Can benzos cause cancer?

September 6, 2019

Potency is not the same as affinity to the receptor, although close. Potency indicates the concentration/dose at which the drug has a certain effect. For example, K at 0.5 mg has the same effect as V at 10 mg. Therefore, K is more potent.

Where are you getting this definition? 0.5mg of K does not have the same effect as 10mg diazepam. That is only a rough equivalency. They have varying hypnotic, amnesic and muscle relaxant properties. If potency referred to the weight of the dosage that is diazepam equivalent, then the potency classification chart in the article I posted would make no sense. In the chart, you can see that Flurazepam is classed as a medium potency benzo, while temazepam is classed as a low-potency benzo. Both have 30mg diazepam equivalent doses. So it makes no sense to class one as low-potency and another as medium potency if the definition of potency has anything to do with the mg dosage that is diazepam equivalent. I think you guys are confusing the matter by continually citing the mg of the equivalent dosages.

Don't get me wrong, I respect you guys and everything, but if I have to choose between your definition of potency and that implied by a chart that is central to a highly cited review article on benzo potency in the Clinical Journal of Psychiatry, I'm going to go with the article

September 7, 2019

Why would lower potency make you doubt the veracity of the research? If you read review articles from mainstream psychiatrists, they acknowledge that stronger potency is positively correlated with adverse events and more severe withdrawal syndromes, as well as tolerance that is quicker to develop and amnesic effects. See this article, for example: https://www.ncbi.nlm.nih.gov/pubmed/15078112
I think potency refers mainly to the strength of affinity for benzodiazepine receptors, if you are able to view the chart in that review. Dosage levels in terms of mg do not really correlate with their definition of potency (ie some benzos that have a higher diazepam equivalency dosages are classed as a similar potency (Flurazepam), whereas some that have the same dosage equivalency (10mg) are classed as low potency.) I'm not sure if that's what you meant in your explanation, though.

Assuming that the rates of higher cancer are not caused by specific, direct effects upon GABA receptors, we'd probably expect less potent benzodiazepines (which would be taken in higher doses) to have greater cancer-causing effects. It also should remembered that diazepam metabolizes into several other benzodiazepines before being excreted, so each of those compounds will have their own negative 'cancer-causing' effects too. This is why the relatively low rates of cancer observed in those taking diazepam makes little sense to me. In fact, they had lower rates of cancer than those who took no benzodiazepines.

One person taking clonazepam; another taking diazepam: all other things being equal, you'd expect the person taking diazeapm to be on 10-20 times the dose of the person taking clonazepam to achieve a similar clinical effect. So, why do those taking diazepam experience lower rates of cancer? Again, diazepam is actually akin to taking (the metabolites) nordiazepam, temazepam, and oxazepam too. Now, oxazepam is the only metabolite which features in the study. I expect that is because the other two are not prescribed in Taiwan.

The above does not prove the study wrong. It is, though, an anomaly I'd expect to be mentioned at least.

Colin, that is a good argument against the potency hypothesis. I think we may be looking at the wrong study though. I've looked it over, and although the results are similar to some of the other studies on cancer, I don't think this particular one is good enough. I've got a few problems with it, like the sample sizes for individual benzos don't seems sufficient, the daily dosage equivalents are all screwy, and they are missing data on important confounding variables. I'm glad they tried to do the research, but the limitations on this one are too great. I'll find a better quality one later. There are quite a few to choose from, such as those collected in this analysis: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731963/

September 7, 2019

Don’t shoot the messenger, folks, and don’t read these if you’re not up to it. For those seeking research results:

ncbi 2015: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4602739/

Mad in America 2016: https://www.madinamerica.com/2016/03/is-long-term-use-of-benzodiazepine-a-risk-for-cancer/

Those 2 links are the same "study". And it is a correlation analysis, and cites zero research regarding causality.

And it states: "The carcinogenicity of benzodiazepines (BZDs) is still unclear"

Yes, and I think if people just want to skip to the end of the study and read the "Limitations", that should say it all. Very often, many of these studies are hardly worth the paper they're printed on.

Seriously ... open, honest discussion is, I believe, all around the best way to go because much of the time we discover that, in reality, the "truth" turns out to be not that scary after all.

Regarding correlational studies. I think the following thread is really a worthwhile read. Not scary, don't worry, lol, it's actually quite humorous and entertaining, and I think very effectively illustrates why it makes sense for everyone to adopt a healthy level of skepticism. And poses the question, how "scientific" exactly is much of the published "science"?

Lean beef linked to atheism?
http://www.benzobuddies.org/forum/index.php?topic=149076.msg2003185#msg2003185

The audio link in the above post appears to be no longer valid, so here, this one works:

https://www.cbc.ca/player/play/2682054298

And read further down on that thread to see whether left-handedness is higher among those suffering from psychosis.

Please update your original post with a working link.

Done!

September 7, 2019

People have been taking benzos for 50-60 years. If they were carcinogen, we would know it by now.

Right, but you would also think a much simpler and more easily demonstrated problem - that anything beyond short-term usage can be extremely problematic - would also be more widely known. But it isn't.

I agree.

It is widely known that benzos cause dependence.

I said problematic, not dependence. Most physicians do not seem to be able to recognize that health problems in patients taking benzodiazepines long term are caused by the drug. Unless you think they do recognize it but choose not to tell the patient. That is possible. The main driver of increasing benzo usage has been long term prescriptions.

September 7, 2019

Potency is not the same as affinity to the receptor, although close. Potency indicates the concentration/dose at which the drug has a certain effect. For example, K at 0.5 mg has the same effect as V at 10 mg. Therefore, K is more potent.

Where are you getting this definition? 0.5mg of K does not have the same effect as 10mg diazepam. That is only a rough equivalency. They have varying hypnotic, amnesic and muscle relaxant properties. If potency referred to the weight of the dosage that is diazepam equivalent, then the potency classification chart in the article I posted would make no sense. In the chart, you can see that Flurazepam is classed as a medium potency benzo, while temazepam is classed as a low-potency benzo. Both have 30mg diazepam equivalent doses. So it makes no sense to class one as low-potency and another as medium potency if the definition of potency has anything to do with the mg dosage that is diazepam equivalent. I think you guys are confusing the matter by continually citing the mg of the equivalent dosages.

Don't get me wrong, I respect you guys and everything, but if I have to choose between your definition of potency and that implied by a chart that is central to a highly cited review article on benzo potency in the Clinical Journal of Psychiatry, I'm going to go with the article

I'm a pharmacologist with a PhD (and an MD) and I got that definition of potency from school. It doesn't come from any chart. Now I agree that the in vivo equivalency of the various benzos are just rough approximations. That is because they have different absorptions and metabolism and thus they don't hit the benzo receptors at the same time and for the same time period. In addition the absorption and metabolism of benzos vary among individuals. The rough approximations that are in part based on Dr. Ashton's studies are pretty good from what I see.

September 7, 2019

These are just some:

Pancytopenia associated with clonazepam

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2915945/?report=reader

Genotoxicity and carcinogenicity studies of benzodiazepines

http://www.sciencedirect.com/science/article/pii/S1043661807001582?via%3Dihub

Suppressive effects of alprazolam on the immune response of mice.

https://www.ncbi.nlm.nih.gov/m/pubmed/2071299/

Assessment of single-dose benzodiazepines on insulin secretion, insulin sensitivity and glucose effectiveness in healthy volunteers: a double-blind, placebo-controlled, randomized cross-over trial

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC387833/?report=reader

Stress, neuropsychiatric disorders and immunological effects exerted by benzodiazepines.

https://www.ncbi.nlm.nih.gov/m/pubmed/9653667/

Identification of a 17-kDa protein associated with the peripheral-type benzodiazepine receptor in vascular and other smooth muscle types.

https://www.ncbi.nlm.nih.gov/m/pubmed/1650838/

Effects of different doses and schedules of diazepam treatment on lymphocyte parameters in rats.

https://www.ncbi.nlm.nih.gov/m/pubmed/20846531/

Cytogenetic activity of newly synthesized 1,5-benzodiazepines in normal human lymphocyte cultures.

https://www.ncbi.nlm.nih.gov/m/pubmed/20373848/

Effects of alprazolam on T-cell immunosuppressive response to surgical stress in mice.

https://www.ncbi.nlm.nih.gov/m/pubmed/1649692/

Enigma of the peripheral benzodiazepine receptor.

https://www.ncbi.nlm.nih.gov/m/pubmed/10581326/

Genetic toxicology of four commonly used benzodiazepines: a review.

https://www.ncbi.nlm.nih.gov/m/pubmed/8692185/

Diazepam leads to enhanced severity of orthopoxvirus infection and immune suppression.

https://www.ncbi.nlm.nih.gov/m/pubmed/20659521/

Immunomodulating effects of tofizopam (Grandaxin) and diazepam in vitro.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1781640/

Calcium channel blockers, apoptosis and cancer: is there a biologic relationship?

https://www.ncbi.nlm.nih.gov/m/pubmed/10588195/

Effects of midazolam on equine innate immune response: a flow cytometric study.

https://www.ncbi.nlm.nih.gov/m/pubmed/12969632/

Effects of diazepam on Mycobacterium bovis-induced infection in hamsters.

https://www.ncbi.nlm.nih.gov/m/pubmed/10464392/

Alprazolam intercalates into DNA.

https://www.ncbi.nlm.nih.gov/m/pubmed/19108581/

Prenatal diazepam induced persisting depression of cellular immune responses.

https://www.ncbi.nlm.nih.gov/m/pubmed/2538699/

Impaired host resistance to Trichinella spiralis as a consequence of prenatal treatment of rats with diazepam.

https://www.ncbi.nlm.nih.gov/m/pubmed/7801325/

The effect of chronic diazepam administration on lipid peroxidation and Ca2+ -ATPase activity in rat liver.

https://www.ncbi.nlm.nih.gov/m/pubmed/18277470/

Benzodiazepine receptor agonists modulate thymocyte apoptosis through reduction of the mitochondrial transmembrane potential.

https://www.ncbi.nlm.nih.gov/m/pubmed/10202853/

Steroidogenic acute regulatory protein and peripheral-type benzodiazepine receptor associate at the mitochondrial membrane.

https://www.ncbi.nlm.nih.gov/m/pubmed/11145616/

September 7, 2019

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3203915/

Differential effects of alprazolam and clonazepam on the immune system and blood vessels of non-stressed and stressed adult male albino rats

Ghada E. Elmesallamy, Marwa A. Abass, [...], and Amal H. Atta

Additional article information

Abstract

Benzodiazepines belongs to one of the most commonly used anxiolytic and anticonvulsant drugs in the world. Full description of toxic effects on different organs is lacking for nearly all the current benzodiazepines. The aim of the current work was to study the immunologic and vascular changes induced by sub-chronic administration of alprazolam and clonazepam in non-stressed and stressed adult male albino rats. Forty-two adult male albino rats were divided into 6 groups (I): (Ia) Negative control rats, (Ib): Positive control rats received distilled water, (II): Stressed rats, (III): Non-stressed rats received daily oral dose of clonazepam (0.5 mg/kg), (IV): Stressed rats received daily oral dose of clonazepam (0.5 mg/kg), (V): Non-stressed rats received daily oral dose of alprazolam (0.3 mg/kg). (VI): Stressed rats received daily oral dose of alprazolam (0.3 mg/kg). At the end of the 4th week, total leukocyte count (WBCs) and differential count were determined, anti-sheep RBC antibody (Anti-SRBC) titer and interleukin-2 (IL-2) level were assessed, thymus glands, lymph nodes, spleens and abdominal aortae were submitted to histopathological examination. Alprazolam was found to induce a significant increase in neutrophil count and a significant decrease in lymphocytes, anti-SRBC titer and IL-2 level with severe depletion of the splenic, thymal and nodal lymphocytes, accompanied by congestion and eosinophilic vasculitis of all organs tested in comparison to clonazepam treated rats. Stress enhanced the toxic effects. It was concluded that the immune system and blood vessels can be adversely affected to a greater extent by short-term chronic administration of alprazolam than by clonazepam, and these toxic effects are aggravated by stress.

Keywords: alprazolam, clonazepam, stress, SRBC, IL-2

Introduction

Recent studies have found that stress plays a role in the etiology of many diseases. Stress is generally considered to be immunosuppressive and to increase susceptibility to infections and cancer. Paradoxically, it also exacerbates inflammatory and autoimmune diseases. Although it is well established that stress alters the release of various hormones and neurotransmitters, the mechanisms by which stress affects immune responses remain elusive (Viswanathan et al., 2005; Salak-Johnson & McGlone, 2007).

Benzodiazepines (BZD) are among the most commonly used groups of anxiolytic drugs in the world. They are indicated for treatment of generalized anxiety disorders, treatment of panic disorders with or without agoraphobia, sedation, light anesthesia and anterograde amnesia of perioperative events, control of seizures, and skeletal muscle relaxation (Iqbal et al., 2002).

Clonazepam, a benzodiazepine derivative, is used for the treatment of epilepsy, psychiatric and neurologic disorders, including panic disorders. It has also been utilized in alleviating movement disorders and restless leg syndrome in patients with end-stage renal disease (Brouns & De Deyn 2004; Morishita, 2009).

Alprazolam is one of the most commonly prescribed short-acting benzodiazepines in the childbearing period. It has replaced diazepam in drug prescription for treatment of anxiety disorders. This shift in the pattern of drug prescription was justified by the low likelihood of its accumulation (compared with diazepam) and by the sedative effects of multiple doses (Pinna et al., 1997).

All benzodiazepines, including clonazepam and alprazolam, act by enhancing γ-aminobutyric acid GABA-ergic neurotransmission through the binding on specific BZD recognition sites, within the GABA (A) receptor-ion channel complex. However, it has been found that BZD also act on peripheral benzodiazepine receptor sites (PBR) or translocator protein 18kDa (TSPO) (Gavish et al., 1999). Evidence for a direct immunomodulatory action for BZD emerged from recent studies demonstrating the presence of TSPO on immune/inflammatory cells (De Lima et al., 2010).

The production of antigen-specific antibodies represents a major defense mechanism of humoral immune responses. Data suggest that the primary antibody response to anti-sheep RBC antibody (Anti-SRBC) may be one of the most sensitive endpoints available to assess chemically induced alterations of the immune system. This endpoint has become the cornerstone of several recently established guidelines for assessing the potential immunotoxicity of xenobiotics (Ladics, 2007).

Interleukin 2 (IL-2) is secreted primarily by activated T-lymphocytes and natural killer (NK) cells. It is necessary for regulatory T cell maturation in the thymus and may also sensitize antigen-activated T cells to apoptosis. The importance of IL-2 in supporting the immune response makes this cytokine and its receptor a prime target for both activation and suppression. Additionally, its inhibition is critical for immunosuppression (Malek, 2003; Leo & Hsieh, 2008).

On reviewing the available literature from a toxicological point of view it was noticed that there was little information regarding the influence of clonazepam and alprazolam on different body tissues and cells, including the immune and vascular system. Most of the studies were focused on their alteration of the immune function rather than the structure. Therefore it was thought to be of particular interest to study the toxic effects of these commonly used drugs on these tissues at their maximum therapeutic doses.

The aim of the current work was to study the differential immunologic and vascular changes induced by sub-chronic administration of clonazepam and alprazolam in non stressed and stressed adult male albino rats.

Material and methods

Drugs

Clonazepam was obtained from Roche, F. Hoffmann-La Roche LTd, Basel, Switzerland in the form of a sterile oral solution containing 2.5 mg/ml, supplied with its dropper (1 drop contains 0.1 mg clonazepam). On administration, each 0.5 mg of the drug was diluted with 5 ml of distilled water.

Alprazolam in the form of white crystalline powder, was obtained from Amoun Pharmaceutical Industries Co., freshly prepared for oral gavage by dissolving it in distilled water (each 0.3 mg dissolved in 5 ml of distilled water).

Kits

Mouse Interleukin-2 (IL-2) ELISA kit of Bioscience, Inc, Catalog Number: 88-7024 was used as an enzyme-linked immunosorbent assay for quantitative measurement of IL-2 in serum.

Sheep RBCs

Sheep RBCs were obtained from the laboratory of Zoology Department, Faculty of Veterinary Medicine, Zagazig University.

Experimental design

Forty-two adult male albino rats of 200 g average weight were brought from the Animal House, Faculty of Medicine, Zagazig University, divided into 6 groups and caged under standardized environmental conditions.

Group I: Twelve rats were equally subdivided into (Ia): Negative control non-stressed rats, received only the regular diet and tap water to determine the normal values of the performed tests. (Ib): Positive control non-stressed rats, gavaged daily with 1 ml of distilled water.

Group II: Six stressed rats, were submitted to daily restraint stress at room temperature.

Group III: Six non stressed rats were given daily oral dose of Clonazepam (0.5 mg/kg) (Paget & Barnes, 1964) for 4 weeks.

Group IV: Six stressed rats were given daily oral dose of Clonazepam (0.5 mg/kg) for 4 weeks.

Group V: Six non-stressed rats were given daily oral dose of Alprazolam (0.3 mg/kg) (Paget & Barnes, 1964) for 4 weeks.

Group VI: Six stressed rats were given daily oral dose of Alprazolam (0.3 mg/kg) for 4 weeks.

Both drugs were assessed in their maximum therapeutic dose used for treatment of generalized anxiety disorders.

At the end of the study, the rats were anesthetized with ether and 5 ml blood was collected from their retro-orbital plexus. Total leukocyte count and differential count were determined and immunological studies were performed by measuring the anti-sheep RBC hemagglutination (anti-SRBC) titer and the level of serum Interleukin-2 (IL-2). The rats were then sacrificed, the thymus glands, lymph nodes, spleens and abdominal aortae were dissected and submitted to histopathological examination.

Restraint stress procedure

It was done by the procedure described by Glavin et al. (1994). Stress was applied by placing the animals (without squeezing or compression) in well-ventilated wire mesh restrainers for a single daily session of 2.5 h beginning at 9:00 a.m. This procedure mimics stress that is largely psychological in nature.

WBCs count and differential count

Total leukocyte count was determined by following the method described by Chanarin et al. (1973), using Coulter T660 hematology analyzer, Beckman Coulter, Inc., USA. Two ml of blood were collected in tubes containing 20 µl EDTA solution and differential count was done on Leishman stained peripheral blood smear.

Humoral immune response

It was assayed by the Sheep RBC Antibody Titer (SRBC): In this test 1.5 ml of blood was collected, the serum was separated and analyzed for hemagglutination titer according to the method described by Ladics et al. (2000). Two-fold dilutions (0.025 mg) of sera were made in the microtiter plates with saline. To each well 0.025 ml of 1% (v/v/) SRBC was added. The plates were incubated at 37 °C for 1 h and then observed for hemagglutination. The highest dilution giving hemagglutination was taken as the antibody titer. The antibody titers were expressed in a graded manner, the minimum dilution (1/2) being ranked as 1. The mean ranks of different groups were compared for statistical analysis.

Cell-mediated immune response

It was assayed through determination of the cytokine Interleukin-2 (IL-2): 1.5 ml blood samples were left to clott and were then centrifuged at 3 000 rpm for 10 minutes. Serum samples were separated and kept frozen at −20 °C for determination of interleukin-2 (IL-2) by Enzyme Linked-Immuno-Sorbent Assay (ELISA) according to the method described by Hollander et al. (1998). The data analysis program automatically determined the concentrations of IL-2 in the samples by comparing the absorbency of the samples to the standard curve which demonstrated an inverse relationship between Optical Density (O.D.) and the cytokine concentration. IL-2 concentration was represented as pg/ml.

Histopathological examination

Paraffin blocks and sections of thymus glands, lymph nodes, spleens and abdominal aortae were prepared, stained with hematoxylin and eosin and subjected to routine histological examination by the method described by Bancroft & Stevens (1996).

Statistical analysis

SPSS Software program was used. Mean values (M)±SD were calculated. t-test and F test were performed. P value of less than 0.05 was considered to be significant.

Results

At the end of the 4th week of the current study, comparison between negative control rats (Group Ia) and positive control rats (Group Ib) showed a non-significant difference in all parameters tested (p>0.05) (Table 1)

Table 1

Immunologic parameters in the different study groups after 4 weeks (Anova test).

Stressed non-treated rats (Group II) showed a significant increase (p<0.05) in the mean values of neutrophils as compared to control group. However, they showed a non-significant change regarding the mean values of WBCs, lymphocytes, eosinophils and monocytes, when compared with those of the control group (p>0.05). They also exhibited a significant decrease (p<0.001) in the mean values of anti-SRBC titer and a non-significant decrease (p>0.05) in the mean values of IL-2 compared to the control group, as shown in Table 1.

Histopathological examination of the same group (Group II) showed minimal changes in the spleens and lymph nodes in the form of slight subcapsular edema, as seen in Figures ((2-a,2-a, -a,2-b),2-b), when compared to the normal architecture of the control group (Figures 1-a, -a,1-b).1-b). The thymuses showed a mild subcapsular edema, while the aortae displayed eosinophilic vasculitis (Figures 2-c, -c,2-d)2-d) as compared to the control group (Figures 1-c, -c,11-d).

Figure 1

Control rat (group I): a) Spleen section showing normal structure (H&E, × 200), b) Lymph node section showing normal structure (H&E, × 200), c) Thymus section showing normal structure (H&E, × 400), d) Large ...

Figure 2

Stressed non-treated rat (group II): a) Spleen section showing normal white pulp and proliferation of reticular cells (H&E, × 200), b) Lymph node section showing normal lymphoid follicles and mild subcapsular edema (H&E, × ...

Clonazepam-treated non-stressed rats (Group III) showed a non-significant change (p>0.05) in the mean values of WBCs, lymphocytes, neutrophils, eosinophils and monocytes when compared with those of the control group (Group I). They also exhibited a significant decrease (p<0.001) in the mean values of anti-SRBC titer and a non significant decrease (p>0.05) in the mean value of IL-2 level as compared to the control group. (Table 1).

Comparison between the clonazepam-treated non stressed rats (Group III) and the stressed non-treated rats (Group II) showed a non-significant change (p>0.05) in the mean values of all immunologic parameters tested except neutrophils. A significant increase (p<0.05) in the mean values of neutrophils was observed when compared with Group II, as shown in Table 2.

Table 2

Comparison of the mean values for each parameter assessed in the different study groups (LSD test).

The observed changes in the tested organs of the same group (Group III) were in the form of congested red pulp of the spleens with normal white pulp and slight depletion of the lymphoid follicles in the lymph node specimens (Figures 3-a, -a,3-b).3-b). Thymus glands showed subcapsular lymphoid follicles (Figure 3-c). Examination of the aortic tissues revealed multiple plaques protruding inside the arterial lumen. These plaques were composed of smooth muscles and deposition of some foam cells (Figure 3-d).

Figure 3

Clonazepam-treated unstressed rat (group III): a) Spleen section showing normal white pulp and congested red pulp (H&E, × 200), b) Lymph node section showing mild edema among slightly depleted lymphoid follicles (H&E, × ...

Clonazepam-treated stressed rats (Group IV) revealed a significant increase (p<0.05) in the mean values of neutrophils. However, the mean values of WBCs, lymphocytes, eosinophils, and monocytes showed a non-significant change (p>0.05) when compared with control rats (Group I). There was also a significant decrease (p<0.001) in the mean values of anti-SRBC titer and IL-2 level as compared to the control group (Tables 1 and and22)

Moreover, in stressed rats (Group IV) clonazepam treatment was found to induce hyaline degeneration of the wall of splenic arterioles with perivascular edema (Figure 4-a). Lymph nodes examination showed mild depletion of lymphocytes from subcapsular lymphoid follicles (Figure 4-b). The thymuses exhibited mild depletion of the cortical lymphoid follicles and medullary congestion (Figure 4-c). However, the media and intima of the arterial wall presented no changes (Figure 4-d).

Figure 4

Clonazepam-treated stressed rat (group IV): a) Spleen section showing hyaline degeneration of the wall of splenic arteriole and perivascular edema (H&E, × 400), b) Lymph node section showing mild depletion of lymphocytes from subcapsular ...

Alprazolam-treated non-stressed rats (Group V) showed a non-significant change (p>0.05) in the mean values of WBCs, lymphocytes, neutrophils, eosinophils and monocytes when compared with control rats (Group I). The mean values of anti-SRBC titer and IL-2 level presented a significant decrease (p<0.001) as compared to the control group (Tables 1 and and22)

Spleen sections of the same group (Group V) showed depletion of the marginal lymphocytes in the white pulp (Figure 5-a) and lymph nodes had a slight depletion of the lymphoid follicles, as shown in Figure 5-b. Thymus glands also had a mild depletion of lymphocytes from the lymphoid follicles and mild interstitial edema (Figure 5-c). On examination of aortic sections, edematous walls, composed of degenerated muscles with endotheliosis were observed (Figure 5-d).

Figure 5

Alprazolam-treated unstressed rat (group V): a) Spleen section showing depletion of the marginal lymphocytes in the white pulp (H&E, × 400), b) Lymph node section showing mild depletion of lymphocytes from subcapsular lymphoid follicles ...

Comparison between alprazolam-treated stressed rats (Group VI) and control rats (Group I), showed a significant decrease (p<0.05) in the mean values of lymphocytes and a significant increase (p<0.05) in those of neutrophils. In contrast, a non-significant change (p>0.05) was detected in the mean values of WBCs, eosinophils and monocytes. The mean values of anti-SRBC and IL-2 presented a significant decrease (p<0.001) when compared with those of control rats. (Tables 1 and and22).

On comparing the immunologic findings of alprazolam-treated stressed rats (Group VI) with those of the stressed non-treated rats (Group II), a significant decrease (p<0.001) was seen in the mean values of anti-SRBC titer and IL-2 level (Table 2)

Histopathological findings of the same group (Group VI) supported the previous results. Severe depletion of the white pulp lymphocytes and extensive hemorrhages in the red pulp with hemosiderosis and degenerated megakaryocytes were noticed on examination of spleen sections. Moreover, edema and histocyte infiltrations were also observed in the red pulp of the spleens (Figures 6-a, -a,6-b).6-b). Focal replacement of subcapsular follicles of the lymph nodes by reticular cells and macrophages was also detected (Figure 6-c). Furthermore, thymus glands showed marked edema and congestion with few erythrocyte and leukocyte infiltrations (Figure 6-d). Eosinophilic vasculitis was evident on examination of aortic sections with thick tunica media. Eosinophils and round cell infiltrations in the tunica adventitia were also noticed, as shown in Figure 6-e.

Figure 6

Alprazolam-treated stressed rat (group VI): a) Spleen section showing severe depletion of lymphocytes from the white pulp and extensive hemorrhages in the red pulp (H&E, × 400), b) Spleen section showing hemosiderosis, degenerated megakaryocytes ...

When comparing clonazepam-treated non-stressed rats (Group III) and alprazolam-treated non-stressed rats (Group V), a non-significant difference (p>0.05) was found in most of the parameters tested. An exception was the anti-SRBC titer, as alprazolam induced a significant decrease (p<0.05) in its mean values when compared to those of clonazepam-treated non-stressed rats. Comparison between clonazepam-treated stressed rats (Group IV) and alprazolam-treated stressed rats (Group VI), showed that alprazolam induced a significant decrease (p<0.05) in the mean values of IL-2 level compared with those induced by clonazepam (Table 2)

Finally, on observing the differential toxic effects of clonazepam treatment in non-stressed rats (Group III) and in stressed rats (Group IV), a significant decrease (p<0.05) in the mean values of anti-SRBC titer and IL-2 level was found in the clonazepam-treated stressed rats. Regarding the differential toxic effects of alprazolam treatment in non-stressed rats (Group V) and stressed rats (Group VI), it was found that alprazolam induced a significant increase (p<0.05) in the mean values of neutrophils and a significant decrease in the mean values of anti-SRBC titer and IL-2 level in stressed rats (Group VI) compared to non-stressed rats (Group V), as shown in Table 2.

Discussion

Benzodiazepines (BZPs) are widely used drugs as tranquilizers, anticonvulsants and in various other indications as light anesthesia and skeletal muscle relaxation. However, not all benzodiazepines have been tested for their immunotoxic effects (Huemer et al., 2010).

In the current study two commonly prescribed BZPs (clonazepam and alprazolam) were selected to study their immunologic and vascular toxic potential. Both anti-SRBC titer and IL-2 level were used to assess the humoral and cell-mediated immune functions.

IL-2 is necessary for the maturation of thymus lymphocytes, facilitation of immunoglobulin production made by B cells, and the differentiation and proliferation of natural killer cells (Malek, 2003; Waldmann, 2006).

Moreover, it was observed that small numbers of sheep red blood cells (SRBC) markedly augmented the proliferation of T lymphocytes activated by antigens or mitogens. This effect occurred with as few as one SRBC per T lymphocyte and with intact or osmotically lysed red cells. It was also accompanied by increase in interleukin-2 (Guo & White, 2010).

After 4 weeks of clonazepam and alprazolam administration, more pronounced immunologic and vascular toxic effects were demonstrated in stressed than in non-stressed adult male albino rats. These toxic changes were significantly expressed in the immunologic parameters as neutrophils, lymphocytes, anti-SRBC, and IL-2 (especially in alprazolam-treated stressed rats), supported by the histopathological findings as depletion of lymphocytes from the spleens, lymph nodes and thymuses, congestion, edema, hemosiderosis, inflammatory cells infiltration, large vessels eosinophilic infiltration, vasculitis, plaques and degeneration.

Our results are in accordance with those of Massoco and Palermo-Neto (2003) and Huemer et al. (2010) who stated that many benzodiazepines induced prolonged impairment of cellular immune functions in experimental animals after chronic low-dosage administration.

It has been substantiated that stressful stimuli in man as well as in animals lead to suppression of the humoral and cellular components of the immune system. The central nervous system is known to be involved in the regulation of stress-induced immune responsiveness (Yin et al., 2000).

The results of the present study also showed that restraint stress produced an inhibition of SRBC antibody, that was worsened by the administration of either clonazepzm or alprazolam with inhibition of IL-2. Kalashnikov et al. (2002) found that exposure to low doses of BDZ resulted in long-lasting reduction of TNF-alpha, IL-1, IL-6, IL-2 and interferon-gamma.

In 1991, Chang et al. found that alprazolam induced severe inhibitory effects on the proliferative responses of both B- and T-cells. It also reduced the production of IL-2 by splenic T-cells, IL-1 and tumor necrosis factor (TNF) by peritoneal macrophages. Moreover, long-lasting depression of lymphocytic proliferation has been described in offspring of rats exposed to either diazepam or clonazepam during pregnancy (Schlumpf et al., 1991).

Regarding the toxic effects on differential WBC counts, Bautista-Quach et al. (2010) reported a case of pancytopenia following oral administration of 0.25 mg clonazepam twice a day for approximately two weeks.

Lymphocytic depletion, similar to that observed in the current study, was noticed in both red and white pulp of the spleen in rats treated with diazepam (0.1 mg) daily for 4 weeks (Moris, 1991). Moreover, the observed hemosideriosis in spleens of alprazolam-treated stressed rats may be attributed to increased erythrophagia (Pacheco and Santos, 2002). In this context, it was found that diazepam accelerateed RBCs destruction via inhibition of Ca+2 ATPase on RBCs membrane (Seckin et al., 2007).

Several reports identified BZP peripheral type binding sites (PBR) in endocrine steroidogenic tissues, organs and cells of the immune system, such as macrophages and lymphocytes. Thus, the PBR may be a possible primary target for the immunotoxic effects of BDZ (Righi et al., 1999).

In the current study, immune and vascular toxic effects might be related to cortisol production. West et al., (2001) stated that stimulation of PBR in steroidogenic tissues such as the adrenals increaseed glucocorticoid production. Glucocorticoid hormones are known for their potent immunosuppressive and anti-inflammatory properties.

Corticosteroids have been shown to promote the immune response during acute stress and to inhibit the immune response during chronic stress (Dhabhar & McEwen, 1997). On the other hand, restraint stress was found to induce corticosterone secretion (Li et al., 2000).

Elevated endogenous corticosteroid levels were linked to reduced spleen cellularity and B cell function in mice (Shi et al., 2003). Moreover, they produced neutrophilic leukocytosis, lymphopenia and reduced anti-SRBC titer and IL-2 level, a picture similar to that detected in the present study (Anderson et al., 1999; Obmiñska-Mrukowicz & Szczypka, 2004).

Alprazolam was tested previously for its effects on corticosteroid production. Chronic administration of alprazolam for 29 days to hamster rats resulted in increased cortisol and total glucocorticoid levels. It was concluded that alprazolam had a stimulative effect on cortisol production (Arvat et al., 1999).

On the other hand, clonazepam was shown to counteract the effect of stress on cortisol level (Chevassus et al., 2004).

In this context, the cytokine system emerges as a good candidate. Indeed, the production and release of cytokines are known to mediate both inflammatory and immune responses (Wiegers & Reul, 1998) and not only cortisol (Almawi et al., 1996). Schlumpf et al., (1994) reported that PBR stimulation of macrophage and lymphocyte membranes changed the cytokine network.

Interestingly, the action of the PBR ligands seems to be connected with blockage of voltage-dependant Ca+2 channels (Ostuni et al., 2004). Calcium release appears to be essential for T cell activation, cytokine synthesis, and proliferation. Both increases and decreases in intracellular Ca2+ have been linked to apoptosis (Lepple-Wienhues et al., 1999; Mason, 1999).

Clonazepam was found to have a strong binding capacity to peripheral benzodiazepine receptors in rat aortic smooth muscles compared to other benzodiazepines. These binding sites were concentrated in the mitochondria (Cox et al., 1991).

Peripheral benzodiazepine receptors bind with high affinity to cholesterol and transport it across the mitochondrial membrane (Papadopoulos et al., 1997). This may explain the appearance of foam cells and degeneration of smooth muscle observed in the aortae of clonazepam treated rats.

Tanimoto et al. (1999) found that stimulation of the thymus PBR induced apoptosis in thymocytes. This action was accentuated by dexamethasone administration.

Ekonomopoulou et al., (2010) reported that alprazolam, diazepam, and lorazepam exhibited cytogenetic activity in normal human lymphocyte cultures. A possible mutagenic action could explain their immunotoxic effects (Giri & Banerjee, 1996).

Furthermore, an in vitro study carried out by Saha et al. (2009) concluded that alprazolam strongly interacted with DNA, resulting in conformational changes in the DNA. Similarly, Iakovidou-Kritsi et al., (2009) found that alprazolam induced genotoxicity and cytotoxicity in human lymphocyte cell culture at doses equivalent to oral doses, with a significant increase of Sister Chromatid Exchanges on peripheral human lymphocytes in vivo.

It seems relevant to point out that alprazolam has a triazolo- ring, and a – CH3 – group that could interact with DNA as an alkylating agent (Brambilla et al., 2007).

In contrast to the present results, Freire-Garabal et al., (1991) found that chronic administration of alprazolam for one month alleviated stress-induced suppression of thymus and spleen cellularity in mice after laparotomy. Covelli et al., (1998) also reported that alprazolam behaved as an immunoenhancer (enhancing the function.of immune cells).

Clonazepam and alprazolam appeared to modulate immune responsiveness in both non-stressed and stressed animals, albeit in a different manner, and these effects were mediated via alteration of the structure of organs of the immune system (histopathological lesions).

It was concluded that the immune system and blood vessels can be adversely affected by sub-chronic administration of alprazolam to a greater extent than by clonazepam, and these toxic effects are aggravated by stress. Further, the results of the present study raise concern regarding the safety of benzodiazepine administration over long periods.

Acknowledgements

Great thanks and gratefulness to Zoology Department, Faculty of Veterinary Medicine, Zagazig University for supplying sheep RBCs and information required for Anti-SRBC titer.

Article information

Interdiscip Toxicol. 2011 Sep; 4(3): 132–143.

Published online 2011 Sep. doi: 10.2478/v10102-011-0021-y

PMCID: PMC3203915

PMID: 22058654

Ghada E. Elmesallamy,1 Marwa A. Abass,1 Nahla A.G. Ahmed Refat,2 and Amal H. Atta3

1Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Zagazig University, Egypt

2Department of Pathology, Faculty of Veterinary Medicine, Zagazig University, Egypt

3Department of Microbiology, Faculty of Medicine, Zagazig University, Egypt

Correspondence address: Assist. Prof. Ghada Elsaid Ahmed Elmesallamy, MD. Assistant Professor of Clinical Toxicology, Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Zagazig University, Egypt. TEL.: +20552302809, E-MAIL: moc.liamtoh@0142annag

Received 2011 Feb 20; Revised 2011 Jul 1; Accepted 2011 Jul 21.

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

This article has been cited by other articles in PMC.

Articles from Interdisciplinary Toxicology are provided here courtesy of Slovak Toxicology Society SETOX & Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences

REFERENCES

Almawi WY, Beyhum HN, Rahme AA, Rieder MJ. Regulation of cytokine and cytokine receptor expression by glucocorticoids. J Leukocyte Biol. 1996;60:563–572. [PubMed]

Anderson BH, Watson DL, Colditz IG. The effect of dexamethasone on some immunological parameters in cattle. Vet Res Commun. 1999;23:399–413. [PubMed]

Arvat EB, Maccagno J, Ramunni L, Di Vito R, Giordano L, Gianotti F, Broglio F, Camanni M, Ghigo E. The inhibitory effect of alprazolam, a benzodiazepine, overrides the stimulatory effect of metyrapone-induced lack of negative cortisol feedback on corticotrophin secretion in humans. J Clin Endocrinol Metabol. 1999;84(:2611–2615. [PubMed]

Bancroft CD, Stevens A. Theory and practice of histological techniques. 4th edition. Edinburgh, London, Melbourne, New York: Churchill Livingstone Press; 1996. pp. 99–112.

Bautista-Quach MA, Liao YM, Hsue CT. Pancytopenia associated with clonazepam. J Hematol Oncol. 2010;3:24. [PMC free article] [PubMed]

Brambilla G, Carrozzino R, Martelli A. Genotoxicity and carcinogenicity studies of benzodiazepines. Pharmacol Res. 2007;56:443–58. [PubMed]

Brouns R, De-Deyn PP. Neurological complications in renal failure: a review. Clin Neurol Neurosurg. 2004;107:1–16. [PubMed]

Chanarin I, Cairns J, Waters D. Coulter blood count. J Clin Pathol. 1973;26:978. [PMC free article] [PubMed]

Chang MP, Castle SC, Norman DC. Suppressive effects of alprazolam on the immune response of mice. Int J Immunopharmacol. 1991;13:259–266. [PubMed]

Chevassus H, Mourand I, Molinier N, Lacarelle B, Jean-Frédéric B, Petit P. Assessment of single-dose benzodiazepines on insulin secretion, insulin sensitivity and glucose effectiveness in healthy volunteers: a double-blind, placebo-controlled, randomized cross-over trial. BMC Clin Pharmacol. 2004;4:1–10. [PMC free article] [PubMed]

Covelli V, Maffione AB, Nacci C, Tatò E, Jirillo E. Stress, neuropsychiatric disorders and immunological effects exerted by benzodiazepines. Immunopharmacol Immunotoxicol. 1998;20:199–209. [PubMed]

Cox DA, Ellinor PT, Kirley TL, Matlib MA. Identification of a 17-kDa protein associated with the peripheral-type benzodiazepine receptor in vascular and other smooth muscle types. J Pharmacol Exp Ther. 1991;258:702–709. [PubMed]

De Lima CB, Sakai M, Latorre AO, Moreau RL, Palermo-Neto J. Effects of different doses and schedules of diazepam treatment on lymphocyte parameters in rats. Int Immunopharmacol. 2010;10:1335–1343. [PubMed]

Dhabhar FS, McEwen BS. Acute stress enhances while chronic stress suppresses cell- mediated immunity in vivo: a potential role for leukocyte trafficking. Brain Behav Immun. 1997;11:286–306. [PubMed]

Ekonomopoulou MT, Tsoleridis CA, Argyraki M, Polatoglou E, Stephanidou-Stephanatou J, Iakovidou-Kritsi Z. Cytogenetic activity of newly synthesized 1,5-benzodiazepines in normal human lymphocyte cultures. Genet Test Mol Biomarkers. 2010;14:377–383. [PubMed]

Freire-Garabal M, Belmonte A, Orallo F, Couceiro J, Núñez MJ. Effects of alprazolam on T-cell immunosuppressive response to surgical stress in mice. Cancer Letter. 1991;58:183–187. [PubMed]

Gavish M, Bachman I, Shoukrun R, Katz Y, Ve enman L, Weisinger G, Weizman A. Enigma of the peripheral benzodiazepine receptor. Pharmacol Rev. 1999;51:629–650. [PubMed]

Giri AK, Banerjee S. Genetic toxicology of four commonly used benzodiazepines: A review. Mut Res Rev Gen Tox. 1996;340:93–108. [PubMed]

Glavin GB, Paré WP, Sandbak T, Bakke HK, Murison R. Restraint stress in biomedical research: an update. Neuroscie Biobehav Rev. 1994;18:223–249. [PubMed]

Guo TL, White KL. Comprehensive Toxicology, 2nd ed. Elsevier Ltd; 2010. Methods to assess immunotoxicity; pp. 567–590.

Hollander GA, Zuklys S, Morel C, Mizoguchi E, Mobisson K, Simpson S, Terhorst C, Wishart W, Golan DE, Burakoff SJ. Monoallelic expression of the interleukin-2 locus. Scie. 1998;279:2118–2121. [PubMed]

Huemer HP, Lassnig C, Nowotny N, Irschick EU, Kitchen M, Pavlic M. Diazepam leads to enhanced severity of orthopoxvirus infection and immune suppression. Vaccine. 2010;28:6152–6158. [PubMed]

Iakovidou-Kritsi Z, Akritopoulou K, Ekonomopoulou MT, Mourelatos D. In vitro genotoxicity of two widely used benzodiazepines: alprazolam and lorazepam. Aristotle Univ Med J. 2009;36:39–44.

Iqbal MM, Sobhan T, Ryals T. Effects of commonly used benzodiazepines on the fetus, the neonate, and the nursing infant. Psychiatr Serv. 2002;53:39–49. [PubMed]

Kalashnikov SV, Kalashnikova EA, Kokarovtseva SN. Immunomodulating effects of tofizopam (Grandaxin) and diazepam in vitro. Mediators Inflamm. 2002;11:53–59. [PMC free article] [PubMed]

Ladics GS. Use of SRBC antibody responses for immunotoxicity testing. Animal Models in Immunotoxicol. 2007;41:9–19. [PubMed]

Ladics GS, Smith C, Bunn TL, Dietert RR, Anderson PK, Wiescinski CM, Holsapple MP. Characterization of an approach to developmental immunotoxicology assessment in the rat using SRBC as the antigen. Toxicol Methods. 2000;10:283–311.

Leo CW, Hsieh CS. Antigen-specific peripheral shaping of the natural regulatory T cell population. J Exp Med. 2008;205:3105–3117. [PMC free article] [PubMed]

Lepple-Wienhues A, Belka C, Laun T, Jekle A, Walter B, Welz M, Heil L, Kun J, Weller M, Gulbins E, Lang F. Stimulation of CD95 (Fas) blocks T lymphocyte calcium channels through sphingomy. Proc Natl Acad Sci USA. 1999;96:13795–13800. [PMC free article] [PubMed]

Li K, Liege S, Moze SE, Neveu PJ. Plasma corticosterone and immune reactivity in restrained female C3H mice. Stress. 2000;3:285–298. [PubMed]

Malek TR. The main function of IL-2 is to promote the development of T regulatory cells. J Leuko Biol. 2003;74:961–965. [PubMed]

Mason RP. Calcium channel blockers, apoptosis and cancer: is there a biologic relationship? J Am Coll Cardiol. 1999;34:1857–1866. [PubMed]

Massoco C, Palermo-Neto J. Effects of midazolam on equine innate immune response: a flow cytometric study. Vet Immunol Immunopathol. 2003;95:11–19. [PubMed]

Moris GA. Autoradiographic studies on the effect of diazepam on the proliferation of rat spleen lymphocytes. Egy Ger Soc Zool. 1991;6:229–244.

Morishita S. Clonazepam as a therapeutic adjunct to improve the management of depression: a brief review. Hum. Psychopharmacol. 2009;24:191–198. [PubMed]

Obmiñska-Mrukowicz B, Szczypka M. Effects of lysozyme dimer on the cellular and humoral response in hydrocortisone treated mice. Pol J Food Nutr Sci. 2004;13:45–49.

Ostuni MA, Marazova K, Peranzi G, Vidic B, Papadopoulos V, Ducroc R, Lacapere JJ. Functional characterization and expression of PBR in rat gastric mucosa: stimulation of chloride secretion by PBR ligands. Am J Physiol Gastrointest. 2004;286:1069–1080. [PubMed]

Pacheco M, Santos MA. Biotransformation, genotoxic, and histopathological effects of environmental contaminants in European eel (Anguilla L.) Ecotoxicol Environ Safety. 2002;53:331–347. [PubMed]

Paget GE, Barnes JM. Toxicity tests. In: Laurence DR, Bacharach AL, editors. Evaluation of drug activities pharmacometrics. London and New York: Academic Press; 1964. pp. 134–166.

Papadopoulos V, Amri H, Boujrad N, Cascio C, Culty M, Garnier M, Hardwick M, Li H, Brown AS, Reversa JL, Drieu K. Peripheral benzodiazepine receptor in cholesterol transport and steroidogenesis. Steroids. 1997;62:21–28. [PubMed]

Pinna G, Galici R, Schneider HH, Stephens DN, Turski L. Alprazolam dependence prevented by substituting with the (-carboline abecarnil. Proc Natl Acad Sci. 1997;94:2719–2723. [PMC free article] [PubMed]

Righi DA, Pinheiro SR, Guerra JL, Palermo-Neto J. Effects of diazepam on Mycobacterium bovis-induced infection in hamsters. Braz J Med Biol Res. 1999;32:1145–1153. [PubMed]

Saha B, Mukherjee A, Santra CR, Chattopadhyay A, Ghosh AN, Choudhuri U, Karmakar P. Alprazolam intercalates into DNA. J Biomol Struct Dyn. 2009;26:421–429. [PubMed]

Salak-Johnson JL, McGlone JJ. Making sense of apparently conflicting data: stress and immunity in swine and cattle. J Anim Sci. 2007;85:81–88. [PubMed]

Schlumpf M, Ramseier H, Lichtensteiger W. Prenatal diazepam induced persisting depression of cellular immune responses. Life Scie. 1991;44:493–501. [PubMed]

Schlumpf M, Lichtensteiger W, Van Loveren H. Impaired host resistance to Trichinella spiralis as a consequence of prenatal treatment of rats with diazepam. Toxicol. 1994;94:223–230. [PubMed]

Seçkin S, Alsancak S, Ba(aran-Küçükgergin C, Uy M. The effect of chronic diazepam administration on lipid peroxidation and Ca 2+ -ATPase activity in rat liver. Acta Biol Hung. 2007;58:441–443. [PubMed]

Shi Y, Devadas S, Greeneltch KM, Yin D, Mufson RA, Zhou JN. Stressed to death: Implication of lymphocyte apoptosis for psycho neuroimmunology. Br Beh Imm. 2003;17:18–26. [PubMed]

Tanimoto Y, Onishi Y, Sato Y, Kizaki H. Benzodiazepine receptor agonist modulate thymocyte apoptosis through reduction of the mitochondrial transmembrane potential. Jpn J Pharmacol. 1999;79:177–183. [PubMed]

Viswanathan K, Daugherty C, Dhabhar FS. Stress as an endogenous adjuvant: augmentation of the immunization phase of cell-mediated immunity. Int Immunol. 2005;17:1059–1069. [PubMed]

Waldmann TA. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nature Rev Immun. 2006;6:595–601. [PubMed]

West LA, Horvat RD, Roess DA, Barisas BG, Juengel JL, Niswender GD. Steroidogenic acute regulatory protein and peripheral-type benzodiazepine receptor associate at the mitochondrial membrane. Endocrinol. 2001;142:502–505. [PubMed]

Wiegers GJ, Reul JM. Induction of cytokine receptors by glucocorticoids: Functional and pathological significance. Trends in Pharmacol Scie. 1998;19:317–321. [PubMed]

Yin D, Tuthill RD, Mufson A, Shi Y. Chronic restraint stress promotes lymphocyte apoptosis by modulating Cd95 expression. J Exp Med. 2000;191:1423–1428. [PMC free article] [PubMed]

September 7, 2019

https://www.ncbi.nlm.nih.gov/pubmed/27667780

International Journal of Cancer

Int J Cancer. 2017 Feb 1;140(3):513-525. doi: 10.1002/ijc.30443. Epub 2016 Oct 5.

Use of benzodiazepine and risk of cancer: A meta-analysis of observational studies.

Kim HB1,2, Myung SK3,4,5, Park YC2,6, Park B2,7.

Author information

Abstract

Several observational epidemiological studies have reported inconsistent results on the association between the use of benzodiazepine and the risk of cancer. We investigated the association by using a meta-analysis. We searched PubMed, EMBASE, and the bibliographies of relevant articles to locate additional publications in January 2016. Three evaluators independently reviewed and selected eligible studies based on predetermined selection criteria. Of 796 articles meeting our initial criteria, a total of 22 observational epidemiological studies with 18 case-control studies and 4 cohort studies were included in the final analysis. Benzodiazepine use was significantly associated with an increased risk of cancer (odds ratio [OR] or relative risk [RR] 1.19; 95% confidence interval 1.16-1.21) in a random-effects meta-analysis of all studies. Subgroup meta-analyses by various factors such as study design, type of case-control study, study region, and methodological quality of study showed consistent findings. Also, a significant dose-response relationship was observed between the use of benzodiazepine and the risk of cancer (p for trend <0.01). The current meta-analysis of observational epidemiological studies suggests that benzodiazepine use is associated with an increased risk of cancer.

September 7, 2019

Intercalation (biochemistry)

https://en.m.wikipedia.org/wiki/Intercalation_(biochemistry)

Intercalation induces structural distortions.

In biochemistry, intercalation is the insertion of molecules between the planar bases of deoxyribonucleic acid (DNA). This process is used as a method for analyzing DNA and it is also the basis of certain kinds of poisoning.

There are several ways molecules (in this case, also known as ligands) can interact with DNA. Ligands may interact with DNA by covalently binding, electrostatically binding, or intercalating.[1] Intercalation occurs when ligands of an appropriate size and chemical nature fit themselves in between base pairs of DNA. These ligands are mostly polycyclic, aromatic, and planar, and therefore often make good nucleic acid stains. Intensively studied DNA intercalators include berberine, ethidium bromide, proflavine, daunomycin, doxorubicin, and thalidomide. DNA intercalators are used in chemotherapeutic treatment to inhibit DNA replication in rapidly growing cancer cells. Examples include doxorubicin (adriamycin) and daunorubicin (both of which are used in treatment of Hodgkin's lymphoma), and dactinomycin (used in Wilm's tumour, Ewing's Sarcoma, rhabdomyosarcoma).

Metallointercalators are complexes of a metal cation with polycyclic aromatic ligands. The most commonly used metal ion is ruthenium(II), because its complexes are very slow to decompose in the biological environment. Other metallic cations that have been used include rhodium(III) and iridium(III). Typical ligands attached to the metal ion are dipyridine and terpyridine whose planar structure is ideal for intercalation.[2]

In order for an intercalator to fit between base pairs, the DNA must dynamically open a space between its base pairs by unwinding. The degree of unwinding varies depending on the intercalator; for example, ethidium cation (the ionic form of ethidium bromide found in aqueous solution) unwinds DNA by about 26°, whereas proflavine unwinds it by about 17°. This unwinding causes the base pairs to separate, or "rise", creating an opening of about 0.34 nm (3.4 Å). This unwinding induces local structural changes to the DNA strand, such as lengthening of the DNA strand or twisting of the base pairs. These structural modifications can lead to functional changes, often to the inhibition of transcription and replication and DNA repair processes, which makes intercalators potent mutagens. For this reason, DNA intercalators are often carcinogenic, such as the exo (but not the endo) 8,9 epoxide of aflatoxin B1 and acridines such as proflavine or quinacrine.

Intercalation as a mechanism of interaction between cationic, planar, polycyclic aromatic systems of the correct size (on the order of a base pair) was first proposed by Leonard Lerman in 1961.[3][4][5] One proposed mechanism of intercalation is as follows: In aqueous isotonic solution, the cationic intercalator is attracted electrostatically to the surface of the polyanionic DNA. The ligand displaces a sodium and/or magnesium cation present in the "condensation cloud" of such cations that surrounds DNA (to partially balance the sum of the negative charges carried by each phosphate oxygen), thus forming a weak electrostatic association with the outer surface of DNA. From this position, the ligand diffuses along the surface of the DNA and may slide into the hydrophobic environment found between two base pairs that may transiently "open" to form an intercalation site, allowing the ethidium to move away from the hydrophilic (aqueous) environment surrounding the DNA and into the intercalation site. The base pairs transiently form such openings due to energy absorbed during collisions with solvent molecules.

September 7, 2019

Why would lower potency make you doubt the veracity of the research? If you read review articles from mainstream psychiatrists, they acknowledge that stronger potency is positively correlated with adverse events and more severe withdrawal syndromes, as well as tolerance that is quicker to develop and amnesic effects. See this article, for example: https://www.ncbi.nlm.nih.gov/pubmed/15078112
I think potency refers mainly to the strength of affinity for benzodiazepine receptors, if you are able to view the chart in that review. Dosage levels in terms of mg do not really correlate with their definition of potency (ie some benzos that have a higher diazepam equivalency dosages are classed as a similar potency (Flurazepam), whereas some that have the same dosage equivalency (10mg) are classed as low potency.) I'm not sure if that's what you meant in your explanation, though.

Assuming that the rates of higher cancer are not caused by specific, direct effects upon GABA receptors, we'd probably expect less potent benzodiazepines (which would be taken in higher doses) to have greater cancer-causing effects. It also should remembered that diazepam metabolizes into several other benzodiazepines before being excreted, so each of those compounds will have their own negative 'cancer-causing' effects too. This is why the relatively low rates of cancer observed in those taking diazepam makes little sense to me. In fact, they had lower rates of cancer than those who took no benzodiazepines.

One person taking clonazepam; another taking diazepam: all other things being equal, you'd expect the person taking diazeapm to be on 10-20 times the dose of the person taking clonazepam to achieve a similar clinical effect. So, why do those taking diazepam experience lower rates of cancer? Again, diazepam is actually akin to taking (the metabolites) nordiazepam, temazepam, and oxazepam too. Now, oxazepam is the only metabolite which features in the study. I expect that is because the other two are not prescribed in Taiwan.

The above does not prove the study wrong. It is, though, an anomaly I'd expect to be mentioned at least.

Colin, that is a good argument against the potency hypothesis. I think we may be looking at the wrong study though. I've looked it over, and although the results are similar to some of the other studies on cancer, I don't think this particular one is good enough. I've got a few problems with it, like the sample sizes for individual benzos don't seems sufficient, the daily dosage equivalents are all screwy, and they are missing data on important confounding variables. I'm glad they tried to do the research, but the limitations on this one are too great. I'll find a better quality one later. There are quite a few to choose from, such as those collected in this analysis: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731963/

Sorry. I thought I had referenced the study I was looking at in an earlier post - I did not. It was the first study referenced in this thread (by Challis, page 1):

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4602739/

I did not realise that there had been many other studies into this. However, I am not going to worry about it. The reality is that we all are exposed to many potential cancer causing substances every day. Unless the added risk is great, the reality is that something else is much more likely to get us.

September 7, 2019

Why would lower potency make you doubt the veracity of the research? If you read review articles from mainstream psychiatrists, they acknowledge that stronger potency is positively correlated with adverse events and more severe withdrawal syndromes, as well as tolerance that is quicker to develop and amnesic effects. See this article, for example: https://www.ncbi.nlm.nih.gov/pubmed/15078112
I think potency refers mainly to the strength of affinity for benzodiazepine receptors, if you are able to view the chart in that review. Dosage levels in terms of mg do not really correlate with their definition of potency (ie some benzos that have a higher diazepam equivalency dosages are classed as a similar potency (Flurazepam), whereas some that have the same dosage equivalency (10mg) are classed as low potency.) I'm not sure if that's what you meant in your explanation, though.

Assuming that the rates of higher cancer are not caused by specific, direct effects upon GABA receptors, we'd probably expect less potent benzodiazepines (which would be taken in higher doses) to have greater cancer-causing effects. It also should remembered that diazepam metabolizes into several other benzodiazepines before being excreted, so each of those compounds will have their own negative 'cancer-causing' effects too. This is why the relatively low rates of cancer observed in those taking diazepam makes little sense to me. In fact, they had lower rates of cancer than those who took no benzodiazepines.

One person taking clonazepam; another taking diazepam: all other things being equal, you'd expect the person taking diazeapm to be on 10-20 times the dose of the person taking clonazepam to achieve a similar clinical effect. So, why do those taking diazepam experience lower rates of cancer? Again, diazepam is actually akin to taking (the metabolites) nordiazepam, temazepam, and oxazepam too. Now, oxazepam is the only metabolite which features in the study. I expect that is because the other two are not prescribed in Taiwan.

The above does not prove the study wrong. It is, though, an anomaly I'd expect to be mentioned at least.

Colin, that is a good argument against the potency hypothesis. I think we may be looking at the wrong study though. I've looked it over, and although the results are similar to some of the other studies on cancer, I don't think this particular one is good enough. I've got a few problems with it, like the sample sizes for individual benzos don't seems sufficient, the daily dosage equivalents are all screwy, and they are missing data on important confounding variables. I'm glad they tried to do the research, but the limitations on this one are too great. I'll find a better quality one later. There are quite a few to choose from, such as those collected in this analysis: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731963/

Sorry. I thought I had referenced the study I was looking at in an earlier post - I did not. It was the first study referenced in this thread (by Challis, page 1):

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4602739/

I did not realise that there had been many other studies into this. However, I am not going to worry about it. The reality is that we all are exposed to many potential cancer causing substances every day. Unless the added risk is great, the reality is that something else is much more likely to get us.

I would have wanted to think so, but I developed tumors in my neck and upper chest during the time I chose to take Xanax and then Klonopin sublingually. I began to get very tired and would feel even more sick in my body, just as if I were ingesting a known poison every time I took a dose. Especially during my last year of prescribed use.

I realized I was unwell, and when I got down to .5 Klonopin in August 2016 I couldn’t taper any longer. I felt my body communicating to me on the 25th not to take one more dose. On bb often it is advised to do a symptoms-based taper and to listen to our bodies. Mine was screaming “Not one more! Stop now!” through physical symptoms, somatic sense and intuition.

At that time the tumors had become large, they had grown significantly over the course of about a week. What had been one enlarged lymph node on the right side of my trachea below my jaw, was now many. The enlarged lymph on the right that I had thought was only a flare up of Epstein-Barr due to the stress of being on the bzd as also assumed by an E.R. doctor the last thanksgiving was now clearly not the only problem area. I was having trouble breathing, swallowing and turning my head at all. I had to sleep propped up on all the pillows I could find in my home.

I was dx’d stage 2 Hodgkin’s Lymphoma (which thankfully my oncologist said has a 98% cure rate) on October 2, 2016. I started six months of chemotherapy about a week later after getting a port placed. I was administered 6 rounds, which is 12 treatments of ABVD (four incredibly powerful "big gun" chemo drugs) plus steroids for extreme nausea every two weeks for six hours at a time during my acute phase of withdrawal.

I could barely recover enough between treatments to even feel like I had any strength to get in a car, to be driven an hour to get to the next one, be there for six hours, and have someone drive to return and pick me up and get home. Scheduling these rides was no fun. It was humiliating and energy consuming. My cognition was so bad very regularly through this that I remember many times not being able to recall all the 26 letters of the English alphabet. I don’t think anyone really wanted to stay with me there, and I really don’t blame them. I don’t think I really wanted to put my mother through having to sit there and I preferred being alone anyway, I think. All I had were the nurses and the grounding contact I was blessed with in another member of bb. I also had the option to check in on the Cancer Support Thread here from time to time. There was another member who was a comfort and a grounding factor too, but we communicated less as I went through this. I am incredibly thankful to both of these buddies, and I will always love and be grateful to them.

I was the only person anywhere close to my age, at the office there receiving treatment. I was certainly the only one in benzo withdrawal. I had to take Olanzepine, because the symptoms and feelings I was having were so unreal combined with a brutal withdrawal from a r/t. I felt, I think, especially because of the steroids like I was loosing my mind completely. It was as if I were taking something/on something in addition to the nearly unbearable symptoms of withdrawal. Wellbutrin was necessary because of how bad the depression was. I ended up having to take cannabis too, though I had been clean and sober for several years (starting 6mo.'s before my first attempt tapering Xanax Dec. '14) and had had no intention of taking any mind-altering substance again in my life. The nausea was indeed horrendously severe, though I still managed to gain 40-45lbs. So many things were so hard about all of it.

If it had not been for my faith (my God,) my cat, for the closest buddy I had at that time, bb, the kind nurses there and my mother I don’t think I would have made it. The discovery of the mess I was in in Dec. '14 along with all the symptoms and difficulty of what happens when some patients wish to discontinue their med and are labeled by professionals and pharmacists for drug-seeking and addiction as well as the severity of my final taper, was almost too much on it's own. Then there was acute withdrawal and the protracted misery to follow interwoven with significant life stressors/events. I had to put down my black lab/retriever while going through treatment whom I had had since I was 15. My intuition, my body and my thinking and research so far into all of this tell me still that benzodiazepines played a significant role in the development of cancer in my system. It is not all that fun to likely be essentially the only voice I am aware of on the planet for what I feel is yet another shocking, horrific and devastating truth about benzodiazepines: which is their carcinogenicity.

I am also thankful to the other members who were/have been wonderfully supportive in that complete nightmare of an experience; Iam, solitudeseeker, Hope76 (Christy Huff, M.D.) and Tryingtobeposotive were key in survival. I didn’t have much in terms of support because I was already going through withdrawal. I owe bb members like these, BlueRose, and so many others a debt of gratitude. This also includes you, Colin, and the moderation and entire team. There are other members who helped a great deal but don't seem open to accepting that what I've been saying about all of this is important information to consider. I do believe it is, because bb is one of the few places that there is any way to talk about this class of drugs openly and honestly. When I feel other members trying to sensor what each of us gets to write about here, I feel incredibly sad. It is frightening to think that there could be no safe place to be open about my own personal experience with these psych drugs and assessment of what I feel and think they did to me.

People here (and in general) can be cruel about this topic, obviously because it is frightening and probably for other reasons. I understand why this is and why it is difficult to be open-minded, curious, strong, compassionate, interested or objective enough to want to take in any of the information regarding the studies. It takes energy and time and also requires some knowledge of biology/immunobiology. None of it really has a whole lot to do with the pharmacokinetics, pharmacodynamics (I would argue this) or neurochemistry of these drugs. The information concerns cells, mitochondria and DNA and not the blood-brain barrier, GABA or glutamate receptors, or the CNS.

I no longer see my oncologist for follow-up scans, etc., because he refuses to acknowledge what I feel could have potentially caused the cancer in the first place. People can be condescending, cruel/accusatory, attacking and dismissive about it. I feel it is important information, however. Had I known all of this when I came to bb, though I would not have been mentally or emotionally prepared to accept this information, I would not have wasted a whole year continuing to consume the drug in order to stabilize and prepare myself for my final taper.

Some members have been invaluable to me for their validation if my experience; including PhotoBugSF, babyrex, RxDamaged, Terry38, Fi Addendum, becksblue and others. I do find it necessary to mention these people for all the invalidation, gaslighting, disbelief, indifference, anger, fear and sometimes what truly seems like outright rage I have been on the receiving end for in trying to have or communicate any personal story, perceptions, thoughts or feelings of my own. Challis was amazing, too, during that time. I am so thankful for Challis, magrita and LeslieAsh. They were and have been consistently nonjudgemental, kind and compassionate with me.

Thank you so much Data_Guy.

September 8, 2019

Thank you mon pilote for taking the time to write how these drugs have affected you. There are few on BB who can relate to this subject. Your voice is important. It takes a lot of courage to speak up on a subject that tends to be feared by so many. Thank you for being a voice for others.

I too feel pretty strongly that my cancer is linked to taking benzos/Z-drugs. Thus your heartfelt comment was easy for me to relate to.

You are a gifted writer....your contributions on BB are an important part of the whole.

September 8, 2019

Thank you mon pilote for taking the time to write how these drugs have affected you. There are few on BB who can relate to this subject. Your voice is important. It takes a lot of courage to speak up on a subject that tends to be feared by so many. Thank you for being a voice for others.

I too feel pretty strongly that my cancer is linked to taking benzos/Z-drugs. Thus your heartfelt comment was easy for me to relate to.

You are a gifted writer....your contributions on BB are an important part of the whole.

:thumbsup:

September 8, 2019

That sounds terrible, MP. Sorry you had to go through that. I can't imagine the horror of it. Benzo withdrawal and chemo would be more than most could handle.

I don't think it is too useful to deny the link between cancer and benzos, especially in this forum. Maybe you intend to ease people's fears by doing so, but we do need to consider that others on the forum have actually lived it. I don't think you can simultaneously claim that the symptoms that long term protracted members have been dealing with for 5 or 10+ years are benzo-related while claiming that other members' cancer diagnosis is unrelated, especially given there is actual evidence for the cancer diagnosis, while, as far as I know, there is comparatively very little for long-term protracted symptoms. But we know they exist. And any of us still dealing with symptoms or tapering could end up in that situation.

September 9, 2019

Thank you Data_Guy for providing some really good articles and thank you mon pilote for sharing what you went through.

To those who argue that bzds have not been proven to cause cancer, I would also add that there is no conclusive evidence/proof that bzds do not cause cancer. Nobody can go there and say with absolutely certainty "no, benzos don't do that!". They have been around for many years, but the studies are still far and few and have not been held up to modern-day FDA standards the way the other, newer classes of psychiatric drugs have. I hate to sound cynical, but there is really very little money to made or glory to be had in researching the disabling effects, including the carcinogenic and other toxic effects of benzodiazepines. At the same time, doing such research may potentially leave a person on the receiving end of lawsuits, firings, license revocations and other nastiness that strongly disincentivizes people to do this sort of research in the first place.

It makes me sad that, other than lack of funding and liability, one of the most likely reasons that these disabling and toxic effects mostly don't get researched is the NIMBY (Not in My Backyard) mentality and just plain fear of what one might find out while researching them.

I can certainly understand many people with severe health anxiety not wanting to go near these topics, but that doesn't mean that the current, up-to-date scientific findings on benzodiazepines need to be ignored, either.

September 9, 2019

Thank you Data_Guy for providing some really good articles and thank you mon pilote for sharing what you went through.

To those who argue that bzds have not been proven to cause cancer, I would also add that there is no conclusive evidence/proof that bzds do not cause cancer. Nobody can go there and say with absolutely certainty "no, benzos don't do that!". They have been around for many years, but the studies are still far and few and have not been held up to modern-day FDA standards the way the other, newer classes of psychiatric drugs have. I hate to sound cynical, but there is really very little money to made or glory to be had in researching the disabling effects, including the carcinogenic and other toxic effects of benzodiazepines. At the same time, doing such research may potentially leave a person on the receiving end of lawsuits, firings, license revocations and other nastiness that strongly disincentivizes people to do this sort of research in the first place.

It makes me sad that, other than lack of funding and liability, one of the most likely reasons that these disabling and toxic effects mostly don't get researched is the NIMBY (Not in My Backyard) mentality and just plain fear of what one might find out while researching them.

I can certainly understand many people with severe health anxiety not wanting to go near these topics, but that doesn't mean that the current, up-to-date scientific findings on benzodiazepines need to be ignored, either.

September 9, 2019

In this thread a large number of studies were cited to support that benzos cause cancer. None of those showed that benzos cause cancer in animals let alone humans.

One study is a genotoxicity study in bacteria, which doesn't mean much. The concentrations of benzos used in that study may have nothing to do with the concentrations of benzos used in humans. If you give high enough concentrations of any drug in these assays you will show toxic effects.

The other 20-30 concern the effect of benzos on the immune system, stress, kidney,etc. They are not about cancer. In addition, most of those studies were done on animals with benzo doses that are not relevant for humans.

I feel very deeply for people who were diagnosed with cancer during the benzo ordeal that we are all going through. Unfortunately, cancer will develop in about half of the population at some time during their lifetime. But this has not been shown to be caused by benzos. I agree that there are no studies showing that benzos do not cause cancer. But that doesn't mean they do.

September 9, 2019

Well said!

September 9, 2019

Well, I can say that I don't believe I would have had bladder cancer if I hadn't been on benzos. I had so many adrenaline surges and so much anxiety that I probably developed inflammation, which is a high marker for cancer. Luckily the doctor told me mine is like skin cancer. They will check it every 3 months for 2 years to make sure it's gone.

September 9, 2019

We all try to find reasons for what is happening to us. Everybody has their belief systems and that's how it should be. When it comes to science, however, the only thing that matters is empirical evidence. That means studies with sufficient statistical power done in the right way. Again, about half of us will develop cancer during our lifetimes. This may be happening at the time or after benzo withdrawal. It doesn't mean that cancer is caused by benzos or benzo withdrawal. We simply don't know as there haven't been studies to address this.

Usually, if there are indicators that some agent might cause cancer, somebody will do studies. A good example is smoking, which was suspected to cause cancer before the 1960s and studies were then conducted that proved that smoking does cause cancer.

September 9, 2019

Maugham1, that’s not correct that these studies are all solely relating to the immune system. Benzos were shown to mutate DNA. They intercalate DNA, that means they unzip the double-helix and alter the structure/sequence of DNA. This is a mutagenic quality.

They were also shown to suppress Natural Killer Cells. This is means that after a cell becomes mutated or is harmful and not healthy in some way, diseased, the odds of it continuing to exist and proliferate, and of replicating or affecting other healthy cells around it are high. Natural Killer Cells are designed for the very purpose of eliminating potentially dangerous, mutated cells.

The immune system and inflammation have a whole lot to do with the body’s ability to kill off cancer cells and assure that we don’t develop cancer. Our bodies don’t have built-in chemotherapy drugs to supply us with, what they do have is an immune system which is closely linked with the digestive and circulatory systems. Also endocrine.

Benzodiazepines were shown to affect the levels of lymphocytes. The lymphocytes are one of the body’s main defenses against diseased cells and foreign substances/agents, and as a result disease and illness. To say that the health of the immune system has nothing to do with this topic is lot like Donald Trump saying that there is no such thing as global warming and that there has been no climate change. The health of the immune system is not a small thing. There is a huge amount more to get into, with this point alone.

If you read much at all through this forum you will see people in great stress, who have massive issues with digestion and inflammation. To say that we don’t understand that inflammation in the body and cancer are connected in the year 2019 is a very uncommon opinion to have. There are many studies that describe that higher rates of inflammation can result in mutagenic changes in cells.

This isn’t to say that I feel we should all become more alarmed than necessary. It still makes sense for many to do slow tapers and ignore whatever other damage that may or may not be occurring. The point that something else will get us doesn’t do much good, nor does the statement that half of all people get cancer. I don’t know where you got “half,” but I believe the numbers are the highest they have ever been. So if we are at greater risk because of all kinds of lifestyle and environmental factors, is it really a protective measure to be ingesting yet another substance that can contribute to a suppressed immune system and further cell changes? These are things to consider, and I don’t think they should be ignored.

I don’t mean to compare you with Donald Trump, but it’s the first comparative example of what I don’t even have another or other words for that comes to my mind. Clearly the immune system plays a role, just as clearly as we are impacting global warming as a species.

I don’t think any of us are saying, “benzodiazepines will absolutely give you cancer.” I feel like/think what some of us are saying is that with the little amount of studies and research done on benzodiazepines at all for the purpose of studying any one of their potentially harmful effects in any capacity, there is enough that has been found here to create curiosity and raise questions about the subject... seeing as researchers themselves have stated at least this much to this point and some have stated that they in fact do increase the likelihood.

September 9, 2019

Thank you you guys, you all mean a lot to me. Thanks for the support and kind words and who you are as individuals.

BlueRose, you have been so lovely with me. I’m so sorry that you and Terry also have felt so many of the same feelings and have had to have the additional pain and complexity of a cancer dx. Do you still have cancer, BlueRose? I hope it would be alright to try PMing again.

I didn’t and don’t have the perfect words for now to each of you to sufficiently express how much your replies mean to me. You’re all my heroes for various and sundry other reasons.

Not that this is all about me. I’m sorry to hear that I’m not the only one who feels the dx and my ingestion of this drug are likely related. I do believe it relevant and feel the topic brings up a variety of thoughts to consider for doctors (one can hope,) those considering taking a benzo and/or using it recreationally, and those of us tapering.

September 9, 2019

This isn’t to say that I feel we should all become more alarmed than necessary. It still makes sense for many to do slow tapers and ignore whatever other damage that may or may not be occurring. The point that something else will get us doesn’t do much good, nor does the statement that half of all people get cancer. I don’t know where you got “half,” but I believe the numbers are the highest they have ever been.

I hope this link will answer your question:

https://www.medicalnewstoday.com/articles/288916.php

In the US, 1 in 2 women and 1 in 3 men will develop cancer in their lifetime. Now, a similar rate has been reported in the UK, with a new study published in the British Journal of Cancer claiming 1 in 2 men and women will be diagnosed with the disease at some point in their lives

September 9, 2019

The difference between Trump and me is that he is not an immunopharmacologist with an MD and PhD and I am. I really appreciate what others wrote about inflammation, the immune cancer and cancer but again they are laypeople and I'm an expert.

Oh, please, Maugham. This whole appeal to authority ... anyone can be anything they want to be on the internet, doesn't necessarily make it so. Has Colin verified your credentials, anyway?

September 9, 2019

The difference between Trump and me is that he is not an immunopharmacologist with an MD and PhD and I am. I really appreciate what others wrote about inflammation, the immune cancer and cancer but again they are laypeople and I'm an expert.

Oh, please, Maugham. This whole appeal to authority ... anyone can be anything they want to be on the internet, doesn't necessarily make it so. Has Colin verified your credentials, anyway?

OK, you're right. I can't claim anything unless I reveal my identity, which I won't. So I've removed that message from the site. Instead I will say that what monpilote mentioned about benzos and NK cells, lymphocytes in inflammation is circumstantial evidence. In other words monpilote says that as benzos can alter NK cell, lymphocyte function and inflammation and since NK cell, lymphocyte dysfunction, and inflammation can lead to cancer therefore benzos cause cancer. In biology that is FAULTY LOGIC. That can be checked without my claim for any type of authority.

Can benzos cause cancer?

Recommended Posts

[Da...]

Link to comment

Share on other sites

Top Posters In This Topic

Popular Days

Top Posters In This Topic

Popular Days

[Da...]

Link to comment

Share on other sites

[...]

Link to comment

Share on other sites

[Ma...]

Link to comment

Share on other sites

[Ma...]

Link to comment

Share on other sites

[mo...]

Link to comment

Share on other sites

[mo...]

Link to comment

Share on other sites

[mo...]

Link to comment

Share on other sites

[mo...]

Link to comment

Share on other sites

[Co...]

Link to comment

Share on other sites

[mo...]

Link to comment

Share on other sites

[Bl...]

Link to comment

Share on other sites

[lo...]

Link to comment

Share on other sites

[Da...]

Link to comment

Share on other sites

[Lo...]

Link to comment

Share on other sites

[Mo...]

Link to comment

Share on other sites

[Ma...]

Link to comment

Share on other sites

[be...]

Link to comment

Share on other sites

[Te...]

Link to comment

Share on other sites

[Ma...]

Link to comment

Share on other sites

[mo...]

Link to comment

Share on other sites

[mo...]

Link to comment

Share on other sites

[Ma...]

Link to comment

Share on other sites

[...]

Link to comment

Share on other sites

[Ma...]

Link to comment