The 5-HT1A receptor (5-HT1AR) is an established anxiolytic target. Buspirone and other 5-HT1AR agonists are approved for the treatment of GAD, with fair response rates . In preclinical studies, 5-HT1AR agonists are anxiolytic in animal models of general anxiety , prevent the adverse effects of stress , and enhance fear extinction . Both pre- and postsynaptic 5-HT1ARs are coupled to various members of the Gi/o protein family. They are expressed on serotonergic neurons in the raphe, where they exert autoinhibitory function, and various other brain areas involved in fear and anxiety [54, 55]. Mechanisms underlying the anxiolytic effects of 5-HT1AR activation are complex, varying between both brain region, and pre- versus postsynaptic locus, and are not fully established . While in vitro studies suggest CBD acts as a direct 5-HT1AR agonist , in vivo studies are more consistent with CBD acting as an allosteric modulator, or facilitator of 5-HT1A signaling .
Our results demonstrate that CBD exerts fast and maintained antidepressant-like effects as evidenced by the reversal of the OBX-induced hyperactivity and anhedonia. In conclusion, our findings indicate that CBD could represent a novel fast antidepressant drug, via enhancing both serotonergic and glutamate cortical signalling through a 5-HT1A receptor-dependent mechanism. (Source)
Because I never go downtown, I had to stop for a latte at my favorite coffee shop—and a second CBD pick-me-up. By the time I stepped into the crowded Indie Beauty Expo, I felt calm and happy. As an introvert, I usually have a hard time making small talk at events. But post-CBD oil, I felt comfortable enough to chat up a storm with every person I met! Three hours later I dragged myself out of the huge exposition and made it to my meditation class, where I took another dropper of CBD oil. Although I really love meditating, I find it particularly challenging to get into the “zone” after a long day at work. Not so much after taking some CBD—it was easy to calm my mind and tune into my breath, despite how fast-paced my day had been.
My mother was thinking about trying CBD because she heard it would help with her diabetes and I was wondering how good is CBD at controlling sugar levels as my mother has tried multiple insulin drugs and they might work for a while but then stop working from what I understand. She got her diabetes from the Growth Hormone Drug back in 2009 and she also got some type of rare mouth Tumor which the doctor did the surgery to remove it wrong and caused it to spread. Will this work at controlling her sugar levels as she gets both high and lows, for example, she once had her sugar levels so high that it was unreadable and the doctors were amazed that she was still alive plus she also gets lows sometimes. Also, because of diabetes, she has neuropathy where she is losing feeling in her toes and does not feel the heat from hot products when she picks them up, will this product also help with the neuropathy and any remaining tumor?
Overall, preclinical evidence supports systemic CBD as an acute treatment of GAD, SAD, PD, OCD, and PTSD, and suggests that CBD has the advantage of not producing anxiogenic effects at higher dose, as distinct from other agents that enhance CB1R activation. In particular, results show potential for the treatment of multiple PTSD symptom domains, including reducing arousal and avoidance, preventing the long-term adverse effects of stress, as well as enhancing the extinction and blocking the reconsolidation of persistent fear memories.
Thirty minutes later, I was surprised by how subtle the effect was. While I expected a hazy nodding-off effect similar to melatonin's, the oil simply relaxed my body ever so slightly—my heart stopped pounding against my chest, my legs stopped kicking beneath my sheets, my mind stopped racing. I wasn't sure if it was the oil or the late hour, but eventually, physical relaxation gave way to mental relaxation, and I drifted off to sleep.
Szaflarski explains that cannabis contains about 500 different compounds, some of which—including CBD and THC—interact with certain chemical receptors in the human nervous system. But unlike THC, CBD isn’t psychoactive—meaning it doesn’t cause any kind of a high. Despite that, the US Drug Enforcement Agency classifies CBD (and other cannabis compounds) as schedule I substances, making their sale illegal in many states.
I have had several neurological conditions like Bells Palsy three times, double vision, paralysis of left side of tongue. I have a lot of relief whenever I have pain by taking an inflamattory drug etoshine90 mg. Presently I have started taking Steroids for my facial palsy. The various pains I was having on the left side of neck, below the left ear, dizziness, pain around the head have subsided immidiately after the first dose of prendisolone 60 mg.I have read that CBD hemp oil can be useful for my condition of neurological and inflammation issues. My question is what concentrate (mg) of the oil should I take and for how long. Any brand that you may suggest that are available in the UK. Thank you.
The founder of Elixinol got his start in the hemp industry back in 1991, when he launched a “9bar,” a healthy snack bar packed with heart-healthy hemp which remains one of the world’s most popular hemp products. Elixinol sells an array of CBD products, including Tinctures, Capsules, Liposomes, Vape Liquids, and Topical Balms, all of which contain the purest-possibly hemp. The company sources hits hemp from farms in Europe, Australia, and America, uses a chemical- and heat-free, broad-spectrum CO2 extraction process, and employs a team of medical professionals to research and develop their product formulations. Most impressive, however, is the company’s standards of testing, which is conducted both in house and third-party, and which covers potency, microbiological contamination, heavy metals, pesticides, and terpene profile. The European-based labs employ equipment and personnel from the pharmaceutical industry, and all test results are posted online alongside product listings. There are a few contenders for best CBD oil for anxiety in their product selection. Their original and cinnamint-flavored CBD tinctures are most popular, and come in strengths of in dosages of 300 or 600 mg per 15 ml bottle, or 3,600 mg per 120 ml (or, available for order from Brazil only, a heavy-duty 5,000 mg). The blend contains CBD suspended in hemp oil, plus Amino acids, Natural Sugars, Aldehydes, Alcohols, Ketones, Flavanoids, Glycosides, and Vitamins. Those In search of a portable CBD for anxiety can try their 15 mg CBD capsules, 300 mg or 600 mg oral spray, or Elixinol’s proprietary “X-Pen”, which is pre-loaded with 1,000 mg CBD and delivers precise dosages on-the-go.
On the other hand, a 2017 comprehensive review of CBD studies in psychiatric disorders found inconclusive results. According to the authors, there isn’t enough evidence to claim CBD as a treatment for depression. However, the authors do note positive results for anxiety disorders. Based on their review, more human tests are needed to better understand how it works, what ideal dosages should be, and if there are potential side effects or hazards.
Due to the anti-inflammatory properties of cannabidiol, insulin resistance (the chief metabolic problem for patients with type 2 diabetes) is reduced, leading to a better prognosis thanks also to the lower incidence of dead tissue. Ever since the discovery of CBD in the 1990’s, speculation existed to its effect on other types of receptors (not just cannabinoid receptors) which could be manipulated and included in the treatment of some cardiovascular diseases like atherosclerosis. In light of these speculations, researchers at the University of Tel Aviv (walking in the footsteps of the “father” of cannabinoid research, Dr. Raphael Mechoulam) demonstrated a 30 percent blood flow increase in rodents with areas of dead tissue in the heart muscle.
On the other hand, marijuana-derived CBD and anything else derived from a cannabis plant was still classified by the DEA as a Schedule I drug (defined as a drug with "no currently accepted medical use and a high potential for abuse") until October 2018. In 2016, the DEA stated that all extracts containing more than one cannabinoid would remain classified as Schedule I. However, the approval of Epidiolex had an influence in changing this, and prescription CBD drugs with a THC content of below 0.1% have now been reclassified as Schedule 5, the lowest rating.
capsules. Tinctures are offered in concentrations of 100 mg, 250 mg, 350mg, 550 mg, 30 ml, 1000 mg, or 1500 mg of crystalline CBD isolates and a broad spectrum of phytocannabinoids. The company’s capsules have a strength of 25 mg CBD, and contain 10% Broad-Spectrum CBD oil 10%, Cannabidiol hemp oil, Safflower oil, and Vegetable cellulose. Another product we recommend for anxiety is their loose-leaf Organic Chamomile CBD Tea. Chamomile has established calming and stomach-soothing effects, and is often used to promote restful sleep. In conjunction with CBD, this botanical contributes to a great product for anxiety-related insomnia. The tea contains 55 mg of CBD, Organic chamomile loose leaf tea, flowers and powder, vanilla, peppermint, and agricultural hemp.
Most CBD oils are available in round-number concentrations such as 250mg, 500mg, and 1,000mg. While these strengths accommodate many CBD users, they may not be sufficient for those with preferences that fall outside round numbers. NuLeaf Naturals offers a less conventional selection of concentrations: 240mg, 725mg, 1,450mg, 2,425mg, and 4,850mg. This range ensures that most users will find a strength that works for them.
A bit of online digging led me to realize that the active ingredient in Charlotte's Web Everyday Plus Hemp Oil, the product I'd been offered to test, was the chemical compound CBD, which stands for Cannabidiol. Unlike THC, the other crucial compound in hemp and marijuana plants, CBD does not produce the psychoactive effects that make you feel "high"; instead, it actually eases anxiety and makes you less likely to freak out.
Cannabis has shown to have positive effects on people suffering from epilepsy and multiple sclerosis. A research conducted in the University College of London, it is also effective in dealing with multiple other neurological conditions like the Dravet syndrome and Parkinson’s disease. It prevents neurodegeneration and cognitive decline, thereby helping those suffering from Alzheimer’s.
CBD is extracted from marijuana plants as either an oil or powder. These can be mixed into creams or gels. They can be put into capsules and taken orally, or rubbed on your skin. The multiple sclerosis drug nabiximols is sprayed as a liquid into your mouth. How CBD should be used depends largely on what it’s being used for. Talk to your doctor before using CBD oil. It hasn’t been approved by the U.S. Food and Drug Administration (FDA) for any medical uses, and it can have side effects.
Some studies have investigated the role of CBD in preventing cancer cell growth, but research is still in its early stages. The National Cancer Institute (NCI) says that CBD may help alleviate cancer symptoms and cancer treatment side effects. However, the NCI doesn’t fully endorse any form of cannabis as a cancer treatment. The action of CBD that’s promising for cancer treatment is its ability to moderate inflammation and change how cell reproduce. CBD has the effect of reducing the ability of some types of tumor cells to reproduce.
The inquiry upon the manner in which THC produces its psychoactive effects on the human body led, in the 1980’s, to the discovery of the endocannabinoid system – a rather loose complex of nerve receptors which under the influence of compounds called cannabinoids trigger many physiological and psychological reactions. Because cannabinoid receptors are present in almost every tissue of a mammal’s body (although they are not limited to mammals), it has wide-ranging influences on the well-being of an organism. Therefore cannabinoids are definitely substances that deserve further attention from scientists.
The CBD oil needs to be taken twice a day everyday. The dosage depends on symptoms and it takes 30 days to awken your natural cannabis system after you begin taking the oil. I personally use Hemp works CBD oil in the 750 strength and only need 5 drops sublingual 2 times daily and results are many. Problem with oil and alz.patients is getting them to hold oil under tongue for 60 seconds. We have just began to get my dad on it. He too is in a nursing home in the state of florida and they cannot deny him any medication my mom has requested that he receive. If she is not their they are supposed to administer and she will call them to make sure he gets it. He is not 30 days into dosing yet so I don't have any results to speak of. I do know that since he has started he has had no more bladder infection and has not fallen in 3 weeks. That's a record for him so we will continue to monitor. Best of luck to you and a lot is going to depend on the state your mom is in and what the state laws are concerning her rights or the rights of whom has her medical power of attorney
CBD oil’s role in cancer treatment still needs more research, but what is available is looking promising. According to the American Cancer Society, CBD oil can slow growth and spread of some kinds of cancer (in animals). Because it fights oxidative stress and inflammation (and both are linked to cancer) it makes sense that CBD oil could help fight cancer cells.
Everything you need to know about marijuana (cannabis) Marijuana, or cannabis, is the most commonly used illicit drug in the world. It alters the mood and affects nearly every organ in the body. With at least 120 active compounds, marijuana may have health benefits as well as risks. We describe these, addiction, and withdrawal. Learn more about cannabis here. Read now
I have been totally off the effexor and all anti-depressants for 2 weeks now. The dizziness is getting much better however my emotions/agitation are horrible. I cry at everything and am extremely crabby/agitated. I realize most of this has to do with the withdrawal. I really want to see this through to find out if I can live without anti-depressants but at the same time I know it's very hard on my family. I have another doctor appt beginning of April and she says that if I don't feel better by then I most likely will need to go back on an anti-depressant. For the most part I agree with her. My hopes of proving her wrong as getting slim however. I'd like to know how long it took some of you who have withdrawn from anti-depressants to feel somewhat 'normal' or you knew you had to go back on them? I guess I'm asking if another month is a good amount of time for me to determine what I should do. In some ways I feel like I should start on them again now but I'm not going there yet? BTW, I am in no way feeling suicidal. Mornings seem to be my worst time and by early evenings I feel somewhat better – is this strange too? I haven't tried the CBD living water yet but did find a place near me to get it. Just havent had the time to get there. I also have the Ativan which I take one night to help with sleep. I'm trying not to take it unless really necessary. Tomorrow I have a huge even that my husband and I are in charge of so I'm planning to take an Ativan in the morning to get me through the day without falling apart (crying scene) in front of everyone (or yelling at them) :)! Thanks for all your input!!
Chronic pain: The body’s ECS plays a role in alleviating and managing pain, so CBD oil can work as a supplement for individuals with medical conditions that cause chronic pain, such as arthritis and multiple sclerosis. CBD oil also increases levels of adenosine in the brain; adenosine is a neurotransmitter that aids cardiovascular function and eases painful inflammation.
Extraction: The method by which CBD oil is processed from hemp plants can be very telling. Some manufacturers extract and process the oil using toxic materials like propane or butane; in most cases, these oils are cheaply priced. Safer extraction and processing agents include ethanol, which cleans the hemp plant of unwanted toxins; and supercritical carbon dioxide extraction, which strips harmful materials from the plant by changing the carbon dioxide’s temperature and pressure settings.
Pharmacists have since moved to metric measurements, with a drop being rounded to exactly 0.05 mL (50 μL, that is, 20 drops per milliliter) - https://en.wikipedia.org/wiki/Drop_(unit)1oz is 30 mL1000mg/30mL = 33.3 mg/mL CBD concentration20 drops * .05 mL/drop = 1mL10 drops * .05 mL/drop = .5mLyou take 33.3 mg in the morning and 16.65mg at nightI might suggest taking 50mg in the morning: 50mg / 33.3 mg/mL = 1.50 mL 30 dropstry it for a couple days and see how it helps
Buying online is less reliable still because there’s no regulation or standardization. What you see on the label may not be what you are getting. A 2017 study in JAMA found that of the 84 CBD products researchers bought online, 43% had more CBD than indicated, while 26% had less, and some had unexpected THC. “There’s a 75% chance of getting a product where the CBD is mislabeled,” says Marcu, one of the study’s coauthors.
I would never endorse anything that I don’t use and benefit from myself, and I can honestly say that this is the most absorbable form of CBD I’ve ever used, it allows me to get all the benefits of smoking weed without actually smoking weed, and it is exact stuff that I personally purchase for myself and that now lives in a special place in my pantry.
Hemp Extract- A Canadian hemp oil extract with naturally occurring terpenes, flavonoids, and other beneficial phytonutrients extracted from the hemp plant. This CO2 extracted hemp oil is free of harmful solvents and uses a gentle, low temperature, alcohol free extraction process that yields the purest form of hemp oil extract available. This clean oil extraction process yields a high quality extracted hemp oil retaining a broad spectrum of terpenes and other phyto compounds derived from the Cannabis Sativa industrial hemp plant like CBD Oil. This does not contain THC and is legal in all 50 states.
the effect of cannabis user can depend upon the dose, the prior experience and/or personal expectations. the user can be high, very happy and relaxed. but it depends upon the user if he takes a higher dose. but base in my researching, cannabis can relief some seizures in the children with autism. I read an article kylekushman.com/topic/lets-make-our-own/ and based on this, cannabis can relief seizures and there’s no high effect on the children who take it.
Later in the 1990’s, the National Institute on Drug Abuse (NIDA) funded research that had the goal of proving that cannabis is addictive. But instead of identifying any biochemical pathway that could cause addiction, any research defined addiction by the presence or absence of some degree of withdrawal, with no specific parameters for withdrawal actually defined. In other words, if you’re thirsty, this NIDA-funded research could argue that this means you are addicted to water.
More recently, 17 states have approved the use of low THC, high CBD products for medical reasons in limited situations. Each state has specific requirements and conditions that need to be followed in order to use CBD legally, such as patient registry requirements and definitions of products that are allowed. (23) The 17 states that allow limited access to marijuana products low in THC and high in CBD include:
The number of people who are suffering from the Social Anxiety Disorder are 15 million. This shows that 6.8% of the US Population suffer from the Social Anxiety Disorder. This is quite a large number of sufferers which show that the situation needs to be addressed as soon as possible. These statistics are not biased and they show the equally likely chances of both the men and the women suffering from the SAD.
Nonetheless, when it comes to CBD oil and cannabidiol, people seem be getting more aware of the fact that you don’t need to be a pothead to get all the relaxing and hormone and metabolism-balancing properties of weed. Not that the image below is based on hard scientific epidemiological data, but a quick glance at a Google trends profile of searches for “CBD Oil” speaks volumes, doesn’t it?
Dosage is important, because CBD can have side effects—the most common are tiredness, diarrhea, and changes in appetite and weight—so it’s best not to take more than you need. As CBD becomes more prevalent, says J. Michael Bostwick, M.D., a psychiatrist at Mayo Clinic in Rochester, MN, “I’m reasonably certain new kinds of side effects will emerge.”
FDA DISCLOSURE Representations regarding the efficacy and safety of Rosebud CBD have not been evaluated by the Food and Drug Administration. The FDA only evaluates foods and drugs, not supplements like these products. These products are not intended to diagnose, prevent, treat, or cure any disease. Click here (https://www.ncbi.nlm.nih.gov/pubmed/22625422) and here (https://www.ncbi.nlm.nih.gov/pubmed/18728714) to find evidence of a test, analysis, research, or study describing the benefits, performance or efficacy of CBD Oil based on the expertise of relevant professionals. These statements have not been evaluated by the FDA and are not intended to diagnose, treat, or cure any disease. Always check with your physician before starting a new dietary supplement program. The Cannabidiol (CBD) in Rosebud CBD is a natural constituent of industrial hemp plant and grown in the United States of America. Rosebud CBD does not sell or distribute any products that are in violation of the United States Controlled Substances Act (US CSA). All products contain less than 0.3% THC. All products are legal in all 50 states.
CBDPure oils are made from domestic Colorado-grown organic hemp. Unlike most other CBD oil brands that we put to the test, CBDPure’s oil contains full spectrum cannabinoids and terpenes, enhancing the oil’s therapeutic effect. Their hemp oil is 100% free of synthetic and artificial ingredients, and every batch is tested for potency and quality by third-party labs.
Hello every one Hey! I can’t believe this. A great testimony that i must share to all cancer patient in the world i never believed that their could be any complete cure for lung cancer or any cancer,i saw people’s testimony on blog sites of how Dr. Mark Sircus cannabis oil brought them back to life again. Glory be to God for leading me to this genuine Dr. Mark Sircus. I am so happy as i am sharing this testimony. My advice to you all who thinks that their is no cure for cancer that is Not true ,just contact him and get cannabis oil from Dr. Mark Sircus and you will be free of cancer and free for ever, Try it and you will not regret it because it truly works. One thing i have come to realize is that you never know how true it is until you try. There is no harm in trying. Remember, delay in treatment leads to death. Here is his email: [email protected]
89. da Silva JA, Biagioni AF, Almada RC, et al. Dissociation between the panicolytic effect of cannabidiol microinjected into the substantia nigra, pars reticulata, and fear-induced antinociception elicited by bicuculline administration in deep layers of the superior colliculus: The role of CB-cannabinoid receptor in the ventral mesencephalon. Eur J Pharmacol. 2015;758:153–163. doi: 10.1016/j.ejphar.2015.03.051. [PubMed] [CrossRef]
Of all the reasons that people use CBD today, pain is the most common. The same can be said of cannabis in general. In the United States, over seventy million people suffer from chronic pain, which is defined as experiencing over one hundred days per year of pain. Physicians differentiate between neuropathic (usually chronic) and nociceptive pains (usually time-limited), and cannabis works on most neuropathic and many nociceptive types of pain. A number of studies have demonstrated that the endocannabinoid system is both centrally and peripherally involved in the processing of pain signals. Most discussions of using CBD for pain treatment suggest that finding the right dosage is critical.
A healthy appetite is vital to a healthy body, especially when the body is healing. Some illnesses decrease the appetite to the point of preventing the body from healing itself. CBD stimulates appetite, according to the National Cancer Institute. In the human body, CBDs bind to cannabinoid receptors in the body. Scientists believe these receptors play an important role in regulating feeding behavior. CBDs stimulate appetite when they dock onto these receptors.
Following cloning of the endogenous receptor for THC, namely the CB1R, endogenous CB1R ligands, or “endocannabinoids” (eCBs) were discovered, namely anandamide (AEA) and 2-arachidonoylglycerol (reviewed in ). The CB1R is an inhibitory Gi/o protein-coupled receptor that is mainly localized to nerve terminals, and is expressed on both γ-aminobutryic acid-ergic and glutamatergic neurons. eCBs are fatty acid derivatives that are synthesized on demand in response to neuronal depolarization and Ca2+ influx, via cleavage of membrane phospholipids. The primary mechanism by which eCBs regulate synaptic function is retrograde signaling, wherein eCBs produced by depolarization of the postsynaptic neuron activate presynaptic CB1Rs, leading to inhibition of neurotransmitter release . The “eCB system” includes AEA and 2-arachidonoylglycerol; their respective degradative enzymes fatty acid amide hydroxylase (FAAH) and monoacylglycerol lipase; the CB1R and related CB2 receptor (the latter expressed mainly in the periphery); as well as several other receptors activated by eCBs, including the TRPV1 receptor, peroxisome proliferator-activated receptor-γ, and G protein-coupled 55 receptor, which functionally interact with CB1R signaling (reviewed in [21, 24]). Interactions with the TRPV1 receptor, in particular, appear to be critical in regulating the extent to which eCB release leads to inhibition or facilitation of presynaptic neurotransmitter release . The TRPV1 receptor is a postsynaptic cation channel that underlies sensation of noxious heat in the periphery, with capsacin (hot chili) as an exogenous ligand. TRPV1 receptors are also expressed in the brain, including the amygdala, periaqueductal grey, hippocampus, and other areas [26, 27].
 N. M. Kogan, E. Melamed, E. Wasserman, B. Raphael, A. Breuer, K. S. Stok, R. Sondergaard, A. V. Escudero, S. Baraghithy, M. Attar-Namdar, S. Friedlander-Barenboim, N. Mathavan, H. Isaksson, R. Mechoulam, R. Müller, A. Bajayo, Y. Gabet, and I. Bab, “Cannabidiol, A Major Nonpsychotropic Cannabis Constituent, Enhances Fracture Healing and Stimulates Lysyl Hydroxylase Activity in Osteoblasts,” Journal of Mineral and Bone Research 30, no. 10 (October 2015): 1905–1913.
Research conducted by Vandrey and his colleagues has even shown that some CBD products contain significant levels of THC—which could get a child high and cause other unpleasant side effects. “This is an area that exists in a grey area of legality,” Vandrey says. “And because of that, anyone thinking about using cannabidiol, of any type, should proceed with caution.”
It is for this reason that all the finished hemp goods that you see for sale in America, from food products to clothing to building materials, are part of an imported hemp industry that has surpassed $688 million annually. The size of this import industry is one of the major catalysts for hemp legalization in the U.S. As a renewable source of a range of products, hemp provides an exciting new step in American agriculture.
Hi Marilyn, I would recommend a topical lotion or salve to start for instant relief.. Maybe 250 to 300 mg tincture to see how you feel. For me, the salve took the pain in my hands away in under a minute. I didn't notice how much the tincture worked until I forgot to take on vacation. Pain that was pretty much gone but came back, I was tired, grumpy and felt horrible. It works, just need to find right product and dosage for you.
In recent years, CBD has generated a tremendous amount of interest among consumers, clinicians, and scientists. Why? Not only does evidence suggest CBD counteracts many of THC’s adverse effects, but numerous animal studies and accumulating evidence from human experimental, clinical, and epidemiological studies suggest CBD has powerful anti-anxiety properties. Administered acutely (“as needed”), it appears safe, well-tolerated, and may be beneficial to treat a number of anxiety-related disorders, including:
Leonard Leinow has three decades of experience growing and studying medical cannabis and brings a unique spiritual perspective to his work. In 2009, he formed Synergy Wellness, a not-for-profit medical cannabis collective in California. Synergy Wellness has over 3,500 members in its collective and is an artisan organization making hand-crafted organic and natural whole plant-based products. They are specialists in CBD (cannabidiol), the non-psychoactive portion of cannabis, and are pioneers in this aspect of the industry. Leinow is known for his proprietary blends of tinctures and medicine used for cancer and epilepsy patients.