cbd oil for low blood count

CBD & Sickle Cell Anemia Pain: What the Research Says

Sickle cell anemia is a type of anemia that involves misshaped blood cells.

This condition can be very painful — here’s how CBD may be able to help.

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Anemia is a common medical condition involving loss, premature breakdown, or dysfunctional manufacture of red blood cells.

It basically means we don’t have enough high-quality blood in our veins and arteries.

There are many different types of anemia, each with its own set of treatment options, and symptoms.

Some people have begun taking CBD oil as a treatment for their anemia.

Here, we discuss what types of anemia CBD oil can be used for, how it works, and when CBD oil doesn’t work for this condition.

MEDICALLY REVIEWED BY

Updated on November 14, 2021

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The Benefits of CBD Oil For Sickle Cell Anemia

CBD oil is useful for many things, but it mainly works by supporting homeostasis in the body — which can be defined as a “state of balance”.

In the case of anemia, there are only a few ways that CBD oil can help; and the people with sickle cell anemia will have the most to benefit from it.

This is because one of the primary side effects of the condition is pain and inflammation as the misshapen red blood cells that get lodged in the tiny capillaries of the cardiovascular system. When this happens, it blocks blood flow from the area, causing the cells to starve for oxygen and nutrients.

This is a significant source of pain for these individuals, often prompting them to take opioids or other pharmaceutical pain medications.

CBD directly inhibits the pain associated with sickle cell anemia, and can dramatically improve the quality of life for these patients.

The benefits of CBD oil for anemia include:

  • Alleviates pain from sickle cell anemia
  • May support the production of red blood cells
  • Supports energy levels in patients with iron-deficient anemia

Anemia: Red Blood Cells & Their Impact On Our Health

One of the most underrated cells in the body is the humble red blood cell.

They are made in the bone marrow before being released into circulation and are responsible for carrying oxygen from the lungs to every other cell in the body – and then bringing some of the CO2 produced in the organs back to the lungs for elimination.

These specialized cells are vital to our health and wellbeing. Any issues with them can leave our cells suffocating for fresh oxygen. This leaves us feeling weak, tired, pale in complexion, and lowers our ability to resist cold and flu.

This is the main problem with anemia.

When we’re anemic, it means that our red blood cells are either misshapen, missing hemoglobin, or not abundant enough. So it’s more difficult for the body to deliver the necessary oxygen to the cells that need it.

Depending on the cause of anemia, other types of blood cells may also be affected, such as the B and T lymphocytes, monocytes, or neutrophils that make up the bulk of our immune system.

A red blood cell has a lifespan of about 90 to 120 days before it’s removed from the blood and recycled through the spleen and liver.

This means that any damage to the red blood cells could have an effect for 3 or 4 months before a new cell is produced to replace it.

This is why anemia is a long-term condition, not something that develops or clears up overnight. It often takes about 3 or 4 months of treatment to improve the condition and alleviate symptoms.

What is Hemoglobin?

The functional unit of the red blood cell is a molecule called hemoglobin. This is the part that does all the heavy lifting.

The hemoglobin molecule is basically made of protein (globin) and what is called a “heme group”, a structure that contains iron. This is the place where oxygen and carbon dioxide bind to the blood cell surface.

When hemoglobin isn’t manufactured correctly, we can end up with anemias such as sickle cell, and thalassemia.

We’ll talk more about this later.

What is Anemia?

Anemia is a condition involving insufficient or dysfunctional red blood cell production. It’s the most common blood condition in the United States, affecting roughly 5.6% of the entire population.

There are many different causes for anemia, and CBD oil is useful for some more than it is for others.

It’s important to understand what type of anemia you have.

Symptoms of Anemia

  • Difficulty concentrating
  • Dizziness
  • Fatigue/tiredness
  • Frequent cold/flu infection
  • Headaches
  • Insomnia
  • Leg cramps
  • Pain in the limbs
  • Pale skin
  • Rapid heartbeat
  • Shortness of breath

1. Anemia From Loss Of Blood

As seen previously, we need iron to build hemoglobin – the main functional unit of the red blood cell. We normally get that iron through our food, and we will lose some of it through the sweat glands and shedding skin cells. However, this loss is so small it is negligible.

The primary source of iron loss is actually through the loss of blood. Since the primary use of iron is in the form of hemoglobin in our blood, when we lose blood, we lose the iron too.

Typically, when a red blood cell wears out, we recycle the iron to make new hemoglobin. Almost none of it ever gets wasted.

Although a traumatic injury resulting in a lot of blood loss can certainly cause anemia, it’s more common for the condition to develop as a result of low-grade, chronic bleeding. This is because people who have lost a lot of blood usually end up receiving blood transfusions in the hospital, effectively replenishing the blood supply and preventing anemia.

Minor bleeding, however, often goes unnoticed, and accounts for many of the leading causes of anemia worldwide.

Some of the Most Common Examples Include:
  • Menstruation, especially if excessive bleeding is present
  • Gastrointestinal bleeding, such as ulcers, hemorrhoids, or cancer
  • NSAID medication use, a common cause of ulcers

2. Anemia Caused by Dysfunctional Red Blood Cell Production

A) Nutritional Deficiencies

Red blood cells take a lot of resources to manufacture. They’re a very complex cell, with multiple stages of development. They’re also needed in ample supplies on a near-constant basis.

If any of these resources become deficient, or any of the stages of development become impeded, red blood cell production begins to suffer.

The nutrients needed to build red blood cells include:
  • Copper
  • Iron
  • Vitamin A
  • Vitamin B12
  • Vitamin B3
  • Vitamin B6
  • Vitamin B9

If any of these nutrients become deficient in the diet, red blood cell production will suffer.

This happens mainly due to iron and B12 deficiencies, which are common in people who eat vegetarian or vegan diets since the majority of foods that contain these nutrients are meats and other animal products.

Pernicious anemia is another related cause for anemia but relies on a condition where the body can’t produce enough intrinsic factor, which is essential for absorbing vitamin B12 from the gastrointestinal tract.

This type of anemia is treated by identifying which nutrients are deficient and adding them to the diet either through food or in supplemental form.

B) Dysfunctional Red Blood Cell Production

Sometimes there are problems in the actual production of red blood cells.

This can be the result of things like:

  • Genetically inherited disorders – such as thalassemia
  • Cancer therapy –damages the bone marrow tasked with producing red blood cells
  • Hereditary spherocytosis – genetic conditions affecting the membrane of red blood cells
  • Sickle cell anemia – misshapen hemoglobin molecules, causing distorted red blood cell shape and function

When talking about CBD oil, perhaps the most significant form of anemia is sickle cell anemia.

Sickle Cell Anemia

With this form of hereditary anemia, dysfunctional hemoglobin causes the red blood cells to develop into abnormal crescent (sickle) shapes.

This abnormality causes a set of problems starting with their function:

  1. Sickle cells don’t work as well as normal cells
  2. Sickle cells break down faster than normal cells
  3. Sickle cells get lodged in microcapillaries, causing pain and damage to the area

The condition is usually first seen in childhood.

The signs and symptoms of sickle cell anemia include:

  • Low immunity (frequent cold and flu infections)
  • Shortness of breath
  • Fatigue
  • Delayed growth development
  • Organ damage
  • Pulmonary hypertension

3. Anemia Caused by Premature Destruction of Red Blood Cells

The final category of anemia is caused by premature destruction of the red blood cells themselves.

This, of course, overlaps with some other forms, such as sickle cell anemia, which leads to a premature breakdown of the misshapen blood cells.

Some examples of anemia caused by premature red blood cell destruction include:
  • Hemolytic anemia causes excessive breakdown of red blood cells
  • Thalassemia, an inherited disorder resulting in misshapen hemoglobin molecules
  • Side effects of certain drugs such as Cephalosporins that can cause hemolytic anemia
  • Snake or spider venom, especially those containing hemolytic toxins such as cobras
  • Liver, kidney, or spleen disease

How to Use CBD Oil For Anemia

So, now that we’ve covered the causes and many different types of anemia let’s get into how CBD oil can benefit anemia patients.

1. CBD Oil and Sickle Cell Anemia

One of the main symptoms of people suffering from sickle-cell anemia is the pain associated with lodgements of the misshapen red blood cells in the microcapillaries. Pain can also occur from poor oxygenation of the tissue resulting from sickle cell anemia.

In some cases, sufferers are prompted to take potent opioid painkillers to manage the pain.

These opioids are a problem over the long-term because they’re highly addictive and bring with them a wide range of negative side effects. So people are now starting to use other methods of pain management for this condition such as marijuana and CBD oil.

A questionnaire-based study done on people living with sickle cell disease involved a few questions on marijuana use and the results found that 36% of the 88 patients in the study had used marijuana to treat symptoms of the disorder.

52% of these people used it to reduce the pain associated with the condition, while 77% suggested they used it for sedation or relaxation purposes.

Another study used an animal model to look at how cannabinoids can be effective at treating the pain from sickle cell anemia. It found that the primary mechanism was through their ability to stabilize mast cells, which are one of the main drivers of inflammation and pain in the body.

In this same study, cannabinoids were also shown to reduce neuropathic (nerve-related) inflammation involved with sickle cell disease.

2. CBD Oil and Iron Deficiency Anemia

CBD itself has little effect on iron-deficient anemia; however, the hemp seed oil often used as the carrier oil in these products is naturally high in iron.

The critical thing to consider here, however, is the dosage.

Typically, the doses used for CBD oil are only a few milliliters per day. But to get the nutritional benefits of hemp seed oil for treating anemia you’d need to consume much more than that.

In 100 mL of hemp seed oil, there’s approximately 8 mg of iron.

According to the National Institute Of Health, the daily requirements for iron in adults between the ages of 19 and 50 is 8 mg/day for men, and 18 mg/day in women.

Daily Iron Requirements:
Age Male Female
7-12 months 11 mg 11 mg
1–3 years 7 mg 7 mg
4–8 years 10 mg 10 mg
9–13 years 8 mg 8 mg
14–18 years 11 mg 15 mg
19–50 years 8 mg 18 mg
51+ years 8 mg 8 mg

These numbers would mean we require about 100-200 mL of hemp seed oil each day.

These are maintenance doses, however – treating iron deficiency anemia is much more difficult and requires much more iron intake.

Most sources for treating iron-deficient anemia recommend taking 150-200 mg of iron each day, which is the equivalent of about 1.9 L of hemp seed oil per day.

That’s a lot of hemp oil.

According to HempOil.ca, this would cost about $50 per day in hemp oil alone and would require you to drink nearly 2000 mL of the stuff each day.

This is simply not reasonable.

Raw, unshelled hemp seeds are a little better, containing about 9.6 mg of iron per 100 g.

You would need to consume 1.5 kg of raw hemp seeds per day.

Instead, it’s probably best to stick to iron supplements and other high-concentration sources of iron, such as dark leafy vegetables, tofu, and red meat.

Final Thoughts: CBD Oil for Anemia

CBD oil offers only minor improvements to most causes of anemia. Most of these benefits regard symptoms of anxiety and stress, rather than the condition itself.

The main benefit of CBD oil towards anemia comes from its ability to lower the pain and discomfort involved with a particular type of anemia, known as sickle cell anemia.

It could be used to help reduce the nerve pain involved with the condition, which is a particularly difficult type of pain to treat.

It also lowers mast cell activation, which helps reduce pain and inflammation involved with sickle cell anemia.

Other types of anemia have shown little benefit from CBD oil; however, it may be useful for secondary symptoms of the condition including mood disorders, anxiety, fatigue, and frequent infection.

Endocannabinoids and the haematological system

Endocannabinoids are blood borne and may also be secreted by the endothelium. Accordingly, there has been interest in the interactions between (endo)cannabinoids and blood cells. There is certainly evidence that (endo)cannabinoids may promote platelet activation, indicating that they may be thrombogenic. Platelets are involved both in the metabolism and release of endocannabinoids, and so it is possible that their circulating levels may be regulated by platelets. This process is altered in disease states such that platelet-derived endocannabinoids contribute towards hypotension in cardiovascular shock. Not only may endocannabinoids regulate platelet function and possibly lead to thrombogenesis, but they may also influence haematopoiesis. Given these emerging roles, the aim of this review is to examine the interactions between cannabinoids and blood.

Introduction

The cardiovascular actions of cannabinoids and endocannabinoids have been extensively reviewed (Randall et al., 2004; Pacher et al., 2006), but far less is known about their actions on blood. There is evidence that endocannabinoids may be produced in the endothelium (Mechoulam et al., 1998; Maccarrone et al., 2002; Gauthier et al., 2005) and blood cells may themselves act as a source; but what is the relationship between endocannabinoids and the haematological system?

Cannabinoids and the risk of thromboembolism

Not only might endocannabinoids affect the functioning of blood, but also cannabinoids used either medicinally or as drugs of abuse should also be considered. Smoking cannabis was identified in the Determinants of Myocardial Infarction Study as a risk factor for initiating a myocardial infarction, such that the risk was increased 4.8-fold in the 60 min after its use (Mittleman et al., 2001). Acutely cannabis smoking is associated with cardiovascular effects including tachycardia and hypertension with orthostatic hypotension. The tachycardia clearly acts as a stressor, and smoking cannabis (when compared to placebo controls) has been shown provoke symptoms in stable angina (Aronow and Cassidy, 1974). Accordingly in patients with atherosclerotic plaques, the risk of myocardial infarction triggered by cannabis smoking might be related to cannabis-induced thromboembolism.

Despite the acute administration of cannabis being associated with an increased risk of myocardial infarction, the Coronary Artery Risk Developing in Young Adults trial (Rodondi et al., 2006) indicated that long-term cannabis smoking was not associated with increased cardiovascular risk. This large-scale trial took account of diet, alcohol consumption and tobacco smoking, and concluded that cannabis was not an independent risk factor for cardiovascular disease but was associated with an unhealthy lifestyle.

Consistent with an increased acute risk of thromboembolism, Deusch et al. (2004) recently reported that Δ-9-tetrahydrocannabinol (THC) increased the expression of glycoprotein IIb–IIIa and P-selectin on platelets. Specifically, Deusch et al. reported that exposure of human platelets to THC (100 n M –10 μ M ) resulted in platelet activation, which would favour thromboembolism. In their study, they also detected platelet expression of cannabinoid CB1 and CB2 receptors, which they speculated might be involved in the THC-induced response, but this was not confirmed pharmacologically. In view of the risk of thrombosis posed by THC, this raises questions over the safety of THC as a medicine. Accordingly, it would be prudent to take account of the patient’s cardiovascular risk factors when using it as a medicine.

Much of the early work on endocannabinoids and platelet function was carried out by Maccarrone and colleagues. In 1999, Maccarrone et al. reported that anandamide caused the activation of platelets. In this study on human platelets, it was found that high concentrations of anandamide (1.3 m M ) caused platelet activation with the release of intracellular calcium. These effects of anandamide were unaffected by inhibition of cyclo-oxygenase and fatty acid amide hydrolase (FAAH) activities, but was sensitive to hydro(pero)oxide derivatives of anandamide. Work carried out by Braud et al. (2000) also confirmed that anandamide causes activation of rabbit platelets, although at lower concentrations (optimum range: 3–10 μ M ). However, in that study, the effects of anandamide were sensitive to both cyclo-oxygenase and FAAH inhibition, but was insensitive to the cannabinoid CB1 receptor antagonist rimonabant and occurred at concentrations similar to those of arachidonic acid which cause platelet activation. Furthermore, the synthetic cannabinoid receptor agonist, HU210, did not mimic the effects of anandamide. Accordingly, they concluded that anandamide caused platelet activation via FAAH-dependent liberation of arachidonic acid. This could indicate that there are species differences with respect to the ways in which endocannabinoids affect platelets.

In subsequent studies, Maccarrone et al. (2001a) also reported that 2-arachidonoylglycerol (2-AG) caused activation of human platelets at lower concentrations (50–400 μ M ) than reported for anandamide, and that these effects were inhibited by high concentrations of the cannabinoid CB1 and CB2 receptor antagonists, rimonabant and SR144528. In addition, the effects of 2-AG were also reduced by anandamide. It was also found that platelets exhibited specific binding of the synthetic cannabinoid radioligand, 3 H-CP55940, which is consistent with the expression of a CB-type receptor, but the binding characteristics did not fit in to the classical CB1 and CB2 classification. Also of interest was the finding that 2-AG’s actions were opposed by ADP and collagen, but enhanced by serotonin. More recent work in this area has confirmed that serotonin enhances the binding of 2-AG to platelets such that platelet activation (including increases in inositol trisphosphate and decreases in cAMP) occurs at lower concentrations (Maccarrone et al., 2003). It was also found that 2-AG enhances the binding of serotonin to platelets. Perhaps, these findings suggest that 2-AG exerts a modulatory role in platelet activation as opposed to a direct action.

Morphological confirmation of platelet activation was provided by Malorni et al. (2004). In their study, they reported that 200 μ M 2-AG caused rapid (within 6 min) morphological changes in human platelets with protrusions and rearrangement of the cytoskeleton. These changes are consistent with platelet activation and confirm that 2-AG is an endogenous platelet activator.

Although some of the work discussed above has examined the actions of endocannabinoids at high concentrations and so their physiological relevance may not be clear, in their 2001(a) paper, Maccarrone and colleagues provided some interesting evidence. They mentioned unpublished findings which indicated that 2-AG is the most abundant endocannabinoid in platelets, and that its platelet concentration may be as high as 1.4 m M and this clearly sheds light on the possible significance of their findings.

Maccarrone et al. (2002) have also shown that anandamide derived from cultured endothelial cells stimulated with oestrogens may in fact reduce the release of serotonin from ADP-stimulated human platelets. On this basis, they suggest that endothelium-platelet interactions may be involved in the vascular effects of oestrogens.

In conclusion, based on these findings, it is clear that high concentrations of endocannabinoids may cause platelet activation and this may be relevant as there is an indication that the endothelium may be a source of endocannabinoids (Mechoulam et al., 1998; Gauthier et al., 2005) and this may also be relevant to thrombosis. However, there is also evidence that the endothelium may be a site of endocannabinoid metabolism (Ho and Randall, 2007), and this may enable the endothelium to represent an antithrombogenic surface. Accordingly, the balance between the release of thrombogenic endocannabinoids and their endothelium-dependent metabolism will determine the role of endocannabinoids in thrombosis but this may be altered in disease states, including atherosclerosis.

Endocannabinoids and atherosclerosis

The link between white blood cells, platelets and atherosclerosis is well established, but do endocannabinoids play a role? There has been little work in this area, but the first clue came from Steffens et al. (2005), who reported that low doses of THC acting via CB2 receptors caused a reduction in the development of atherosclerotic plaques in a murine knockout model of atherogenesis. These effects appeared via suppression of macrophage chemotaxis. Whether endocannabinoids play a role in atherosclerosis remains to be determined, but a recent study has shown that low levels of palmitoylethanolamide (PEA) may protect low-density lipoprotein (LDL) against oxidation, which is a feature of atherogenesis (Zolese et al., 2005). By contrast, higher concentrations of PEA appear to promote the oxidation.

The role of platelets in endocannabinoid reuptake and metabolism

Not only may platelets be activated by endocannabinoids, although at very high concentrations, but they may also be involved in metabolic conversion. Edgemond et al. (1998) reported that human platelets convert anandamide via 12-lipoxygenase to 12(S)-hydroxyeicosatetraenoylethanolamide (12(S)-HAEA). This metabolite is pharmacologically active at both CB1 and CB2 receptors with similar affinities to anandamide. Furthermore, 12(S)-HAEA was shown to be relatively resistant to metabolism by FAAH, and the authors proposed that the platelet-dependent conversion was a means by which the activity of endogenous cannabinoid ligands might be prolonged in the circulation.

Maccarrone et al. (1999, 2001a) also provided evidence of platelet-dependent metabolism of endocannabinoids. In their initial paper (Maccarrone et al., 1999), it was reported that platelets exhibited uptake of anandamide by a system which was stimulated by nitric oxide donors (and one could speculate that endothelium-derived nitric oxide may have similar effects). From these observations of cellular uptake, it was also suggested that platelets might be a site of FAAH activity. These findings were then extended to 2-AG, when they reported that platelets show uptake for 2-AG and FAAH-dependent hydrolysis with a Km=8 μ M . To date, the precise mechanisms of uptake of endocannabinoids into cells are unclear and the existence of a specific transporter is controversial; indeed the uptake may be a passive process driven by a FAAH-dependent gradient. In the case of platelets, Fasia et al. (2003) have examined the uptake of tritiated anandamide into rabbit platelets. From these studies, it was found that rabbit platelets exhibit temperature-independent and non-saturable uptake of anandamide, which indicates that this process is carrier-independent. On entry into the platelets, there was evidence of rapid FAAH-dependent metabolism of anandamide and the production of methanol/water soluble metabolites. On this basis, the authors suggested that the products of FAAH metabolism might have undergone further metabolism, possibly via cyclo-oxygenases. A question to emerge is, the metabolism designed to regulate levels of endocannabinoids or generate pharmacologically active metabolites?

Although the precise role platelets play in the regulation of circulating levels of endocannabinoids is unclear, an interesting observation has been reported by Cupini et al. (2005). In their paper, they argue that anandamide might be involved in modulating pain associated in migraine. In their investigation, they examined the metabolism of anandamide in a number of patients with migraine. Intriguingly, they reported that the uptake of anandamide and FAAH activity were both upregulated in platelets from female, but unaffected in male patients with migraine. From these findings, they suggested that sex-related differences might mean that in female patients with migraine, the circulating levels of anandamide were reduced by platelets and that this might reduce the pain threshold and contribute towards the pathophysiology of migraine. Although it should be noted that Akerman et al. (2004) have proposed that anandamide may, in fact, be involved in or modulate the neurovascular mechanisms in migraine, depending whether it acts via transient release potential family vanilloid type-1 receptors or cannabinoid CB1 receptors. These findings would suggest that in the central nervous system, endocannabinoids contribute towards the symptoms of migraine.

Interest in cannabinoids, platelets and migraine actually goes back to the 1980s when Volfe et al. (1985) reported that THC inhibited the release of serotonin in platelets incubated in plasma obtained from patients during a migraine attack. This clearly provides a link between cannabinoids and the modulation of migraine.

The uptake of endocannabinoids in other blood-borne cells

Platelets do not necessarily represent the sole sink for endocannabinoids in blood. A mechanistic study by Bojesen and Hansen (2005) has demonstrated in ghost human red cells that there is a transport system which does not require ATP-derived energy but is saturable. However, whether this is of relevance to the metabolism of endocannabinoid is dependent on the absence or presence of FAAH in the red blood cells.

The role of endocannabinoids in haematopoiesis

The production of blood cells is a tightly regulated process and is designed to maintain physiological levels of cells but also to respond to pathophysiology. Valk et al. (1997), reported that in vitro anandamide (at low micromolar concentrations) acted via cannabinoid CB2 receptors to synergize with colony-stimulating factors (CSFs), interleukin-3 and erythropoietin to stimulate haematopoesis. This finding at low concentrations may suggest a role in the modulation of blood cell production, while the effects on white cells may contribute towards their established role in immune responses. More recently, the same group has also reported that 2-AG acts via cannabinoid CB2 receptors to cause haematopoietic cell migration and this effect was synergistic with interleukin-3 and granulocyte-CSF (Jorda et al., 2002). This may indicate that 2-AG is important in immune cell mobilization.

There has also been interest in the involvement of endocannabinoids in abnormal blood cell development. Specifically, Jorda et al. (2004) have reported that the CB2 receptor is expressed in acute myeloid leukaemia blast cells from patients, but is absent in normal myeloid cells. The expression of CB2 receptor was also associated with oncogenic effects such as altered cell differentiation and migration.

The production of endocannabinoids by platelets and other blood cells

The ability of various blood cells to produce endocannabinoids is well established (Bisogno et al., 1997). Interest in the role endocannabinoids play in cardiovascular pathophysiology was initiated when Wagner et al. (1997) demonstrated, in a rat model of haemorrhagic shock, that activated macrophages release anandamide which may contribute towards the hypotension. Subsequently it was also found in endotoxic shock that the synthesis of 2-AG in platelets and anandamide in macrophages are increased and that these may contribute towards the associated hypotension (Varga et al., 1998). Further studies have confirmed that circulating cells produce endocannabinoids, for example, macrophages produce and release 2-AG (Di Marzo et al., 1999). Platelet-activating factor has also been shown to stimulate both platelets and a mouse macrophage cell line to produce 2-AG (Berdyshev et al., 2001). So, clearly blood cells represent an important circulating source of endocannabinoids which may participate in pathophysiological responses. Additionally, Maccarrone et al. (2001b) reported that lipopolysaccharide, a key component in endotoxic shock, causes a downregulation of FAAH expression in human lymphocytes, and the reduction in the metabolism of anandamide leads to increased levels. This mechanism could lead to further increases in circulating levels of anandamide in endotoxic shock.

Endotoxic shock is associated with disseminated intravascular coagulation (which involves widespread platelet aggregation). If the endocannabinoids released in circulatory shock are associated with causing uncontrolled platelet aggregation, then this might be the means of causing microemboli formation and contribute towards tissue-perfusion mismatches contributing to multi-organ failure.

On a methodological note, blood cell production and release of anandamide may complicate measurement of endocannabinoids in blood. This complication arises from the observation that ex vivo blood samples have high rates of anandamide release and this may clearly confound analytical measurements (Vogeser et al., 2006).

White blood cells, inflammation and cannabinoids

This review has focused on the emerging roles of endocannabinoids on the haematological system. However, it is well established that cannabinoids have significant effects on white blood cells and inflammation, such that endocannabinoids are viewed as important immunomodulators. Indeed, the therapeutic potential of cannabinoid-based drugs in managing inflammation and neuroinflammation is under investigation. This area of cannabinoid pharmacology is now well established and the reader is referred to reviews elsewhere (for example, Maccarrone et al., 2002; Walter and Stella, 2004; Croxford and Yamamura, 2005).

Conclusions

The effects of cannabinoids and the physiological/pathophysiological actions of endocannabinoids on blood cells is clearly an important and fertile area for research. To date, much work in this area has emanated from Professor Maccarrone’s group and includes important findings such as endocannabinoids being thrombogenic. However, platelets may also act as an important site of endocannabinoid metabolism, perhaps regulating their circulating levels. It is tempting to speculate that role of endocannabinoids in both vascular control and thrombosis may be governed by the relationship between the endothelium and platelets ( Figure 1 ).

A schematic diagram of established and putative interactions between cannabinoids, platelets and the endothelium. (1) The ability of THC to increase expression of glycoprotein (GP) IIb–IIIa (Deusch et al., 2004); (2) the positive interactions between 2-AG and 5-hydroxytryptamine (5-HT) (Maccarrone et al., 2001a, 2003); (3) endothelial release of 2-AG (Mechoulam et al., 1998; Maccarrone et al., 2002); (4) the production and release of 2-AG from platelets (Maccarrone et al., 2001a; (5) the increased production of 2-AG in endotoxic shock (Varga et al., 1998); (6) endothelium-dependent metabolism of endocannabinoids (Ho and Randall, 2007); (7) metabolism of endocannabinoids by platelets (Edgemond et al., 1998; Maccarrone et al., 1999, 2001a). 2-AG, 2-arachidonoylglycerol; THC, Δ-9-tetrahydrocannabinol.

Alterations of the hematologic cells in synthetic cannabinoid users

Functions, morphology, distributions, and index of the circulating cells are the most useful parameters that indicate various inflammatory and toxic conditions. The aim of this study was to investigate the clinical significance of these parameters in patients diagnosed with (synthetic) cannabis use disorder.

Methods

This study included a total of 40 patients in the study group ( SG ) with synthetic cannabis use; and 40 healthy individuals as the control group ( CG ). Participants, who had hematological disorders and other chronic diseases, were excluded from the study. All hematological parameters of SG were compared with CG . Neutrophil/lymphocyte ratio ( NLR ) and platelet/lymphocyte ratio ( PLR ) values were calculated and compared between groups.

Results

There were statistically significant differences between the groups in terms of WBC , MCH , RDW , MCV , MPV , and NEU , LYM %, MONO % parameters (P<.05). MPW and LYM % were significantly lower in SG compared to CG . WBC , MCH , RDW , MCV , MPV , MONO , and NEU parameters were significantly higher in SG compared to CG (P<.05). UIBC and TIBC levels were significantly higher in SG compared to CG (P<.001). Although there was statistically significant difference between groups in terms of NLR , there was no significant difference for PLR values.

Conclusion

Our data suggested that chronic use of cannabinoids can lead to deterioration of hematopoietic cells. Chronic use of cannabinoids was consistent with subthreshold/subclinical megaloblastic anemia with iron deficiency. Inflammatory cells, especially neutrophil and monocyte counts were higher in SG compared to CG . Thus, recovery of subclinical hematological parameters should be considered in cannabis use disorder patients.

1. Introduction

Over the last 20 years, there have been considerable researches involving the cannabinoids and its importance in regulating a variety of physiological and psychological processes such as pain, feeding behavior, lipid metabolism, pleasure sensation, and immune system.1, 2, 3 Cannabinoids are usually classified as endocannabinoids, phytocannabinoids, and synthetic cannabinoids.4 Synthetic cannabinoids are in the group of drugs called “new psychoactive substances” and these technically synthetic cannabinoid receptor agonists are designer drugs that mimic the psychoactive effects of cannabis.5, 6 They were synthesized in the 1970s, and most known and common synthetic cannabinoids were coded as JWH‐series (John W. Huffman), HU‐series (Hebrew University), and AM‐series (Alexandros Makriyannis). They were first marketed as legal cannabis alternatives in Europe in the early 2000s.7 Synthetic cannabinoids are synthesized in underhand laboratories and are usually in white color like salt, mixed with acetone, and then the mixture is sprayed on dried plant materials. They are generally used like marijuana by smoking and other inhalation ways (pipes, water pipes (bongs or hookahs), cigarettes (joints or reefers), or, most recently, in the paper from hollowed out cigars (blunts)).8, 9 The prevalence of use of synthetic cannabinoid is low in the large segment of the community (<1%), but it is higher among students, youngsters, and some special groups according to the drug tests.10 Synthetic cannabinoids are widely used in Turkey; however, there is no study for the epidemiologic data. It has both similar and different pharmacokinetic and pharmacodynamic mechanisms with the major active component of marijuana (Δ(9)‐tetrahydrocannabinol‐THC).11, 12 They have hundreds of chemical types, which are usually called K2, Spice, Bonsai, Jamaica etc.13

DSM‐V (The Diagnostic and Statistical Manual of Mental Disorders) defines cannabis use disorder as the problematic pattern of cannabis use leading to clinically significant impairment or distress, as manifested by at least two symptoms, forming within a 12‐month period. Cannabis use disorder and the other cannabis‐related disorders include problems that are associated with substances derived from the cannabis plant and chemically similar synthetic compounds.13

Effects of synthetic cannabinoids on the central nervous system are similar to other cannabinoids.14, 15 In reference to these effects, cannabinoid ligands bind with specific G protein‐coupled receptors (CB1 receptor and the CB2 receptor) and activate the endocannabinoid system. Synthetic cannabinoids have potent agonism to cannabinoid receptors differentially from THC; thus, THC has partial agonism.12 CB1 receptors influence the central nervous system and cause thermoregulation disorders, psychotic episodes, memory disorders, antiemetic activity, appetite enhancer activity, anxiety, and stress relieving activities.16, 17 CB2 receptors were found in immune system such as thymus, tonsils, marginal zone of the spleen, B lymphocytes, T lymphocytes, macrophages, monocytes, natural killer (NK) cells, and polymorphonuclear cells. According to the earlier studies in the literature, cannabinoids appear to influence immune function, especially through CB2 receptors18, 19, such as inhibition of the functions of macrophage and macrophage‐like cells, suppression of B and T lymphocytes and cytolytic activity of NK cells, proliferation and maturation of cytotoxic T lymphocytes, affecting immune cells’ consolidation and chemotaxis, suppressing the antibody response in humans and animals, suppressing a variety of activities of T lymphocytes. It is well known that endocannabinoid‐anandamides have anti‐inflammatory effects but endocannabinoid 2‐Arachidonoylglycerol (2‐AG) shows agonist behavior against CB1 and CB2 receptors and it is speculated that it has pro‐inflammatory effects on immune function in contrast to anandamides20. So there are different hypotheses about the kind of effects of endocannabinoids on immune system.

Some effects such as inflammatory disorders may impair function or synthesis processes resulting in some changes on the cell morphology. For example, hemocytometer parameters like red blood cell (RBC) count, mean red blood cell volume (MCV), and red blood cell distribution width (RDW) are frequently used for anemia diagnosis.21, 22 Previous studies have showed that RDW is an important diagnostic and prognostic predictor of various non‐hematologic diseases such as cardiovascular and metabolic diseases,23, 24, 25 autoimmune disease26, and cancer.27 However, the exact mechanisms underlying the association between RDW and these diseases remain unknown.

Platelets (PLTs) have major effects on homeostasis cascades, and they are also related to inflammatory events. MPV is a reflection of both pro‐inflammatory and prothrombotic conditions and it has been regarded as a prognostic marker of arterial and venous thrombosis.28 PLTs are highly activated when inflammatory mediators are released29 and the mean platelet volume (MPV) and platelet distribution width (PDW) are affected in patients with inflammatory and infectious disorders such as rheumatoid arthritis and ankylosing spondylitis.29, 30, 31, 32 According to literature, psychiatric disorders such as schizophrenia, unipolar depression, and bipolar disorder have abnormal (too low or too high) platelet counts and MPV parameters. For example, the mean number of platelets are lower in patients with schizophrenia and higher in patients with unipolar depression.33 According to the results of several studies in the literature, platelet activation is associated with an increased risk of other comorbidity.34, 35 Previous studies demonstrated endocannabinoids’ effects on platelet aggregation in blood and platelet shape change, secretion, and aggregation.36 Interactions between endothelial surface, platelets, and white blood cells during the inflammatory cascade may promote chronic illnesses and psychiatric disorders.37, 38 In addition, many psychiatric disorders are shown to have a strong relationship with the immune system.

White blood cells, especially neutrophils, play a crucial role in the regulation of inflammatory response. During the inflammatory response, circulating neutrophils are increased and formed with relative lymphopenia, primarily due to increased apoptosis and secondarily due to increased stress hormones such as corticosteroids.39, 40 The earlier studies indicated that increased leukocyte damages the endothelium surface and causes venous thrombosis.41 Neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR), which are currently investigated for systemic inflammatory diseases and psychological stress, are the new predictors rising in the literature. This ratio reflects both neutrophilia, which demonstrates the acute inflammatory condition and lymphopenia, as well as physiological stress. High NLR has been reported to be a predictor for prognosis of various disorders such as cancer,42 cardiovascular diseases,43 and autoimmune and inflammatory disorders.44 Hemogram panels can reflect various toxic or inflammatory systemic deteriorations, although, some subclinical influences may be masked if the calculated value is in the normal range.

Synthetic cannabinoids have growing usage rate among substance users. There are many kinds of synthetic cannabinoids and it is hard to accept all of these effects of synthetic cannabinoid similar to the ones of cannabinoids or each other’s. There are very limited data about the hematological effects of synthetic cannabinoids and NLR and PLR are not investigated yet to the best of our knowledge. We wondered what happens with the chronic usage of synthetic cannabinoids on hematological parameters including the new trend parameters such as NLR and PLR. The aim of our study was to investigate the clinical significance of these parameters in cannabis use disorder patients, who had normal blood hemogram test results.

2. Materials and Methods

2.1. Study design

Cannabis use disorder patients, who were admitted to Sakarya University Education and Research Hospital Alcohol and Substance Treatment and Education Center inpatient clinic between October 2014 and Jun 2016, were evaluated. The control group consisted of healthy individuals, who have voluntarily participated in the study. Ethics committee approval was received from the local ethics committee.

Patients were interviewed by an experienced psychiatrist and evaluated according to the criteria of DSM‐V for cannabis use disorder.45 A total of 110 subjects, who have been synthetic cannabinoid users for more than 1 year, were subjected to pre‐assessment. The ones who have polysubstance use disorder or comorbid chronic or active organic disorders were excluded from the study. All patients included in the study were active cannabinoid users according to their urine analysis. All patients were also evaluated for HIV, hepatitis, and tuberculosis and the ones with positive markers were excluded. Finally, 70 patients were excluded and the remaining 40 patients were included in the study according to the inclusion criteria. Since the majority of patients with the cannabis use disorder were cigarette smokers; the control group was similarly created with matching number of smoking individuals.

2.2. Laboratory analysis

2.2.1. Hematological analysis

At the first day of their hospitalization, EDTA blood samples (BD Vacutainer K2EDTA Plus plastic tubes; Becton Dickinson, Franklin Lakes, NJ, USA) were collected from each patient at the time of admission and hemogram parameters were measured using aperture‐impedance technology. Neutrophil/lymphocyte ratio (NLR) was calculated by rating neutrophil count to lymphocyte count (PLR), which was calculated by rating the count of lymphocyte to platelet count. Unsaturated iron‐binding capacity (UIBC) and total iron‐binding capacity (TIBC) were measured to understand iron levels for etiology of anemia diagnosis. The same procedure was applied for the control group. All hematological parameters of CG and SG groups were compared with each other.

2.2.2. Analysis of the urine tests

Cloned Enzyme Donor Immune Assay (CEDIA) was used as the immunoassay method during the analysis of the urine tests. Detected substrates consisted of amphetamine, benzodiazepine, barbiturate, opioids, 3,4‐metilenedioksi‐N‐metilamfetamin (MDMA), synthetic cannabinoids, THC, and buprenorphine for drugs consumption, and ethyl glucuronide for alcohol consumption.

We used the cut‐off levels in workplace drug testing that are recognized values for groups of drugs to determine whether a sample is positive or negative. Any result below the cut‐off level was reported as negative, and results above the cut‐off value were reported as either non‐negative (for screening tests) or positive (for confirmed positive results).

Statistical analysis

SPSS for Windows statistical package version 22 (SPSS Inc., Chicago, IL, United States) was used for all statistical analyses. The numerical data were expressed as means and standard deviations, and the categorical data were expressed as frequencies and percentages. Chi‐square test was used for categorical variables and independent samples t‐test was used to make comparisons between two groups to determine significant differences between groups. Linear variables of hematological parameters of the SG and CG were compared with student’s t‐test. In addition, neutrophil/platelet ratio and neutrophil/lymphocyte ratio were compared between two groups. A level of P<.05 indicated statistical significance.

3. Results

3.1. Sociodemographic attributes and clinical features of patients with cannabis use disorders

Cannabis use disorders group (Synthetic Cannabinoid) (SG) with 40 patients (mean age: 28.55±7.08 years), and 40 healthy subjects group (CG) (mean age: 30.77±6.30 years) were included in the study. There was no statistically significant difference between groups in terms of age. Both groups consisted of 38 men and 2 women.

Erythrocyte series and serum iron profiles’ characteristics of SG and CG groups and inflammatory series and platelets’ characteristics of both groups are given in Tables  1 and ​ and2 2 .

Table 1

Erythrocyte series and serum iron profiles’ parameters of groups