parents found amphetamine powder spread near the infant’s bed (Soong, et.al., 1991). When prescribing amphetamines, due regard must be given to its potential for misuse and addiction.

REFERENCES

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