Most stem cells intended for regenerative therapy are generally isolated either from the patient's  bone marrow  or from  adipose tissue . [ 15 ] [ 16 ]   Mesenchymal stem cells  can differentiate into the cells that make up bone, cartilage, tendons, and ligaments, as well as muscle, neural and other progenitor tissues. They have been the main type of stem cells studied in the treatment of diseases affecting these tissues. [ 17 ] [ 18 ]  The number of stem cells transplanted into damaged tissue may alter the efficacy of treatment. Accordingly, stem cells derived from bone marrow aspirates, for instance, are cultured in specialized laboratories for expansion to millions of cells. [ 15 ] [ 16 ]  Although adipose-derived tissue also requires processing prior to use, the culturing methodology for adipose-derived stem cells is not as extensive as that for bone marrow-derived cells. [ 19 ]  While it is thought that bone-marrow-derived stem cells are preferred for bone, cartilage, ligament, and tendon repair, others believe that the less challenging collection techniques and the multi-cellular microenvironment already present in adipose-derived stem cell fractions make the latter the preferred source for autologous transplantation. [ 20 ]


New sources of  mesenchymal stem cells  are being researched, including stem cells present in the skin and dermis which are of interest because of the ease at which they can be harvested with minimal risk to the animal. [ 21 ]  Hematopoietic stem cells have also been discovered to be travelling in the blood stream and possess equal differentiating ability as other  mesenchymal stem cells , again with a very non-invasive harvesting technique. [ 22 ]


There has been more recent interest in the use of extra embryonic  mesenchymal stem cells . Research is underway to examine the differentiating capabilities of stem cells found in the umbilical cord, yolk sac and placenta of different animals. These stem cells are thought to have more differentiating ability than their adult counterparts, including the ability to more readily form tissues of endodermal and ectodermal origin. [ 23 ]


As of 2010, there was widespread controversy over the use of human  embryonic stem cells . This controversy primarily targets the techniques used to derive new embryonic  stem cell lines , which often requires the destruction of the  blastocyst . Opposition to the use of human embryonic stem cells in research is often based on philosophical, moral, or religious objections. [ 24 ]  There is other stem cell research that does not involve the destruction of a human embryo, and such research involves adult stem cells, amniotic stem cells, and induced pluripotent stem cells.


In January 2009, the US  Food and Drug Administration  gave clearance to  Geron Corporation  for the first clinical trial of an embryonic stem-cell-based therapy on humans. The trial aimed to evaluate the drug GRNOPC1,  embryonic stem cell -derived  oligodendrocyte  progenitor cells, on people with acute  spinal cord injury . The trial was discontinued in November 2011 so that the company could focus on therapies in the "current environment of capital scarcity and uncertain economic conditions". [ 25 ]  In 2013 biotechnology and  regenerative medicine  company  BioTime  ( AMEX :  BTX ) acquired Geron's stem cell assets in a stock transaction, with the aim of restarting the clinical trial. [ 26 ]


Scientists reported 2012 that MSCs when transfused immediately within few hours post thawing may show reduced function or show decreased efficacy in treating diseases as compared to those MSCs which are in log phase of cell growth (fresh), so cryopreserved MSCs should be brought back into log phase of cell growth in  in vitro  culture before administration. Re-culturing of MSCs will help in recovering from the shock the cells get during freezing and thawing. Various MSC clinical trials which used cryopreserved product immediately post thaw have failed as compared to those clinical trials which used fresh MSCs. [ 27 ]


The ability to grow up functional adult tissues indefinitely in culture through  Directed differentiation  creates new opportunities for drug research. Researchers are able to grow up differentiated cell lines and then test new drugs on each cell type to examine possible interactions  in vitro  before performing  in vivo  studies. This is critical in the development of drugs for use in veterinary research because of the possibilities of species-specific interactions. The hope is that having these cell lines available for research use will reduce the need for research animals used because effects on human tissue  in vitro  will provide insight not normally known before the animal testing phase. [ 28 ]


To be used for research or treatment applications, large numbers of high-quality stem cells are needed. Thus, it is necessary to develop culture systems which produce pure populations of tissue-specific stem cells  in vitro  without the loss of stem-cell potential. Two main approaches are taken for this purpose: two-dimensional and three-dimensional cell culture. [ 29 ]


Cell culture in two dimensions has been routinely performed in thousands of laboratories worldwide for the past four decades. In two-dimensional platforms, cells are typically exposed to a solid, rigid flat surface on the basal side and to liquid at the apical
surface. Inhabiting such a two-dimensional rigid substrate requires a dramatic adaption for the surviving cells because they lack the extracellular matrix that is unique to each cell type which may alter cell metabolism and reduce its functionality. [ 29 ]


Three-dimensional cell culture systems may create a biomimicking microenvironment for stem cells, resembling their native three-dimensional extracellular matrix (ECM). Advanced biomaterials have significantly contributed to three-dimensional cell culture systems in recent decades, and more unique and complex biomaterials have been proposed for improving stem-cell proliferation and controlled differentiation. Among them, nanostructured biomaterials are of particular interest because they have the advantage of a high surface-to-volume ratio, and they mimic the physical and biological features of natural ECM at the nanoscale. [ 29 ]


Stem cells are thought to mediate repair via five primary mechanisms: 1) providing an anti-inflammatory effect, 2) homing to damaged tissues and recruiting other cells, such as  endothelial progenitor cells , that are necessary for tissue growth, 3) supporting tissue remodeling over scar formation, 4) inhibiting  apoptosis , and 5) differentiating into bone, cartilage, tendon, and ligament tissue. [ 30 ] [ 31 ]


To further enrich blood supply to the damaged areas, and consequently promote tissue regeneration, platelet-rich plasma could be used in conjunction with stem cell transplantation. [ 20 ] [ 15 ]  The efficacy of some stem cell populations may also be affected by the method of delivery; for instance, to regenerate bone, stem cells are often introduced in a scaffold where they produce the minerals necessary for generation of functional bone. [ 20 ] [ 15 ] [ 32 ] [ 16 ]


Stem cells have been shown to have low immunogenicity due to the relatively low number of MHC molecules found on their surface. In addition, they have been found to secrete chemokines that alter the immune response and promote tolerance of the new tissue. This allows for  allogeneic  treatments to be performed without a high rejection risk. [ 23 ]


Research has been conducted on the effects of stem cells on animal models of  brain degeneration , such as in  Parkinson's disease ,  Amyotrophic lateral sclerosis , and  Alzheimer's disease . [ 33 ] [ 34 ] [ 35 ]  Preliminary studies related to  multiple sclerosis  have been conducted, [ 36 ] [ 37 ] [ 38 ]  and a 2020 phase 2 trial found significantly improved outcomes for  mesenchymal stem cell  treated patients compared to those receiving a sham treatment. [ 39 ]  In January 2021 the FDA approved the first clinical trial for an investigational stem cell therapy to restore lost brain cells in people with advanced Parkinson's disease. [ 40 ]


Healthy adult brains contain  neural stem cells , which divide to maintain general stem-cell numbers, or become  progenitor cells . In healthy adult laboratory animals, progenitor cells migrate within the brain and function primarily to maintain neuron populations for  olfaction  (the sense of smell). Pharmacological activation of  endogenous  neural stem cells has been reported to induce  neuroprotection  and behavioral recovery in adult rat models of neurological disorders. [ 41 ] [ 42 ] [ 43 ]


Stroke and  traumatic brain injury  lead to  cell death , characterized by a loss of neurons and  oligodendrocytes  within the brain. Clinical and animal studies have been conducted into the experimental use of stem cells in cases of  spinal cord injury . [ 44 ] [ 45 ] [ 46 ] [ 38 ]


In 2017, a small-scale study on individuals 60 years or older with aging frailty showed, after intravenous treatment with  Mesenchymal stem cells (MSC)  from healthy young donors, significant improvements in physical performance measures. MSC helps with the blockade of inflammation by decreasing it, causing the effects of frailty to reverse. [ 47 ]


In 2012, stem cells were studied in people with severe  heart disease . [ 48 ]  The work by  Bodo-Eckehard Strauer [ 49 ]  was discredited by identifying hundreds of factual contradictions. [ 50 ]  Among several clinical trials reporting that adult stem cell therapy is safe and effective, actual evidence of benefit has been reported from only a few studies. [ 51 ]  Some preliminary clinical trials achieved only modest improvements in heart function following the use of  bone marrow  stem cell therapy. [ 52 ] [ 53 ]


Stem-cell therapy for the treatment of myocardial infarction usually makes use of autologous bone marrow stem cells, but other types of adult stem cells may be used, such as adipose-derived stem cells. [ 54 ]


Possible mechanisms of recovery include: [ 33 ] Generation of heart muscle cells, Stimulating growth of new blood vessels to repopulate damaged heart tissue and secretion of  growth factors .


The specificity of the human immune-cell repertoire is what allows the human body to defend itself from rapidly adapting antigens. However, the immune system is vulnerable to degradation upon the pathogenesis of disease, and because of the critical role that it plays in overall defense, its degradation is often fatal to the organism as a whole. Diseases of hematopoietic cells are diagnosed and classified via a subspecialty of pathology known as  hematopathology . The specificity of the immune cells is what allows recognition of foreign antigens, causing further challenges in the treatment of immune disease. Identical matches between donor and recipient are no longer required for successful transplantation.  Rather, haploidentical matches have facilitated numerous transplants, given improvements in post-transplant immunosuppressive regimens. [ 55 ]  Research using both hematopoietic adult stem cells and embryonic stem cells has provided insight into the possible mechanisms and methods of treatment for many of these ailments. [ 56 ]


Fully mature human  red blood cells  may be generated  ex vivo  by  hematopoietic stem cells  (HSCs), which are precursors of red blood cells. In this process, HSCs are grown together with  stromal cells , creating an environment that mimics the conditions of bone marrow, the natural site of red-blood-cell growth.  Erythropoietin , a  growth factor , is added, coaxing the stem cells to complete terminal differentiation into red blood cells. [ 57 ]  Further research into this technique should have potential benefits for gene therapy, blood transfusion, and topical medicine.


In 2004, scientists at  King's College London  discovered a way to cultivate a complete tooth in mice [ 58 ]  and were able to grow bioengineered teeth stand-alone in the laboratory. Researchers are confident that   tooth regeneration  technology can be used to grow live teeth in people.


In theory, stem cells taken from the patient could be coaxed in the lab turning into a tooth bud which, when implanted in the gums, will give rise to a new tooth, and would be expected to be grown in a time over three weeks. [ 59 ]  It will fuse with the jawbone and release chemicals that encourage nerves and blood vessels to connect with it. The process is similar to what happens when humans grow their original adult teeth. Many challenges remain, however, before stem cells can be a choice for the replacement of missing teeth in the future. [ 60 ] [ 61 ]


Heller has reported success in re-growing cochlea hair cells with the use of  embryonic stem cells . [ 62 ]


In a 2019 review that looked at hearing regeneration and regenerative medicine, stem cell-derived otic progenitors have the potential to greatly improve hearing. [ 63 ]


Since 2003, researchers have successfully transplanted corneal stem cells into damaged eyes to restore vision. "Sheets of retinal cells used by the team are harvested from aborted fetuses, which some people find objectionable." When these sheets are transplanted over the damaged  cornea , the stem cells stimulate renewed repair, eventually restoring vision. [ 64 ]  The latest such development was in June 2005, when researchers at the  Queen Victoria Hospital  of  Sussex , England were able to restore the sight of forty people using the same technique. The group, led by  Sheraz Daya , was able to successfully use adult stem cells obtained from the patient, a relative, or even a  cadaver . Further rounds of trials are ongoing. [ 65 ]


People with  Type 1 diabetes  lose the function of insulin-producing  beta cells  within the pancreas. In a 2007 publication of experiments, scientists have been able to coax embryonic stem cells to turn into beta cells in the lab. In theory, if the beta cell is transplanted successfully, they will be able to replace malfunctioning ones in a diabetic patient. [ 66 ]  There are adverse effects of high glucose concentrations on stem cell therapy, however. [ 67 ]


As of 2017, use of  mesenchymal stem cells (MSCs)  derived from adult stem cells was under preliminary research for potential  orthopedic  applications in bone and muscle trauma,  cartilage  repair,  osteoarthritis ,  intervertebral disc  surgery,  rotator cuff  surgery, and  musculoskeletal disorders , among others. [ 68 ]  Other areas of orthopedic research for uses of MSCs include  tissue engineering  and  regenerative medicine . [ 68 ]


Stem cells can also be used to stimulate the growth of human tissues. In an adult, wounded tissue is most often replaced by  scar tissue , which is characterized in the skin by disorganized collagen structure, loss of hair follicles and irregular vascular structure. In the case of wounded fetal tissue, however, wounded tissue is replaced with normal tissue through the activity of stem cells. [ 69 ]  A possible method for tissue regeneration in adults is to place adult stem cell "seeds" inside a tissue bed "soil" in a wound bed and allow the stem cells to stimulate differentiation in the tissue bed cells. This method elicits a regenerative response more similar to fetal wound-healing than adult scar tissue formation. [ 69 ]  As of 2018, researchers were still investigating different aspects of the "soil" tissue that are conducive to regeneration. [ 69 ]  Because of the general healing capabilities of stem cells, they have gained interest for the treatment of cutaneous wounds, such as in  skin cancer . [ 70 ]


In 2013, scientists have been investigating an alternative approach to treating HIV-1/AIDS, based on the creation of a disease-resistant immune system through transplantation of autologous, gene-modified (HIV-1-resistant) hematopoietic stem and progenitor cells (GM-HSPC). [ 71 ]


In 2013, studies of autologous bone marrow stem cells on ventricular function were found to contain "hundreds" of discrepancies. [ 50 ]  Critics report that of 48 reports, just five underlying trials seemed to be used, and that in many cases whether they were randomized or merely observational accepter-versus-rejecter, was contradictory between reports of the same trial. One pair of reports of identical baseline characteristics and final results, was presented in two publications as, respectively, a 578-patient randomized trial and as a 391-subject observational study. Other reports required (impossible) negative standard deviations in subsets of people or contained fractional subjects, negative NYHA classes. Overall, many more people were reported as having receiving stem cells in trials, than the number of stem cells processed in the hospital's laboratory during that time. A university investigation, closed in 2012 without reporting, was reopened in July 2013. [ 72 ]


In 2014, a  meta-analysis  on stem cell therapy using bone-marrow stem cells for heart disease revealed discrepancies in published clinical trial reports, whereby studies with a higher number of discrepancies showed an increase in effect sizes. [ 73 ]  Another meta-analysis based on the intra-subject data of 12 randomized trials was unable to find any significant benefits of stem cell therapy on primary endpoints, such as major  adverse events  or increase in heart function measures, concluding there was no benefit. [ 74 ]


2018 results of the TIME trial, which used a randomized, double-blind, placebo-controlled trial design, concluded that "bone marrow mononuclear cells administration did not improve recovery of LV function over 2 years" in people who had a myocardial infarction. [ 75 ]  Accordingly, the BOOST-2 trial conducted in 10 medical centers in Germany and Norway reported that the trial result "does not support the use of nucleated BMCs in patients with STEMI and moderately reduced LVEF". [ 76 ]  Furthermore, the trial also did not meet any other secondary MRI endpoints, [ 77 ]  leading to a conclusion that intracoronary bone marrow stem cell therapy does not offer a functional or clinical benefit. [ 78 ]


In 2021, stem cell injections in the US have caused grave infections in at least 20 patients who received umbilical cord blood-derived products marketed as "stem cell treatment". [ 79 ]  In 2023, the case of a woman who was infected with  Mycobacterium abscessus  and sustained meningitis after stem cell treatment for multiple sclerosis at a commercial clinic in Baja California, Mexico was published. [ 80 ]


Research conducted on horses, dogs, and cats has led to the development of stem cell treatments in veterinary medicine which can target a wide range of injuries and diseases, such as  myocardial infarction , stroke,  tendon  and  ligament  damage,  osteoarthritis ,  osteochondrosis  and  muscular dystrophy , both in large animals as well as in humans. [ 81 ] [ 82 ] [ 83 ] [ 84 ]  While investigation of cell-based therapeutics generally reflects human medical needs, the high degree of frequency and severity of certain injuries in  racehorses  has put veterinary medicine at the forefront of this novel regenerative approach. [ 85 ]  Companion animals can serve as clinically relevant models that closely mimic human disease. [ 86 ] [ 87 ]


Veterinary applications of stem cell therapy as a means of tissue regeneration have been largely shaped by research that began with the use of adult-derived  mesenchymal stem cells  to treat animals with injuries or defects affecting bone, cartilage, ligaments and/or tendons. [ 88 ] [ 17 ] [ 89 ]  There are two main categories of stem cells used for treatments: allogeneic stem cells derived from a genetically different donor within the same species, [ 16 ] [ 90 ]  and  autologous   mesenchymal stem cells , derived from the patient before use in various treatments. [ 20 ]  A third category,  xenogenic  stem cells, or stem cells derived from different species, are used primarily for research purposes, especially for human treatments. [ 28 ]


Bone has a unique and well-documented natural healing process that normally is sufficient to repair fractures and other common injuries. Misaligned breaks due to severe trauma, as well as treatments like tumor resections of bone cancer, are prone to improper healing if left to the natural process alone. Scaffolds composed of natural and artificial components are seeded with  mesenchymal stem cells  and placed in the defect. Within four weeks of placing the scaffold, newly formed bone begins to integrate with the old bone and within 32 weeks, full union is achieved. [ 91 ]  Further studies are necessary to fully characterize the use of cell-based therapeutics for treatment of bone fractures.


Stem cells have been used to treat degenerative bone diseases in dogs. The normally recommended treatment for dogs that have Legg–Calve–Perthes disease is to remove the head of the femur after the degeneration has progressed. Recently,  mesenchymal stem cells  have been injected directly in to the head of the femur, with success not only in bone regeneration, but also in pain reduction. [ 91 ]


Autologous stem cell-based treatments for  ligament  injury,  tendon  injury,  osteoarthritis ,  osteochondrosis , and sub-chondral bone cysts have been commercially available to practicing veterinarians to treat horses since 2003 in the United States and since 2006 in the United Kingdom. Autologous stem cell based treatments for tendon injury, ligament injury, and  osteoarthritis  in dogs have been available to veterinarians in the United States since 2005. Over 3000 privately owned horses and dogs have been treated with autologous adipose-derived stem cells. The efficacy of these treatments has been shown in double-blind clinical trials for dogs with osteoarthritis of the hip and elbow and horses with tendon damage. [ 92 ] [ 93 ]


Race horses are especially prone to injuries of the tendon and ligaments. Conventional therapies are very unsuccessful in returning the horse to full functioning potential. Natural healing, guided by the conventional treatments, leads to the formation of fibrous scar tissue that reduces flexibility and full joint movement. Traditional treatments prevented a large number of horses from returning to full activity and also have a high incidence of re-injury due to the stiff nature of the scarred tendon. Introduction of both bone marrow and adipose derived stem cells, along with natural mechanical stimulus promoted the regeneration of tendon tissue. The natural movement promoted the alignment of the new fibers and tendocytes with the natural alignment found in uninjured tendons. Stem cell treatment not only allowed more horses to return to full duty and also greatly reduced the re-injury rate over a three-year period. [ 23 ]


The use of embryonic stem cells has also been applied to tendon repair. The embryonic stem cells were shown to have a better survival rate in the tendon as well as better migrating capabilities to reach all areas of damaged tendon. The overall repair quality was also higher, with better tendon architecture and collagen formed. There was also no tumor formation seen during the three-month experimental period. Long-term studies need to be carried out to examine the long-term efficacy and risks associated with the use of embryonic stem cells. [ 23 ]  Similar results have been found in small animals. [ 23 ]


Osteoarthritis is the main cause of joint pain both in animals and humans. Horses and dogs are most frequently affected by arthritis. Natural cartilage regeneration is very limited. Different types of  mesenchymal stem cells  and other additives are still being researched to find the best type of cell and method for long-term treatment. [ 23 ]


Adipose-derived  mesenchymal cells  are currently the most often used for stem cell treatment of osteoarthritis because of the non-invasive harvesting. This is a recently developed, non-invasive technique developed for easier clinical use. Dogs receiving this treatment showed greater flexibility in their joints and less pain. [ 94 ]


Stem cells have successfully been used to ameliorate healing in the heart after myocardial infarction in dogs. Adipose and bone marrow derived stem cells were removed and induced to a cardiac cell fate before being injected into the heart. The heart was found to have improved contractility and a reduction in the damaged area four weeks after the stem cells were applied. [ 95 ]


In 2007, a trial was underway for a patch made of a porous substance onto which the stem cells are "seeded" in order to induce tissue regeneration in heart defects. Tissue was regenerated and the patch was well incorporated into the heart tissue. This is thought to be due, in part, to improved angiogenesis and reduction of inflammation. Although cardiomyocytes were produced from the  mesenchymal stem cells , they did not appear to be contractile. Other treatments that induced a cardiac fate in the cells before transplanting had greater success at creating contractile heart tissue. [ 96 ]


2018 research, such as the European  nTRACK  research project, aims to demonstrate that multimodal nanoparticles can structurally and functionally track stem cell in muscle regeneration therapy. The idea is to label stem cells with gold nano-particles that are fully characterised for uptake, functionality, and safety. The labelled stem cells will be injected into an injured muscle and tracked using imaging systems. [ 97 ]  However, the system still needs to be demonstrated at lab scale.


Spinal cord injuries are one of the most common traumas brought into veterinary hospitals. [ 91 ]  Spinal injuries occur in two ways after the trauma: the primary mechanical damage, and in secondary processes, like inflammation and scar formation, in the days following the trauma. These cells involved in the secondary damage response secrete factors that promote scar formation and inhibit cellular regeneration.  Mesenchymal stem cells  that are induced to a neural cell fate are loaded onto a porous scaffold and are then implanted at the site of injury. The cells and scaffold secrete factors that counteract those secreted by scar forming cells and promote neural regeneration. Eight weeks later, dogs treated with stem cells showed immense improvement over those treated with conventional therapies. Dogs treated with stem cells were able to occasionally support their own weight, which has not been seen in dogs undergoing conventional therapies. [ 98 ] [ 99 ] [ 100 ]


In a study to evaluate the treatment of experimentally induced MS in dogs using laser activated non-expanded adipose derived stem cells. The results showed amelioration of the clinical signs over time confirmed by the resolution of the previous lesions on MRI. Positive migration of the injected cells to the site of lesion, increased remyelination detected by Myelin Basic Proteins, positive differentiation into Olig2 positive oligodendrocytes, prevented the glial scar formation and restored axonal architecture. [ 38 ]


Treatments are also in clinical trials to repair and regenerate peripheral nerves. Peripheral nerves are more likely to be damaged, but the effects of the damage are not as widespread as seen in injuries to the spinal cord. Treatments are currently in clinical trials to repair severed nerves, with early success. Stem cells induced to a neural fate injected in to a severed nerve. Within four weeks, regeneration of previously damaged stem cells and completely formed nerve bundles were observed. [ 21 ]


Stem cells are also in clinical phases for treatment in ophthalmology. Hematopoietic stem cells have been used to treat corneal ulcers of different origin of several horses. These ulcers were resistant to conventional treatments available, but quickly responded positively to the stem cell treatment. Stem cells were also able to restore sight in one eye of a horse with retinal detachment, allowing the horse to return to daily activities. [ 22 ]


Stem cells are being explored for use in conservation efforts. Spermatogonial stem cells have been harvested from a rat and placed into a mouse host and fully mature sperm were produced with the ability to produce viable offspring. Currently research is underway to find suitable hosts for the introduction of donor spermatogonial stem cells. If this becomes a viable option for conservationists, sperm can be produced from high genetic quality individuals who die before reaching sexual maturity, preserving a line that would otherwise be lost. [ 101 ]


In the late 1990s and early 2000s, there was an initial wave of companies and clinics offering stem cell therapy, while not substantiating  health claims  or having regulatory approval. [ 102 ]  By 2012, a second wave of companies and clinics had emerged, usually located in developing countries where medicine is less regulated and offering stem cell therapies on a  medical tourism  model. [ 103 ] [ 104 ]  Like the first wave companies and clinics, they made similar strong, but unsubstantiated, claims, mainly by clinics in the United States, Mexico, Thailand, India, and  South Africa . [ 103 ] [ 104 ]  By 2016, research indicated that there were more than 550 stem cell clinics in the US alone selling generally unproven therapies for a wide array of medical conditions in almost every state in the country, [ 105 ]  altering the dynamic of  stem cell tourism . In 2018, the FDA sent a warning letter to StemGenex Biologic Laboratories in San Diego, which marketed a service in which it took body fat from people, processed it into mixtures it said contained various forms of stem cells, and administered it back to the person by inhalation, intravenously, or infusion into their spinal cords; the company said the treatment was useful for many chronic and life-threatening conditions. [ 106 ]


One common marketing tactic is registering on  ClinicalTrials.gov , the US government database for clinical trials. Registration of a study notifies the agency but does not prove that review has taken place. Registration with the FDA similarly does not prove that approval has been granted. [ 107 ]


Costs of stem cell therapies range widely by clinic, condition, and cell type, but most commonly range between $10,000-$20,000. [ 108 ]  Insurance does not cover stem cell injections at clinics so patients often use on-line fundraising. [ 109 ]  In 2018, the US  Federal Trade Commission  found health centers and an individual physician making unsubstantiated claims for stem cell therapies, and  forced refunds  of some $500,000. [ 110 ]  The FDA filed suit against two stem cell clinic firms around the same time, seeking permanent injunctions against their marketing and use of unapproved adipose stem cell products. [ 111 ]


Although according to the NIH no stem cell treatments have been approved for  COVID-19 , and the agency recommends against the use of MSCs for the disease, [ 112 ]  some stem cell clinics began marketing both unproven and non-FDA-approved stem cells and exosomes for COVID-19 in 2020. [ 113 ]  The FDA took prompt action by sending letters to the firms in question. [ 114 ] [ 115 ]  The FTC also warned a stem cell firm for misleading COVID-19-related marketing. [ 116 ] [ 117 ]


Tumor-homing bacteria  are  facultative  or  obligate anaerobic bacteria  (capable of producing ATP when oxygen is absent or is destroyed in normal oxygen levels) that are able to target  cancerous cells  in the body, suppress tumor growth and survive in the body for a long time even after the infection. When this type of bacteria is administered into the body, it migrates to the cancerous tissues and starts to grow, and then deploys distinct mechanisms to destroy solid tumors. Each bacteria species uses a different process to eliminate the tumor. Some common tumor homing bacteria include  Salmonella ,  Clostridium ,  Bifidobacterium ,  Listeria , and  Streptococcus . [ 1 ]  The earliest research of this type of bacteria was highlighted in 1813 when scientists began observing that patients that had  gas gangrene , an infection caused by the bacteria  Clostridium , were able to have tumor regressions. [ 2 ]


Different strains of tumor homing bacteria in distinct environments use unique or similar processes to inhibit or destroy tumor growth.


Bacterial cancer therapy is an emerging field for cancer treatment. Although many clinical trials are taking place, as of right now only a few confirmed treatments are being administered to patients.


Tumor homing bacteria can be genetically engineered to enhance their anti-tumor activities and be used to transport therapeutic materials based on medical needs. [ 7 ]  They are usually transformed into a  plasmid  that contains the specific gene expression of these therapeutic proteins of the bacteria. After the plasmid reaches the target site, the protein's genetic sequence is expressed and the bacteria can have its full biological effect. Currently, there is no approved treatment with genetically engineered bacteria. However, research is being conducted on  Listeria  and  Clostridium  as vectors to transport  RNAi  (suppresses genes) for  colon cancer . [ 8 ]


Some active tumor-homing bacteria can be harmful to the human body, since they produce toxins that disturb the  cell cycle  which results in altered cell growth and chronic infections. However, many ways to enhance the safety of tumor homing bacteria in the body has been found. For example, when the virulent genes of the bacteria are removed by  gene targeting , a process where genes are deleted or modified, it can be reduced in  pathogenicity [ citation needed ]  (property of causing disease).


The most researched bacteria for cancer therapy are  Salmonella ,  Listeria,  and  Clostridium.  A genetically engineered strain of  Salmonella  (TAPET-CD) has completed phase 1 clinical trials for patients with stage 4 metastatic cancer. [ 11 ]   Listeria- based cancer vaccines are currently being produced and are undergoing many clinical trials. [ 12 ]  Phase I trials of the  Clostridium  strain called  Clostridium novyi  ( C. novyi -NT) for patients with treatment-refractory tumors or tumors that are unresponsive to treatment is currently underway. [ 13 ]


Sex and drugs  refers to the influence of substances on sexual function and experience. Sex and drugs date back to ancient humans and have been interlocked throughout human history. Sexual performance is known as the execution of the act of sex and the quality of  sexual activity . This includes elements such as  libido  (a person's sexual drive),  sexual function  (including  erection  in males and  vaginal lubrication  in females), sensation (the ability to achieve  orgasm ).  Drugs  are termed as any chemical substance that produces a physiological and or psychological change in an organism. Drugs categorized as  psychoactive drugs ,  antihypertensive drugs ,  antihistamines ,  cancer treatment , and hormone medication have a significant impact on sexual performance. Various drugs result in different effects, both positive and negative. Negative effects may include low libido, erection issues (in males), vaginal dryness (in females) and  anorgasmia . Positive effects usually address these issues, overall enhancing sexual performance and contributing to a more enjoyable sexual experience. It is crucial to know that the impact of drugs on sexual performance varies among individuals, especially among different genders.


Understanding sexual performance involves recognizing various factors that are responsible for a person's combined sexual experience and function. This includes libido, a person's overall sexual desire, and drive; sexual function, which encompasses the male's erectile function and a female's vaginal lubrication; and sensations, which in this context refers to a person's ability to have orgasms and/or ejaculations.


Libido is primarily regulated by the  hypothalamus , where  sex hormones  ( testosterone  and  estrogen ), and  neurotransmitters  ( dopamine ,  oxytocin  and  serotonin ), are the main components that influence sex drive. [ 1 ] [ 2 ]  A decreased libido is predominantly caused by low testosterone in males [ 2 ]  For females, serotonin acts as a inhibitor for sexual desire as it reduces the ability of stimulatory systems for sexual cues. [ 3 ]


Penile erection for men is a vascular event caused by the innervation of both  autonomic  (sympathetic and parasympathetic) and  somatic nervous systems  (sensory and motor). [ 4 ]   Sensory information  is received from the  genitals  towards these nervous systems, in which neurotransmitters such as  serotonin ,  dopamine ,  noradrenaline , and  adrenaline  would be released to control erectile function. [ 5 ]


Vaginal dryness refers to the situation when the vagina lacks lubrication which leads to serious pain during sexual intercourse. [ 6 ]  The production of lubricants in the vagina are highly sensitive to changes in hormones such as estrogen and testosterone, that are also responsible for blood flow. [ 7 ]  Low estrogen and testosterone circulating in the body contributes to vaginal dryness. [ 7 ]


Orgasms are sensory phenomena that take place in the cerebral cortex with an association with the  spinal reflex . [ 8 ]  Men can achieve orgasm through the penis, and can be categorised to two parts: emission and ejaculation. Neurotransmitters such as  serotonin ,  norepinephrine  and  dopamine  affect ejaculation in males the most. [ 9 ]  For women, orgasms are induced by stimulation of erotic sites, currently there are no definitive explanations on the chemical triggers for female orgasm. [ 10 ]


Drugs are frequently associated with reduced sexual inhibition, both when used voluntarily in social circumstances, and involuntarily, as in the case of some  date rape drugs . Because the use of drugs, including  alcohol , is commonly presented as an excuse for risky or socially unacceptable behavior, it is necessary to treat the idea of a direct causal relation between drug use and  unsafe sex  with caution. Drugs may provide a socially acceptable excuse for engaging in sexual behaviors in which people may want to engage but perhaps feel that they should not. [ 11 ]


Some forms of sexual dysfunction such as  erectile dysfunction  can be treated with drugs. Because of their effects, erectile dysfunction drugs are sometimes used for recreational purposes. Many drugs, both legal and illegal, some sold online, have side effects that affect the user's sexual function. Many drugs can cause  loss of libido  as a side effect. [ 12 ]


Since a partial cause of the  refractory period  is the inhibition of  dopamine  by an orgasm-induced  secretion  of  prolactin , [ 13 ]  such potent  dopamine receptor   agonists  as  cabergoline  may help achieve multiple  orgasms  as well as the retention of sexual arousal for longer periods of time. [ 13 ]


According to some studies, up to 22.1% of teenagers abused substances during their most recent sexual experience. [ 14 ]


Likewise, studies have shown adolescents who regularly abuse substances are more likely to initiate sexual activity at an earlier age, [ 15 ]  have a more significant number of sexual partners, [ 16 ]  and engage in unprotected sex more often. [ 17 ]


Additionally, substance abuse has been linked to an increased risk of  sexually transmitted infection  (STI). [ 18 ]


Drugs on the market provide both benefits and detrimental effects to the person, especially regarding sexual performance, depending on the use and dosage. [ 19 ]  Drugs are classified into different categories in respect to their functions, including psychoactive drugs, antihypertensive drugs, antihistamines, cancer treatment drugs and hormone medication.


Psychoactive drugs  refer to chemical substances that affect an individual's mental processes, such as emotions, cognition, perception, and consciousness. [ 20 ]  These substances directly impact the  central nervous system (CNS) , which also has an impact on the neurophysiologic phases of sexual response. [ 21 ]   Antidepressants  are a group of drugs that treat individuals with clinical depression, as well as other mental disorders. [ 22 ]  This group of drugs have shown to affect sexual functions in both male and females. [ 23 ]   Alcohol  is a group of psychoactive substances where signals of pleasure, rewards are sent to the human brain. It also causes a series of adverse effects on the body, including the brain and the liver, leading to health problems and sexual dysfunction. [ 24 ] [ 25 ]   Antipsychotics  are drugs that treat mental disorders such as schizophrenia, and other psychoses. [ 26 ]  These drugs block certain pathways in humans that contribute to sexual dysfunction, including reduced arousal and sexual desire. [ 27 ]


Alcohol inhibits neuronal excitability through acting on  gamma-aminobutyric acid (GABA)  receptors. [ 28 ]  Alcohol is often accessible in a number of social situations across many cultures and is frequently connected with uninhibited social activities. Alcohol has been shown in human research to have surprising effects on the human libido.


While some studies indicates that alcohol improves sexual behavior and desire, other research indicates that alcohol impairs sexual function.


The conditions under which the drinking occurs, laboratory research vs self-report studies from users, as well as the amounts of alcohol consumed, may all contribute to these controversial outcomes. [ 29 ] [ 30 ]


Laboratory studies have demonstrated that while low blood alcohol levels have no effect on or slightly enhance sexual arousal and responsiveness in men, elevated blood alcohol levels result in decreased erectile responsiveness, decreased arousal, and impaired ability to ejaculate. [ 29 ] [ 30 ]  Other laboratory research, on the other hand, found no significant influence of either low or high blood alcohol levels on measures of arousal. [ 31 ]


Even with mild alcohol use, women have decreased vaginal flow responses. In apparent contrast, women self-report heightened  sexual desire  and pleasure when they consume more alcohol and are more likely to engage in sexual activities with someone when intoxicated. [ 30 ]


Heavy alcohol intake impairs sexual and reproductive function, erectile, and ejaculatory dysfunction in males, and sexual arousal, interest, and orgasm in women. [ 29 ] [ 32 ]


Alcohol and sex  although alcohol may have varying impacts on sexual performance depending on the amount drank, it generally impairs sexual functioning and contributes to increased sexual risk taking. [ 33 ] [ 34 ]


Psychiatrists and doctors commonly prescribe different types of antidepressants to patients.  SSRIs ,  SNRIs , and  NDRIs  are the most common types of antidepressants. [ 35 ]  Each has slightly different effects on sexual functioning, but generally, it has been found that antidepressants can delay/decrease orgasms and cause females to have  breast enlargement . [ 36 ]   Dapoxetine  in particular takes advantage of the side effect of delayed orgasm and is approved specifically as a medication for the treatment of  premature ejaculation  rather than as an antidepressant.


The side effects on sexual functioning can impact mental health and quality of life. [ 36 ]  However, the decrease in depressive symptoms from antidepressants make it worth the sexual side effects for many people. They can be managed by changing the dose, switching drugs, or taking "antidotes". [ 37 ]   Maca , a plant that grows in central Peru, aids with sexual dysfunction caused by antidepressant drugs for women. There are specific Maca products that can also increase sexual desire in men. [ citation needed ]


2C-B  was first sold commercially in 5 mg pills as a purported aphrodisiac under the trade name "Erox", which was manufactured by the German pharmaceutical company Drittewelle. [ 38 ]  While being primarily a  psychedelic  it is also a mild  entactogen .  5-MeO-MiPT  is another psychedelic that some users find to be euphoric and tactile in low to moderate doses of 4-8 milligrams. [ 39 ]


Antihypertensive drugs are a group of drugs that prevent, control and treat hypertension. Hypertension imposes negative sexual effects on both men and women, where antihypertensive drugs help alleviate  erectile dysfunction  in men. [ 40 ]


Antihistamines are used for relieving symptoms of allergies and hay fever. [ 41 ]  Antihistamines may cause a drying effect of the mouth, nose and throat but can also cause a drying effect on other parts of the body, such as the vagina, decreasing moisture and lubrication. [ 42 ]


There are a variety of treatment types for  cancer , depending on the cancer type. [ 43 ]  The therapies for treating cancer vary, including hormone therapy, medications that treat pain, depression, nerves and blood vessels. These therapies will affect one's sexual desire and pose possible consequences on sexual response. [ 44 ]


Hormone therapy  directs its treatment towards hormones in the body, including reproductive hormones. One type is hormonal replacement therapy (HRT), which is used to supply menopausal women that lack estrogen and progesterone, increasing vaginal lubrication. [ 45 ]  Another type is testosterone replacement therapy, which treats men with hypogonadism and it helps increase libido. [ 46 ]  On the contractionary, selective oestrogen receptor modulators (SERMs) lead to a drop in oestrogen levels that would cause vaginal dryness. [ 47 ]


Amphetamines  may lead to an increase in  sexual drive  and delay in orgasm. [ 48 ]


Cocaine  is a potent  psycho-stimulant  that boosts dopamine levels by inhibiting dopamine transporters. It has been often linked to enhanced libido and risk-taking behavior in humans. [ 49 ]


Cocaine has been observed to increase sexual arousal or to trigger spontaneous erections and orgasms. [ 50 ]


In contrast, other data has shown that persistent cocaine use impairs sexual desire and the capacity of both men and females to achieve orgasm. [ 30 ]


Cannabis is the most commonly used illicit substance. [ 51 ] [ 52 ]  Studies on  cannabis and sex  have shown that THC has been linked to improved sexual desire and function. Specifically, in one study, 70 percent of users said marijuana was an  aphrodisiac , and 81 percent said it improved their sexual pleasure and satisfaction. [ 53 ]


Other research has found that long-term marijuana use lowers testosterone levels and other reproductive hormones, causing erectile dysfunction in males. [ 54 ] [ 48 ]


MDMA  or "ecstasy" originally gained popularity in the 1980s among college students. According to a survey conducted, 10% of college students at a big US institution reported using  MDMA , with alcohol and marijuana being the most often used substances. [ 55 ]   MDMA  users report increased enjoyment in physical contact and proximity rather than a  sexual experience . [ 56 ] [ 57 ]   MDMA  has been shown to impair sexual performance, including erectile dysfunction and  delayed orgasm , [ 58 ] [ 59 ]  as well as to suppress  sex desire . [ 60 ] [ 61 ] [ 62 ]


Opioids  (also known as  narcotics ) such as  morphine  and  heroin  attach to  opioid receptors  in the brain. These substances have long been known to inhibit sexual behavior. [ 63 ]


Similar to the effects of  psycho-stimulants , both men and women who use  heroin  report engaging in high-risk sexual practices.


Subjects typically report having several sexual partners, using  condoms  seldom or not at all, and having a high frequency of  STI  diagnosis. [ 64 ]


While small doses of heroin may enhance sexual desire and performance, [ 65 ]  chronic opiate use, including  methadone  and  buprenorphine , synthetic and semi-synthetic opiates prescribed for  opiate addiction   treatment , results in decreased sexual desire, response, and orgasms for both men and women, as well as  erectile ,  ejaculatory dysfunction , and  vaginismus . [ 50 ] [ 65 ] [ 30 ]


Libido  refers to a person's overall sexual desire and drive. Since low testosterone levels are associated with low sexual desire, testosterone replacement therapy can be prescribed for increasing testosterone in the body, increasing libido and restoring hormonal balance. [ 66 ]  While Phosphodiesterase-5 (PDE5) inhibitors such as sildenafil, tadalafil, vardenafil, and avanafil are primarily known for treating erectile dysfunction, it also has a positive effect on libido. [ 67 ]


Flibanserin is a drug that is both a  serotonin antagonist  and agonist that treats  hypoactive sexual desire disorder  (HSDD) for  premenopausal  women. The drug acts as  antagonist  and  agonist  on two different receptors. The binding of flibanserin causes downstream release of dopamine and  noradrenaline  and reduces the production of serotonin, increasing sex drive. [ 68 ]  However, currently there is still no evidence that this drug would enhance sexual performance, therefore this drug still needs to be further investigated. [ 68 ]


For males, several drugs increases the blood flow to the penis which allows for the achievement and maintenance of an erection. [ 69 ]   Phosphodiesterase-5  (PDE5) inhibitors are widely known and commonly prescribed for erectile dysfunction. [ 70 ]  PDE5 enzymes are blocked by PDE5 inhibitors to prevent their function, this allows for the relaxation of penile blood vessels and muscles, facilitating increased blood circulation to the penis. [ 71 ]   Alprostadil  injections as a  vasodilator  are also used for the treatment of erectile dysfunction, expanding blood vessels that result in increasing blood flow to the penis. [ 72 ]


For females, vaginal lubricant production can be increased by hormone replacement therapy (HRT) medicine such as  vaginal estrogen . [ 73 ]  Vaginal dryness results from a declined level in circulating estrogen within the body, most likely during  menopause . [ 74 ]  Treatment for vaginal dryness typically involves the use of localised estrogen, such as HRT medicine. This drug works by increasing estrogen in the body circulation, thereby enhancing lubrication production in the vaginal area. [ 74 ]


Delayed ejaculation , a type of male sexual disorder that is characterised by the delay of ejaculation or inability to achieve ejaculation. [ 75 ]  There are no approved drugs for the treatment of delayed ejaculation as of now, The majority of medications used for treating delayed ejaculation are primarily intended for treating different medical conditions. [ 76 ]   Amantadine , a Parkinson's medication, is known to enhance  dopamine agonist  release and activate  dopamine receptors , which helps with ejaculation. [ 77 ]  However, there is not sufficient evidence to support the effectiveness of these medications on delayed ejaculation. [ 77 ]


Several common medications can contribute to low libido. Antidepressants, especially selective serotonin reuptake inhibitors (SSRIs) antidepressants, increase serotonin levels that decrease testosterone, leading to a decrease in libido. [ 78 ]  Antipsychotic drugs create blockages of  dopamine D2 receptors  that are  responsible  for dopamine production can lead to a low libido. [ 27 ]  Additionally, these drugs can increase production of  prolactin  in males which contribute to lower levels of testosterone. [ 27 ] [ 79 ]   Chemotherapy drugs  also lead to a decrease in testosterone but it is only temporary during the course of therapy. [ 27 ]


Drinking large amounts of alcohol regularly can lead to low libido due to a process called  aromatisation . [ 80 ]  This process refers to the conversion of testosterone or its precursors into  estrogen , leading to a decrease in testosterone levels in circulation. [ 80 ]


Impotence  refers to the inability of a male's penis to become erect for sexual intercourse, in which the male is not able to get or maintain an erection. [ 81 ]  The medical term for this phenomenon is erectile dysfunction. Drugs such as antihypertensives including  thiazide diuretics ,  loop diuretics , and  beta-blockers  used for lowering blood pressure limiting blood flow to the penis area, making it difficult to get or maintain an erection. [ 82 ]  Direct effects caused by antihypertensives on the penile  vascular smooth muscle  lead to  vasoconstriction  which leads to impaired  perfusion . [ 83 ]  Antipsychotic drugs are also responsible for several mechanisms that lead to erectile dysfunction. Mechanisms such as  acetylcholine receptor   antagonism  and  alpha-adrenergic receptor  antagonism reduces periphery vasodilation, inducing erectile dysfunction. [ 27 ]


Overindulgence in alcohol may also cause temporary inability to achieve an erection. Alcohol, being a  diuretic , can cause a person to urinate more frequently, resulting in  dehydration . [ 84 ]  Dehydration reduces the volume of blood in the body, consequently decreasing blood flow towards the penis [ 84 ]  Additionally, dehydration also increases  angiotensin  levels in the body, which is a hormone associated with erectile dysfunction. [ 84 ]


Birth control pills affect hormone levels in the body such as a decrease in estrogen, leading to vaginal dryness by thinning and shrinking of the vaginal tissue. [ 7 ]  Moreover, SERMs such as Evista and Tamoxifen which are used to treat breast cancer, results in vaginal dryness. [ 47 ]


Antihistamines narrow blood vessels, leading to lowering of moisture levels as well as mucous production, which includes lubricant production in the vagina. [ 47 ]  Anti-hypertensive drugs help reduce blood pressure by decreasing blood flow to organs in the body, resulting in decreased vaginal lubrication as well. [ 85 ]


Antidepressants, particularly SSRIs, cause delayed ejaculation and orgasm due to its function of retaining serotonin, which inhibits ejaculation. [ 86 ]  Similarly, antipsychotics also contribute to delayed ejaculation by affecting  dopamine transporters , where dopamine plays a role in ejaculation via  D2 receptors . [ 87 ] [ 88 ]


SSRI prevents reuptake of serotonin, thereby increasing serotonin in the body and decreasing their ability to produce lubricant in the vagina. It has been reported that around 42% of women that intake this type of medication have problems with orgasm production. [ 89 ]  Other medications such as antipsychotic drugs also reported signs of impaired orgasm. [ 90 ]


Intake of too much alcohol can potentially cause depressant effects on the  central nervous system  (CNS). [ 91 ]  These effects contribute to sensory dullness, which leads to a delay effect on orgasm and ejaculation. [ 91 ]


A  date rape drug  is any drug that is an  incapacitating agent  which—when administered to another person—incapacitates the person and renders them vulnerable to a  drug-facilitated sexual assault  (DFSA), including  rape . One of the most common types of DFSA are those in which a victim consumes a recreational drug such as  alcohol  that was administered surreptitiously. [ 92 ]  The other most common form of DFSA involves the non-surreptitiously administered consumption of alcohol. [ 93 ]  Here, the victims in these cases are drinking voluntarily which then makes them unable to make informed decisions or  give consent .


Party and play , or chemsex, is the consumption of drugs to facilitate  sexual activity . Sociologically, both terms refer to a  subculture  of  recreational drug  users who engage in high-risk  sexual activities  under the influence of drugs within groups. [ 94 ]  The term PnP is commonly used by  gay men [ 94 ] [ failed verification ]  and other  men who have sex with men  (MSM) in North America, while chemsex is more associated with the gay scene in Europe. [ 95 ]  The drug of choice is typically  methamphetamine , known as tina or T, [ 96 ]  but other drugs are also used, such as  mephedrone ,  GHB ,  GBL [ 97 ]  and  alkyl nitrites  (known as  poppers ). [ 98 ]


Drug-based contraception has been available since the development of the  contraceptive pill . As well as their contraceptive effects, contraceptive drugs can also have adverse sexual and reproductive side-effects. Prior to the availability of effective contraceptives, some substances were also used as  abortifacients  to terminate pregnancy;  medical abortion  exists as a modern medical practice.


Alcohol and sex  deals with the effects of the consumption of  alcohol  on  sexual behavior . [ 2 ]  The effects of alcohol are balanced between its suppressive effects on sexual physiology, which will decrease sexual activity, and its suppression of  sexual inhibitions . [ 3 ]  A large portion of  sexual assaults  involve alcohol consumption by the perpetrator, victim, or both. [ 4 ]


Alcohol is a depressant. After consumption, alcohol causes the body's systems to slow down. Often, feelings of  drunkenness  are associated with elation and happiness but other feelings of anger or depression can arise. Balance, judgment, and coordination are also negatively affected. One of the most significant short term side effects of alcohol is reduced inhibition. Reduced inhibitions can lead to an increase in sexual behavior. [ 3 ]


Low to moderate alcohol consumption is shown to have protective effect for men's erectile function. Several reviews and  meta-analyses  of existing literature show that low to moderate alcohol consumption significantly decreases  erectile dysfunction  risk. [ 5 ] [ 6 ] [ 7 ] [ 8 ]


Men's sexual behaviors can be affected dramatically by high alcohol consumption. Both chronic and acute alcohol consumption have been shown in most studies
 [ 9 ] [ 10 ] [ 11 ]  (but not all [ 12 ] ) to inhibit  testosterone  production in the testes. This is believed to be caused by the metabolism of alcohol reducing the  NAD + / NADH  ratio both in the liver and the testes; since the synthesis of testosterone requires NAD + , this tends to reduce testosterone production. [ 13 ] [ 14 ]


As testosterone is critical for libido and physical arousal, alcohol tends to have deleterious effects on male sexual performance. Studies have been conducted that indicate increasing levels of alcohol intoxication produce a significant degradation in male masturbatory effectiveness (MME). This degradation was measured by measuring  blood alcohol concentration  (BAC) and ejaculation latency. [ 15 ]  Alcohol intoxication can decrease sexual arousal, decrease pleasureability and intensity of  orgasm , and increase difficulty in attaining orgasm. [ 15 ]


In women, the effects of alcohol on libido in the literature are mixed. Some women report that alcohol increases sexual arousal and desire, however, some studies show alcohol lowers the physiological signs of arousal. [ 16 ]  A 2016 study found that alcohol negatively affected how positive the sexual experience was in both men and women. [ 17 ]  Studies have shown that acute alcohol consumption tends to cause increased levels of testosterone and  estradiol . [ 18 ] [ 19 ]  Since testosterone controls in part the strength of libido in women, this could be a physiological cause for an increased interest in sex. Also, because women have a higher percentage of body fat and less water in their bodies, alcohol can have a quicker, more severe impact. Women's bodies take longer to process alcohol; more precisely, a woman's body often takes one-third longer to eliminate the substance. [ 20 ]


Sexual behavior in women under the influence of alcohol is also different from men. Studies have shown that increased BAC is associated with longer orgasmic latencies and decreased intensity of orgasm. [ 16 ]  Some women report a greater  sexual arousal  with increased alcohol consumption as well as increased sensations of pleasure during orgasm. Because ejaculatory response is visual and can more easily be measured in males, orgasmic response must be measured more intimately. In studies of the female orgasm under the influence of alcohol, orgasmic latencies were measured using a  vaginal photoplethysmograph , which essentially measures vaginal blood volume. [ 16 ]


Psychologically, alcohol has also played a role in sexual behavior. It has been reported that women who were intoxicated believed they were more sexually aroused than before consumption of alcohol. [ 16 ]  This psychological effect contrasts with the physiological effects measured, but refers back to the loss of inhibitions because of alcohol. Often, alcohol can influence the capacity for a woman to feel more relaxed and in turn, be more sexual. Alcohol may be considered by some women to be a sexual disinhibitor. [ 16 ]


Some studies have made a connection between  hookup culture  and substance use. [ 21 ]  Most students said that their hookups occurred after drinking alcohol. [ 21 ] [ 22 ] [ 23 ]  Frietas stated that in her study, the relationships between drinking and the party scene and between alcohol and hookup culture were "impossible to miss". [ 24 ]


Studies suggest that the degree of  alcoholic intoxication  in young people directly correlates with the level of risky behavior, [ 25 ]  such as engaging in  multiple sex partners . [ 26 ]


In 2018, the first study of its kind, found that  alcohol and caffeinated   energy drinks  is linked with casual, risky sex among college-age adults. [ 27 ]


Alcohol intoxication is associated with an increased risk that people will become involved in  risky sexual behaviors , such as unprotected sex. [ 15 ]  Both men, [ 28 ]  and women, [ 29 ]  reported higher intentions to  avoid using a condom  when they were intoxicated by alcohol.


Coitus interruptus , also known as withdrawal, pulling out or the pull-out method, is a method of  birth control  during penetrative  sexual intercourse , whereby the  penis  is withdrawn from a  vagina  or  anus  prior to  ejaculation  so that the ejaculate ( semen ) may be directed away in an effort to avoid  insemination . [ 30 ] [ 31 ]  Coitus interruptus carries a risk of  STIs  and  unintended pregnancy . This risk is especially high during  alcohol intoxication  because lowered  sexual inhibition  can make it difficult to withdraw in time.


Women with  unintended pregnancies  are more likely to  smoke tobacco , [ 32 ]  drink alcohol during pregnancy, [ 33 ] [ 34 ]  and binge drink during pregnancy, [ 32 ]  which results in poorer health outcomes. [ 33 ]  (See also:  fetal alcohol spectrum disorder )


Rape is any sexual activity that occurs without the freely given  consent  of one of the parties involved. This includes  alcohol-facilitated sexual assault  which is considered rape in most if not all jurisdictions, [ 35 ]  or  non-consensual condom removal  which is criminalized in some countries (see the map below).


A 2008 study found that rapists typically consumed relatively high amounts of alcohol and infrequently used condoms during assaults, which was linked to a significant increase in STI transmission. [ 36 ]  This also increases the risk of  pregnancy from rape  for female victims. Some people turn to drugs or alcohol to cope with emotional trauma after a rape; use of these during pregnancy can harm the fetus. [ 37 ]


One of the most common  date rape drugs  is alcohol, [ 39 ] [ 40 ] [ 41 ]  administered either surreptitiously [ 42 ]  or consumed voluntarily, [ 39 ]  rendering the victim unable to make informed decisions or give consent. The perpetrator then facilitates  sexual assault  or  rape , a crime known as alcohol- or  drug-facilitated sexual assault  (DFSA). [ 43 ] [ 35 ] [ 44 ]  Many perpetrators use alcohol because their victims often drink it willingly, and can be encouraged to drink enough to lose inhibitions or consciousness. [ 45 ]  However, sex with an unconscious victim is considered rape in most if not all jurisdictions, and some assailants have committed "rapes of convenience" whereby they have assaulted a victim after he or she had become unconscious from drinking too much. [ 46 ]  The risk of individuals either experiencing or perpetrating  sexual violence  and  risky sexual behavior  increases with  alcohol abuse , [ 47 ]  and by the consumption of  caffeinated alcoholic drinks . [ 48 ] [ 49 ]


Non-consensual condom removal , or "stealthing", [ 50 ]  is the practice of a person removing a  condom  during  sexual intercourse  without consent, when their sex partner has only  consented  to condom-protected sex. [ 51 ] [ 52 ]  Purposefully damaging a condom before or during intercourse may also be referred to as stealthing, [ 53 ]  regardless of who damaged the condom.


Consuming alcohol can be risky in sexual situations. It can impair judgment and make it difficult for both people to give or receive informed  sexual consent . However, a history of sexual aggression and  alcohol intoxication  are factors associated with an increased risk of men employing non-consensual condom removal and engaging in sexually aggressive behavior with female partners. [ 54 ] [ 55 ]


The use of alcohol is a documented factor in  wartime sexual violence .


For example,  rape during the liberation of Serbia  was committed by Soviet  Red Army  soldiers against women during their advance to Berlin in late 1944 and early 1945 during  World War II . Serbian journalist Vuk Perišić said about the rapes: "The rapes were extremely brutal, under the influence of alcohol and usually by a group of soldiers. The Soviet soldiers did not pay attention to the fact that Serbia was their ally, and there is no doubt that the Soviet high command tacitly approved the rape." [ 56 ]


While there wasn't a codified international law specifically prohibiting rape during World War II,  customary international law  principles already existed that condemned violence against civilians. These principles formed the basis for the development of more explicit laws after the war, [ 57 ]  including the  Nuremberg Principles  established in 1950.


A study published in 2003 supported the beer goggles hypothesis; however, it also found that another explanation is that regular drinkers tend to have personality traits that mean they find people more attractive, whether or not they are under the influence of alcohol at the time. [ 58 ]  A 2009 study showed that while men found adult women (who were wearing  makeup ) more attractive after consuming alcohol, the alcohol did not interfere with their ability to determine a woman's age. [ 59 ]


A 2021 study found that bar patrons rated themselves as more attractive towards the end of the night, regardless of their level of intoxication, and that this effect had more to do with motivations to attract a mate. The "closing time effect" was tested in Danish bars, with researchers separating responses based on whether bar patrons had filled out their survey in the afternoon, evening, or night, and finding that people attending the bar at night rated themselves as more attractive than earlier visitors. [ 60 ]


An  anaphrodisiac  (also  antaphrodisiac  or  antiaphrodisiac ) is a substance that quells or blunts the  libido . It is the opposite of an  aphrodisiac , something that enhances sexual appetite. The word  anaphrodisiac  comes from the  Greek   privative   prefix   ἀν- , denoting negation, and  aphrodisiac , from the Greek goddess of love,  Aphrodite . Some people use anaphrodisiacs in order to curb a very high libido or due to  hypersexuality . [ 1 ]  However anaphrodisiacs are also used by those with an average libido, at times due to having incessant schedules. [ 2 ]


Some common anaphrodisiacs are  ethanol  (alcohol) and  tobacco , but this is typically an unintended consequence and not often the main reason for use. While alcohol is used socially because it initially reduces mental inhibitions, studies have shown that over time alcohol physically decreases arousal and makes achieving climax more difficult. [ 3 ]  For this reason, alcohol is considered an anaphrodisiac.


Opioids , a class of pain-reducing substances which include  morphine ,  heroin , and  hydrocodone , are anaphrodisiacs.


Side effects  of certain  antidepressant   medications  commonly include those taking anaphrodisiac form (there is even a term for the phenomenon among one particularly notorious group –  SSRI -induced  sexual dysfunction ); however, psychotropic drugs are not currently prescribed for reliable anaphroditic effects.


Antiandrogens  such as  cyproterone acetate  and  medroxyprogesterone acetate , or the LHRH agonist  leuprolide , are sometimes prescribed to convicted male sex offenders who are released on parole in an effort to stop them reoffending, in a treatment sometimes referred to as  chemical castration , however the high doses required often cause a range of side effects which may limit  compliance . Other antiandrogens such as  finasteride  and  spironolactone  may also lower sex drive, as can certain  antipsychotics  such as  benperidol .  Estrogens  can act as anaphrodisiacs in men by suppressing  testosterone  production by the  testicles .


Herbal anaphrodisiacs have been employed by various religious sects and orders throughout history. Barrister Sir  Edward Marshall Hall  theorised that murderer  Hawley Harvey Crippen  was using  hyoscine  on his wife as an anaphrodisiac but accidentally gave her an  overdose  and then panicked when she died. [ 4 ] [ 5 ]  Various forms of anaphrodisiacs have been tried to cure  hypersexuality  in both  humans [ 6 ]  and non-human animals. [ 7 ]  In both medieval history and modern times, anaphrodisiacs have been used as a tool intended to reduce the sex drive of  sex offenders . [ 8 ]


Studies have evaluated the effect of herbal anaphrodisiacs on men and women. These include studies on the effect of substances on both hormone levels and behaviour.


The mechanism of the active component of some plant-based anaphrodisiacs may be the inhibition of enzymes that catalyze the conversion of sex-hormone precursors into  androstenedione , which promotes the reduction of sexual urges. Studies have demonstrated that some of these products inhibit 17β-hydroxysteroid dehydrogenase and 17,20-lyase, which catalyzes the conversion of 17α-hydroxyprogesterone to androstenedione to testosterone. [ 9 ]


In one study a group of men were given an anaphrodisiac and the effect on the metabolism of mineralocorticoids in these men was recorded.  During the period of administration, the testosterone concentrations decreased and the serum 17α-hydroxyprogesterone concentrations increased.  Testosterone levels fell by about 40% after administration and returned to normal after usage was discontinued. [ 10 ]  However, the actual effect of these medicines on sexual desire was not measured in the study.


The amino acid 5-HTP, or  5-hydroxytryptophan , has been anecdotally reported to be a mild anaphrodisiac, as has the serotonergic empathogen  MDMA , popularly known as "ecstasy". However, systematic study of these chemicals is lacking, due to the off-patent nature of 5-HTP, and the legal control of MDMA. In addition, other serotonergic euphoriant drugs, like the psychedelic  LSD , have been reportedly used to drastically increase sexual pleasure. MDMA in combination with a  PDE5 inhibitor  (trade names  Viagra ,  Levitra , and  Cialis ) is termed "sextasy". This combination increases libido and performance simultaneously.  A PDE5 inhibitor taken alone has no effect on sex drive, suggesting that serotonergic euphoriants like MDMA may actually increase libido while decreasing performance, similar to  alcohol .


A 2003 study has found that  glycyrrhizin , the compound in  liquorice  root, can lower levels of testosterone. The findings back up a previous study about the hormonal effects of liquorice (whose results could not be replicated in other studies in the past). The scientists came to the conclusion that the regular consumption of liquorice can lower libido in men. However, the study also showed that the level of testosterone normalizes after abstinence of liquorice within a few days and the effects completely disappear. [ 11 ]


An  aphrodisiac  is a substance alleged to increase  libido ,  sexual desire ,  sexual attraction ,  sexual pleasure , or sexual behavior. [ 1 ] [ 2 ] [ 3 ]  These substances range from a variety of plants, spices, and foods to synthetic chemicals. [ 1 ] [ 4 ]  Natural aphrodisiacs, such as  cannabis  or  cocaine , are classified into plant-based and non-plant-based substances. [ 4 ] [ 5 ]  Synthetic aphrodisiacs include  MDMA  and  methamphetamine . Aphrodisiacs can be classified by their type of effects (psychological or physiological). [ 1 ]  Aphrodisiacs that contain  hallucinogenic  properties, such as  bufotenin , have psychological effects that can increase sexual desire and sexual pleasure. [ 1 ] [ 3 ]  Aphrodisiacs that have smooth muscle relaxing properties, such as  yohimbine , have physiological effects that can affect hormone concentrations and increase blood flow. [ 1 ] [ 4 ]


Aphrodisiac effects may be due to the  placebo effect . [ 2 ]  Substances that inhibit effects that aphrodisiacs aim to enhance are called  anaphrodisiacs , [ 2 ]  which have the opposite effects on libido.


Both males and females can potentially benefit from the use of aphrodisiacs, but they are more focused on males, as their properties tend to increase testosterone concentrations rather than estrogen concentrations. [ 3 ]  This is in part due to the historical context of aphrodisiacs, which focused solely on males. Only recently has attention  been paid to understanding how aphrodisiacs can aid female sexual function. [ 5 ]  In addition, cultural influences on appropriate sexual behavior of males and females also play a part in the research gap. [ 5 ]


The word comes from the  Greek  ἀφροδισιακόν,  aphrodisiakon , i.e. "sexual, aphrodisiac", from  aphrodisios , i.e. "pertaining to  Aphrodite ", [ 6 ] [ 7 ]  the  Greek   goddess  of love. Throughout human history, food, drinks, and behaviors have had a reputation for making sex more attainable and/or pleasurable. However, from a historical and scientific standpoint, the alleged results may have been mainly due to mere belief on the part of their users that they would be effective (a  placebo effect ). Likewise, many medicines are reported to  affect  libido in inconsistent or idiopathic ways: [ 8 ]  enhancing or diminishing overall sexual desire, depending on the circumstances. For example, bupropion ( Wellbutrin ) is known as an  antidepressant  that can counteract other co-prescribed antidepressants with libido-diminishing effects. However, because bupropion increases libido only when it is already impaired by related medications, it is not generally classed as an aphrodisiac.


Ancient civilizations like Chinese, Indian, Egyptian, Roman, and Greek cultures believed that certain substances could provide the key to improving sexual desire, sexual pleasure, and/or sexual behavior. [ 1 ] [ 4 ] [ 9 ]  This was important, because some men suffered from  erectile dysfunction  and could not reproduce. [ 1 ] [ 4 ]  Men who could not impregnate their wives and father large families were seen as failures, whereas those who could were respected. Hence, a stimulant was needed. [ 1 ] [ 5 ]  Others who did not suffer from this also desired performance enhancers. [ 4 ]  Regardless of their usage, these substances gained popularity and began to be documented, information being passed down generations. [ 3 ]  There are Hindu poems dated back to around 2000 to 1000 BCE that spoke of performance enhancers, ingredients, and usage tips. [ 3 ]  Chinese texts date back to 2697 to 2595 BC. [ 5 ]  Roman and Chinese cultures documented their belief in aphrodisiac qualities in animal genitalia, while Egyptians wrote tips for treating erectile dysfunction. [ 5 ]  In  Post-classical  West Africa, a volume titled  Advising Men on Sexual Engagement with Their Women  from the  Timbuktu Manuscripts  acted as a guide on aphrodisiacs and infertility remedies. It offered advice to men on "winning back" their wives. According to Hammer, "At a time when women’s sexuality was barely acknowledged in the West, the manuscript, a kind of  Baedeker  to orgasm, offered tips for maximizing sexual pleasure on both sides." [ 10 ]


Ambergris ,  Bufo toad ,  yohimbine ,  horny goat weed ,  ginseng ,  alcohol , and certain foods are recorded throughout these texts as possessing aphrodisiac qualities. [ 1 ]  While many plants,  extracts , or manufactured hormones have been proposed as aphrodisiacs, there is little high-quality  clinical evidence  of their efficacy or long-term safety. [ 8 ] [ 11 ]


There has been increasing attention in recent years surrounding the use of aphrodisiac drugs. [ 12 ]  In 2020,  Brian Earp  and  Julian Savulescu  published a philosophy book entitled  Love Drugs: The Chemical Future of Relationships  (UK title  Love Is the Drug: The Chemical Future of Our Relationships) . They argued that certain forms of medications can be ethically consumed as a "helpful complement" in relationships. Both to fall in love and to fall out of it. [ 12 ]


Ambergris  is found in the gut of sperm whales. It is commonly used in Arab cultures as relief medication for headaches or as a performance enhancer.  The derived chemical  Ambrein  increases testosterone concentrations, triggering sexual desire and sexual behavior, but in animal studies only.  Further research is needed to know the effects in humans. [ 3 ]


Bufotenin  is found in the skin and glands of Bufo toads. It is commonly used in Caribbean and China. In the Caribbean, it is used as an aphrodisiac called 'Love Stone'.  In China, it is used as a heart medication called  Chan su . [ 3 ]  Research shows that the toad skin secretion containing this compound can reduce a toad’s heart rate, but its effect on humans is unknown. [ 13 ]


Yohimbine  is a substance found in the bark of yohim trees in West Africa. [ 4 ]  It was traditionally used in West African cultures, in which the bark would be boiled and the resulting water drunk until it increased sexual desire. [ 1 ]  It  has been approved by the Food and Drug Administration and can be prescribed for sexual dysfunction in the USA and Canada. [ 1 ] [ 5 ]  It is also found in over-the-counter health products. [ 1 ]  Yohimbine is an indole alkaloid and is an adrenoceptor antagonist. It affects the central nervous system, autonomic nervous system, and the penile tissue and vascular smooth muscle cells that are involved in penile erection and it is also used to treat physiologically impaired and psychogenic erectile dysfunction, [ 1 ] [ 4 ]  preferably in combination with other treatments. [ 14 ]  Known adverse effects include nausea, anxiety, irregular heartbeats, and restlessness. [ 4 ]


Horny goat weed  ( Epimedii herba ) is used in Chinese folk medicine. [ 1 ]  It was thought to be useful for treating medical conditions and improving sexual desire, sexual pleasure, and/or sexual behavior. [ 1 ]  Horny goat weed contains  icariin , a flavanol glycoside. Its exotic name comes from the tendency of goats in the region to seek out this weed. Once farmers saw its effects on the goat population they began to use it to increase the number of workers on their farms. [ 1 ] [ 4 ]


Alcohol  has been associated as an aphrodisiac, owing to its effect as a central nervous system depressant. [ 5 ]  Depressants can increase sexual desire and sexual behavior through disinhibition. [ 2 ] [ 5 ]  Alcohol affects people both physiologically and psychologically, and it is therefore difficult to determine exactly how people experience its aphrodisiac effects (aphrodisiac qualities or the expectancy effect). [ 2 ]  Alcohol taken in moderate quantities can elicit a positive increase in sexual desire, whereas larger quantities are associated with difficulties in reaching sexual pleasure. [ 2 ] [ 15 ]  As the porter in Shakespeare's  Macbeth  observes, "it provokes the desire, but it takes away the performance". Chronic alcohol consumption is related to sexual dysfunction. [ 2 ]


Marijuana  reports are mixed. Half of users claim an increase in sexual desire and sexual pleasure while the other half report no effect. [ 2 ]  Consumption, individual sensitivity, and possibly marijuana strain, are factors that affect outcomes. [ 2 ]


Many cultures have turned to foods as sources of increasing sexual desire; however, significant research is lacking in the study of the aphrodisiac qualities of foods. Most claims can be linked to the placebo effect. [ 2 ]  Misconceptions revolve around the visual appearance of these foods in relation to male and female genitalia ( carrots ,  bananas ,  oysters , and the like). [ 2 ] [ 5 ]  Other beliefs arise from the thought of consuming animal genitalia and absorbing their properties (e.g. cow cod soup in  Jamaica  and balut in the  Philippines ). [ 1 ]   Korean bug  is a popular aphrodisiac in China, Korea, and Southeast Asia, either eaten alive or in gelatin form. [ 16 ]  The caterpillar fungus ( Ophiocordyceps sinensis ) is used as an aphrodisiac in China. [ 17 ]  The story of Aphrodite, who was born from the sea, is another reason why individuals believe seafood is another source of aphrodisiacs. [ 5 ]  Foods that contain volatile oils have gained little recognition in their ability to improve sexual desire, sexual pleasure, and/or sexual behavior, because they are irritants when released through the urinary tract. [ 3 ]   Chocolate  has been reported to increase sexual desire in women who consume it over those who do not. [ citation needed ]  Cloves and sage have been reported to demonstrate aphrodisiac qualities, but their effects have not been specified. [ 1 ]  Tropical fruits, such as  Borojó  and  Chontaduro , are considered to be energizers in general and sexual energizers in particular. [ 18 ] [ 19 ]


Ginseng  is the root of any member of the genus  Panax . [ 1 ] [ 4 ]  Ginseng's active ingredients are ginsenosides and saponin glycosides. [ 20 ]  There are three different ways of processing ginseng. Fresh ginseng is cut at four years of growth, white ginseng is cut at four to six years of growth, and red ginseng is cut, dried, and steamed at six years of growth.  Red ginseng has been reported to be the most effective aphrodisiac of the three. [ 4 ]  Known adverse effects include mild gastrointestinal upsets. [ 5 ]


Maca  is a Peruvian plant sometimes called "Peruvian ginseng", although it is not related to  Panax . It has been used as a tonic to improve sexual performance.


Popular party substances have been reported by users to consist of aphrodisiac properties because of their enhancing effects with sexual pleasure.  Ecstasy  users have reported an increase in sexual desire and sexual pleasure; however, there have been reports of delayed orgasm in both sexes and erectile difficulties in men.  Poppers , containing drugs for inhalation, have been linked to increased sexual pleasure. Known adverse effects are headaches, nausea, and temporary erectile difficulties. [ 2 ]


Amphetamine ,  methylphenidate , and  methamphetamine  are  phenethylamine derivatives , which increase libido and cause frequent or prolonged erections as potential adverse effects, particularly in  supratherapeutic  doses, when sexual hyperexcitability and hypersexuality can occur; [ 21 ] [ 22 ] [ 23 ] [ 24 ]  however, in some individuals who use these drugs, libido is reduced. [ 22 ] [ 24 ]


2C-B  was sold commercially in 5 mg pills as a purported aphrodisiac under the trade name "Erox", which was manufactured by the German pharmaceutical company Drittewelle. [ 25 ] [ 26 ]


Libido  in males is linked to concentrations of sex hormones, particularly  testosterone . [ 11 ] [ 27 ] [ 28 ]  When there is reduced sex drive in individuals with relatively low concentrations of testosterone, particularly in  postmenopausal  women or men over the age of 60, [ 29 ]   dietary supplements  that are purported to increase  serum  testosterone concentrations have been used, with the intention of increasing libido, although with limited benefits. [ 11 ] [ 29 ]  Long-term therapy with synthetic oral testosterone is associated with increased risks of  cardiovascular diseases . [ 30 ]


Solid evidence is hard to obtain, as these substances come from many different environments cross-culturally and therefore give variable results, because of variations in growth and extraction. [ 4 ]  The same is also true for unnatural substances, because variations in consumption and individual sensitivity can affect outcomes. [ 2 ]  Folk medicine and self-prescribed methods can be potentially harmful, as their adverse effects are not fully known and are therefore not made aware to the people searching this topic on the internet. [ 1 ] [ 3 ]


The invention of an aphrodisiac is the basis of a number of films including  Perfume: The Story of a Murderer ,  Spanish Fly ,  She'll Follow You Anywhere ,  Love Potion No. 9 ,  and  A Serbian Film .
The first segment of  Woody Allen 's movie  Everything You Always Wanted to Know About Sex* (*But Were Afraid to Ask)  is called "Do Aphrodisiacs Work?", and casts Allen as a  court jester  trying to seduce the  queen .
The "Despair Arc" of  Danganronpa 3: The End of Hope's Peak High School  features a class being dosed with aphrodisiacs.
In episode 2 of the anime  The Apothecary Diaries , Maomao makes aphrodisiacs and three of the  Ladies-in-waiting  eat them unaware that they are aphrodisiacs. In the film  Sexually Bewitched , a witch creates consumables that bring out and enhance the lust of whomever eats them; resulting in hijinks as the magic liberates the libido repressed by those who eat her magic.


Hormonal contraception  refers to  birth control  methods that act on the  endocrine system . Almost all methods are composed of  steroid hormones , although in  India  one  selective estrogen receptor modulator  is marketed as a contraceptive. The original hormonal method—the  combined oral contraceptive pill —was first marketed as a contraceptive in 1960. [ 1 ]  In the ensuing decades, many other delivery methods have been developed, although the oral and injectable methods are by far the most popular. Hormonal contraception is highly effective: when taken on the prescribed schedule, users of steroid hormone methods experience pregnancy rates of less than 1% per year. Perfect-use pregnancy rates for most hormonal contraceptives are usually around the 0.3% rate or less. [ 2 ]  Currently available methods can only be used by women; the development of a  male hormonal contraceptive  is an active research area.


There are two main types of hormonal contraceptive formulations:  combined methods  which contain both an  estrogen  and a  progestin , and  progestogen-only methods  which contain only  progesterone  or one of its synthetic analogues (progestins). Combined methods work by suppressing  ovulation  and thickening  cervical mucus ; while progestogen-only methods reduce the frequency of ovulation, most of them rely more heavily on changes in cervical mucus. The incidence of certain side effects is different for the different formulations: for example,  breakthrough bleeding  is much more common with progestogen-only methods. Certain serious complications occasionally caused by estrogen-containing contraceptives are not believed to be caused by progestogen-only formulations:  deep vein thrombosis  is one example of this.


Hormonal contraception is primarily used for the prevention of  pregnancy , but is also prescribed for the treatment of  polycystic ovary syndrome , menstrual disorders such as  dysmenorrhea  and  menorrhagia , and  hirsutism . [ 3 ]


Hormonal treatments, such as hormonal contraceptives, are frequently successful at alleviating symptoms associated with  polycystic ovary syndrome .  Birth control pills  are often prescribed to reverse the effects of excessive  androgen  levels, and decrease ovarian hormone production. [ 4 ]


Hormonal birth control methods such as  birth control pills , the  contraceptive patch ,  vaginal ring ,  contraceptive implant , and  hormonal IUD  are used to treat cramping and pain associated with primary  dysmenorrhea . [ 5 ] [ 6 ]


Oral contraceptives  are prescribed in the treatment of  menorrhagia  to help regulate menstrual cycles and prevent prolonged menstrual bleeding. The  hormonal IUD  ( Mirena ) releases  levonorgestrel  which thins the uterine lining, preventing excessive bleeding and loss of iron. [ 7 ]


Birth control pills are the most commonly prescribed hormonal treatment for  hirsutism , as they prevent  ovulation  and decrease  androgen  production by the  ovaries . Additionally,  estrogen  in the pills stimulates the liver to produce more of a protein that binds to androgens and reduces their activity. [ 8 ]


Modern contraceptives using steroid hormones have  perfect-use  or  method  failure rates of less than 1% per year. The lowest failure rates are seen with the implants Jadelle and Implanon, at 0.05% per year. [ 9 ] [ 10 ]  According to  Contraceptive Technology , none of these methods has a failure rate greater than 0.3% per year. [ 10 ]  The SERM ormeloxifene is less effective than the steroid hormone methods; studies have found a perfect-use failure rate near 2% per year. [ 11 ] [ 12 ]


Long-acting methods  such as the implant and the IUS are user-independent methods. [ 13 ]  For user-independent methods, the  typical  or  actual-use  failure rates are the same as the method failure rates. [ 10 ]  Methods that require regular action by the user—such as taking a pill every day—have typical failure rates higher than perfect-use failure rates.  Contraceptive Technology  reports a typical failure rate of 3% per year for the injection Depo-Provera, and 8% per year for most other user-dependent hormonal methods. [ 10 ]  While no large studies have been done, it is hoped that newer methods which require less frequent action (such as the patch) will result in higher user compliance and therefore lower typical failure rates. [ 14 ]


Currently there is little evidence that there is an association between being overweight and the effectiveness of hormonal contraceptives. [ 15 ]


While unpredictable  breakthrough bleeding  is a possible side effect for all hormonal contraceptives, it is more common with progestogen-only formulations. [ 16 ]  Most regimens of COCPs, NuvaRing, and the contraceptive patch incorporate a placebo or break week that causes regular withdrawal bleeding. While women using combined injectable contraceptives may experience  amenorrhea  (lack of periods), they typically have predictable bleeding comparable to that of women using COCPs. [ 17 ]


Although high-quality studies are lacking, [ 18 ]  it is believed that estrogen-containing contraceptives significantly decrease the quantity of milk in breastfeeding women. [ 19 ]  Progestogen-only contraceptives are not believed to have this effect. [ 19 ]  In addition, while in general the progestogen-only pill is less effective than other hormonal contraceptives, the added  contraceptive effect of breastfeeding  makes it highly effective in breastfeeding women. [ 20 ]


While combined contraceptives increase the risk for  deep vein thrombosis  (DVT – blood clots), progestogen-only contraceptives are not believed to affect DVT formation. [ 21 ]


Combined oral contraceptives can increase the risk of certain types of cardiovascular disease in women with a pre-existing condition or already-heightened risk of cardiovascular disease. Smoking (for women over 35), metabolic conditions like diabetes, obesity and family history of heart disease are all risk factors which may be exacerbated by the use of certain hormonal contraceptives. [ 2 ]  Oral contraceptives have also been linked to an inflated risk of myocardial infarction, arterial thrombosis, and ischemic stroke. [ 27 ]


Hormonal contraception methods are consistently linked with the risk of developing blood clots. However, the risk does vary depending on the hormone type or birth control method being used. [ 28 ] [ 29 ]


There are two main classes of hormonal contraceptives:  combined contraceptives  contain both an estrogen and a  progestin , [ 30 ]  and  progestogen-only contraceptives  that contain only  progesterone  or a synthetic analogue (progestin). There is also a non-hormonal contraceptive called  ormeloxifene  which acts on the hormonal system to prevent pregnancy.


The most popular form of hormonal contraception, is the  combined oral contraceptive pill  (COCP) known colloquially as  the pill . It is taken once a day, most commonly for 21 days followed by a seven-day break, although other regimens are also used. For women not using ongoing hormonal contraception, COCPs may be taken after intercourse as  emergency contraception : this is known as the  Yuzpe regimen . COCPs are available in  a variety of formulations . [ citation needed ]


The  contraceptive patch  is applied to the skin and worn continuously. A series of three patches are worn for one week each, and then the user takes a one-week break.  NuvaRing  is worn inside the vagina. A ring is worn for three weeks. After removal, the user takes a one-week break before inserting a new ring. As with COCPs, other regimens may be used with the contraceptive patch or NuvaRing to provide  extended cycle combined hormonal contraception .


Some  combined injectable contraceptives  can be administered as one injection per month.


The  progestogen-only pill  (POP) is taken once per day within the same three-hour window.  Several different formulations  of POP are marketed. A low-dose formulation is known as  the minipill . Unlike COCPs, progestogen-only pills are taken every day with no breaks or placebos. For women not using ongoing hormonal contraception, progestogen-only pills may be taken after intercourse as  emergency contraception . There are a number of  dedicated products  sold for this purpose. [ citation needed ]


Hormonal intrauterine contraceptives are known as  intrauterine systems  (IUS) or Intrauterine Devices (IUD). An IUS/IUD must be inserted by a health professional. The copper IUD does not contain hormones. While a copper-containing IUD may be used as emergency contraception, the IUS has not been studied for this purpose.


Depo-Provera  is an injection that provides three months of contraceptive protection. Noristerat is another injection; it is given every two months. [ 31 ]


Contraceptive implants  are inserted under the skin of the upper arm, and contain progesterone only.  Jadelle  (Norplant 2) consists of two rods that release a low dose of hormones. It is effective for five years. Nexplanon has replaced the former  Implanon  and is also a single rod that releases etonogestrel (similar to the body's natural progesterone). The only difference between Implanon and Nexplanon is Nexplanon is radio opaque and can be detected by x-ray. This is needed for cases of implant migration. It is effective for three years and is usually done in office. It is over 99% effective. It works in 3 ways:
1. Prevents ovulation- usually an egg does not mature
2. thickens cervical mucus so to prevent sperm from reaching the egg
3. If those 2 fail, the last is the progesterone causes the lining of the uterus to be too thin for implantation.


Ormeloxifene  is a  selective estrogen receptor modulator  (SERM). Marketed as Centchroman, Centron, or Saheli, it is pill that is taken once per week. Ormeloxifene is legally available only in  India . [ 32 ]


The effect of hormonal agents on the reproductive system is complex. It is believed that combined hormonal contraceptives work primarily by preventing ovulation and thickening cervical mucus. Progestogen-only contraceptives can also prevent ovulation, but rely more significantly on the thickening of cervical mucus. Ormeloxifene does not affect ovulation, and its mechanism of action is not well understood. [ citation needed ]


Combined hormonal contraceptives were developed to prevent  ovulation  by suppressing the release of  gonadotropins . They inhibit  follicular development  and prevent ovulation as a primary mechanism of action. [ 33 ] [ 34 ] [ 35 ] [ 36 ]


Progestogen  negative feedback  decreases the pulse frequency of  gonadotropin-releasing hormone  (GnRH) release by the  hypothalamus , which decreases the release of  follicle-stimulating hormone  (FSH) and greatly decreases the release of  luteinizing hormone  (LH) by the  anterior pituitary . Decreased levels of FSH inhibit follicular development, preventing an increase in  estradiol  levels. Progestogen negative feedback and the lack of estrogen  positive feedback  on LH release prevent a  mid-cycle  LH surge. Inhibition of follicular development and the absence of a LH surge prevent ovulation. [ 33 ] [ 34 ] [ 35 ]


Estrogen was originally included in oral contraceptives for better cycle control (to stabilize the endometrium and thereby reduce the incidence of breakthrough bleeding), but was also found to inhibit follicular development and help prevent ovulation. Estrogen negative feedback on the anterior pituitary greatly decreases the release of FSH, which inhibits follicular development and helps prevent ovulation. [ 33 ] [ 34 ] [ 35 ]


Another primary mechanism of action of all progestogen-containing contraceptives is inhibition of  sperm  penetration through the  cervix  into the upper  genital tract  ( uterus  and  fallopian tubes ) by decreasing the amount of and increasing the  viscosity  of the  cervical mucus . [ 33 ]


The estrogen and progestogen in combined hormonal contraceptives have other effects on the reproductive system, but these have not been shown to contribute to their contraceptive efficacy: [ 33 ]


Insufficient evidence exists on whether changes in the endometrium could actually prevent implantation. The primary mechanisms of action are so effective that the possibility of fertilization during combined hormonal contraceptive use is very small. Since pregnancy occurs despite endometrial changes when the primary mechanisms of action fail, endometrial changes are unlikely to play a significant role, if any, in the observed effectiveness of combined hormonal contraceptives. [ 33 ]


The mechanism of action of progestogen-only contraceptives depends on the  progestogen  activity and dose. [ 36 ]


Low dose progestogen-only contraceptives include traditional progestogen-only pills, the subdermal implant  Jadelle  and the  intrauterine system  Mirena. These contraceptives inconsistently inhibit ovulation in ~50% of cycles and rely mainly on their progestogenic effect of thickening the  cervical mucus  and thereby reducing sperm viability and penetration.


Intermediate dose progestogen-only contraceptives, such as the progestogen-only pill Cerazette (or the subdermal implant  Implanon ), allow some follicular development but much more consistently inhibit ovulation in 97–99% of cycles. The same cervical mucus changes occur as with low dose progestogens.


High dose progestogen-only contraceptives, such as the injectables  Depo-Provera  and Noristerat, completely inhibit follicular development and ovulation. The same cervical mucus changes occur as with very low dose and intermediate dose progestogens.


In  anovulatory cycles  using progestogen-only contraceptives, the endometrium is thin and atrophic. If the endometrium was also thin and atrophic during an ovulatory cycle, this could theoretically interfere with implantation of a blastocyst (embryo). [ citation needed ]