04/29/16

A Pill for a Mythical Ill

© zurijeta | stockfresh.com

© zurijeta | stockfresh.com

On August 18, 2015, the FDA approved flibanserin (Addyi) to treat acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. If that sounds like a mouthful of medical and psychiatric techno-babble, it’s also known popularly as “pink Viagra.”  Not only has there been controversy over whether or not HSDD should even be a DSM-defined disorder, now it’s “treated” by a medication that requires special warnings and regulations because of its potentially serious side effects. The FDA rejected flibanserin twice (in 2010 and 2013) as a treatment for HSDD before it was finally approved.

Writing an Op-Ed for the LA Times, Emily Nagoski, a sex educator, said she was less concerned about the risk of low blood sugar and fainting from flibanserin than she was about “the drug maker’s reinforcement of an outdated, scientifically invalid model of sexual desire.” She went on to note how the “problem” flibanserin is supposed to help women with is an absence of spontaneous, out-of-nowhere desire. She noted that research over the last 20 years has found there is another “totally legitimate” way to experience desire called responsive desire, which “emerges in response to pleasure, whereas spontaneous desire emerges in anticipation of pleasure.”  Therefore the ‘disorder’ treated by flibanserin is actually “a normal, healthy variation in human sexual response,” according to Nagoski.

She also said spontaneous desire was not an essential part of sexual well-being. Most people will experience both spontaneous and responsive desire at different times in their lives. But there is some disagreement among researchers about how many people experience either kind of sexual desire. “Responsive desire isn’t worse than spontaneous desire, it’s just different.” Yet Sprout, the company that owned the patent rights to flibaserin, seemed to disregard the fact that they were treating normal, healthy women with their drug.

During an FDA hearing on the drug, one panelist noted the women in the study were averaging two or three “sexually satisfying events” per month before the trial began. So if they lacked desire, why were they having any sex, the panelist asked. A Sprout presenter explained, “Once they engage in activity, it’s pleasurable.” Nagoski commented how this was a “tidy definition of responsive desire.” Disturbingly, she also related where the FDA’s analysis of the data submitted for approval showed that only 10% of the research participants taking flibanserin experienced “at least minimal improvement.” Then 90% of those participants taking flibanserin experienced NO IMPROVEMENT!

The potential side effects from the drug are so serious that the FDA announced it was requiring special training and certification before providers could prescribe it. Addyi (flibanserin) can cause severely low blood sugar and fainting (syncope). And these risks become more severe when women drink alcohol or take certain medications that interfere with the breakdown of Addyi in the body. So drinking alcohol is contraindicated; and health care professionals are supposed to assess the likelihood of the patient reliably abstaining from alcohol while using Abbyi. It comes with a black box warning to highlight the risks of severe hypotension and fainting in patients who drink alcohol while taking Addyi.

Addyi is being approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use (ETASU). The FDA is requiring this REMS because of the increased risk of severe hypotension and syncope [fainting] due to the interaction between Addyi and alcohol. The REMS requires that prescribers be certified with the REMS program by enrolling and completing training. Certified prescribers must counsel patients using a Patient-Provider Agreement Form about the increased risk of severe hypotension and syncope and about the importance of not drinking alcohol during treatment with Addyi. Additionally, pharmacies must be certified with the REMS program by enrolling and completing training. Certified pharmacies must only dispense Addyi to patients with a prescription from a certified prescriber. Additionally, pharmacists must counsel patients prior to dispensing not to drink alcohol during treatment with Addyi.

The most common side effects with Addyi are dizziness, sleepiness, nausea, fatigue insomnia and dry mouth. Given the risk of adverse events like hypotension, fainting and central nervous system depression (sleepiness and sedation), it is recommended to take Addyi at bedtime. On average, treatment with Addyi supposedly increased the number of satisfying sexual events by .5 to 1.0 additional events per month. Although about 10% more of the Addyi-treated patients reported feeling improved satisfaction in sexual events the three trials reviewed by the FDA, “Addyi has not been shown to enhance sexual performance.”

Flibanserin was originally proposed as a potential fast-acting antidepressant (here and here). Unfortunately it failed to gain approval three times. So it was repositioned as a treatment for HSDD by Sprout. Part of its attempt to gain approval for flibanserin was to initiate a marketing campaign called “Even the Score,” which claimed there was inherent sexism in the number of FDA-approved treatments for sexual dysfunction. Looking at its website, Even the Score claims “men outscore women 26 to 1 when it comes to FDA-approved treatments marketed for Sexual Dysfunction.” Writing for Mad in America, Emily Wheeler et al. noted that this claim is false. “There are only 8 drugs to treat male sexual dysfunction, and none are FDA-approved for low libido.”

Wheeler et al. described how Sprout was able to “game the system” and get Addyi (flibanserin) approved. “Not surprisingly, Sprout and its marketing tactics have come under fire.” The authors went on to note that HSDD is a classic example of “disease mongering,” creating a disease in order to promote a drug to treatment. They noted how the empirical evidence supporting the validity of HSDD was sparse; that numerous experts, clinicians and policy makers have questioned the validity of HSDD. Furthermore, one of the main assessment tools used to measure sexual dysfunction, the Female Sexual Dysfunction Index, was developed and validated with support from pharmaceutical companies.

Reporting on November 17, 2015 for Bloomberg Business, Anna Edney said in “The Female Libido Pill Is No Viagra,” that the number of Addyi prescriptions in the U.S.  through November 6th totaled 227. Some 5,600 doctors were cleared by then to prescribe Addyi. Cost may have been a factor in the lack of sales. Sprout wouldn’t provide a price to Edney, but a pharmacy was selling it for $26 a pill. That is about the cost for Viagra. However, Addyi is supposed to be taken on a daily basis, meaning a monthly cost of $780.

According to an article published online by JAMA Internal Medicine on February 29, 2016, “the meaningful change caused by flibanserin is minimal.”  This review found it to be at the lower end of the meaningful change reported above. Treatment resulted in an average of .5 additional satisfactory sexual events per month. “Overall, the quality of the evidence was graded as very low.” The authors said before flibanserin could be recommended in guidelines and clinical practice, future studies of women in diverse populations, particularly those with co-morbidities, medication use and surgical menopause should be done. Listen to a brief audio file where the lead author of the study, Loes Jaspers, and Steve Woloson comment on its findings.

An editorial response to that article also appeared online by JAMA Internal Medicine. The authors, Steven Woloshin and Lisa Schwartz, described the process flibanserin went through on its path to FDA approval under Sprout Pharmaceuticals. Among the interesting facts reported there, Sprout bought the rights to filbanserin from Boehringer Ingelheim in 2013 despite 2 failed efficacy trials for HSDD. It had also previously failed to be approved as a new antidepressant treatment. The strangeness of such a move is seen when considering the FDA clinical reviewers and an external advisory committee voted unanimously (11 to 0) against approving the drug to treat HSDD. Read on for a clue to why Sprout bought the drug from Boehringer Ingelheim.

In their letter, the FDA said it would require a third efficacy trial. They also requested studies to better define the interactions of filbansertin with other drugs and alcohol. In 2013, Sprout resubmitted flibanserin to the FDA for approval, along with the requested new efficacy trials and interaction studies. The alcohol interaction study was done with 23 of its 25 participants being MALE. Four of the 23 men developed hypotension, requiring further medical intervention. The FDA rejected flibanserin again in 2013. Sprout unsuccessfully appealed the FDA decision.

But in 2015, Sprout resubmitted flibanserin to the FDA and it was approved. “The Committee voted 18 to 6 for approval.” Within days, Sprout sold flibanserin to Valeant Pharmaceuticals for $1 billion. Nothing had changed with regard to the efficacy data in the interim. But the Even the Score campaign had occurred. When the FDA held a third advisory committee meeting on the drug, Even the Score members attended and testified in support of it. Woloshin and Schwartz commented:

The FDA’s own clinical reviewers, however, still recommended rejection. The 2 medical reviewers and team leader believed—as in both prior review cycles—that the benefit-harm balance was unfavorable: “We do not believe that it is reasonable for the approximately 90% of treated patients who will not respond to the product to be exposed to the numerous serious risks posed by flibanserin therapy.”

The requested alcohol studies were supposed to help assess how often hypotension and fainting occurred before approval. For men, as little as 2 drinks caused symptomatic hypotension and fainting in some trials participants. For women, although the combination could be worse, there were only TWO WOMEN in the study. The successful marketing campaign, Even the Score, meant the FDA didn’t get that information before it was pressured to approve flibanserin. There are three required postmarketing alcohol studies required, but it will take 1 to 2.5 years for those results to be known.

Within a month of the FDA approval, three of the FDA advisory committee members authored an editorial for JAMA describing a convergence of factors that led to the committee’s recommendation to approve flibanserin. Within the editorial, it was acknowledged that Even the Score was initially created through “the efforts of a consultant to flibanserin’s manufacturer who formerly directed the FDA’s Office of Women’s Health.” It also pointed to the fact that the 25-person alcohol interaction study only had 2 female participants. When flibanserin failed to demonstrate efficacy as an antidepressant, it was noticed that it was more effective than placebo in responses of the study’s participants to the question: “How strong is your sex drive?” So the drug’s development was shifted to a potential treatment for HSDD.

You can read a discussion of the editorial on Mad in America here.

The authors on the advisory committee understood that “there are few reliable estimates of the prevalence of HSDD” and that the product “is all but certain to be used off-label among a broader population of women than has been studied… many of whom may have conditions or concomitant medication use that increases the risk of adverse events.”  They also point out that many of the women who were brought in for public comments to express the need for flibanserin, were not part of the population approved for the drug’s use.  Because they reported “conditions that may have excluded them from on-label treatment, such as a cancer diagnosis or postmenopausal status,” they effectively reinforced concerns about dangerous off-label use.

04/26/16

MDMA—Not!

Ecstasy tablets © portokalis | 123rf.com

Ecstasy tablets © portokalis | 123rf.com

There are a handful of names for 3,4-methylenedioxymethamphetamine (MDMA), including: E, X, XTC, Rolls, Adam, Molly and Ecstasy. The pro-drug website Erowid noted it is one of the most popular recreational psychoactives, known for its euphoric, stimulant and empathogenic (feelings of oneness, emotional openness, empathy or sympathy) effects. This last effect indicates it has a past and current history of use in psychotherapy. But when you see a warning that, “Ecstasy tablets are notoriously impure, often containing chemicals other than MDMA,” be forewarned you may not be actually using MDMA.

The MDMA timeline on Erowid indicated MDMA was first synthesized and patented by Merck Pharmaceuticals in 1912. And the first animal testing of MDMA occurred at Merck in 1927. An article titled, ‘The Origin of MDMA (“Ecstasy”)’ indicated the 1912 Merck patent was a procedural patent, meaning MDMA was a precursor compound for another therapeutic and was not isolated as a drug in its own right. “Obviously, it was never intended for sale. MDMA was not tested pharmacologically in 1912.” The 1927 experiments were only aimed at exploring the potential pharmacological actions of MDMA. You can also read about MDMA and it history here on Wikipedia.

The first scientific paper on MDMA wasn’t published until 1960—in Polish. Alexander Shulgin resynthesized MDMA in 1965 while working at Dole Pharmaceuticals, but did not try it on himself at this time. Between 1967 and 1975 there were reports of small underground batches of MDMA being used recreationally, but Erowid said it had no clear documentation of its use before the mid 1970s. It didn’t become widely available as a street drug until around 1977.

Schulgin first heard of the psychoactive effects of MDMA from a student, and he tried it himself in September of 1976. He then reported on MDMA at a conference in December of 1976. Along with David Nichols, Schulgin wrote and published a report on the drug’s psychoactive effects in 1978. They described MDMA as inducing “’an easily controlled altered state of consciousness with emotional and sensual overtones”’ comparable ‘to marijuana, to psilocybin devoid of the hallucinatory component, or to low levels of MDA.’” Schugin referred to MDMA as “window”, because it allowed users to strip away habits and perceive the world clearly.

Because of its disinhibiting effects, Schulgin thought it could be useful in psychotherapy, so in 1977 he gave some to Leo Zeff, a psychotherapist. Zeff was so impressed with the effects, he came out of semi-retirement to promote its therapeutic use. Reportedly, he eventually trained an estimated four thousand therapists in the therapeutic use of MDMA. Zeff referred to MDMA as “Adam”, as he saw it putting users into a state of “primordial innocence.” It is believed that MDMA eliminates fear and increases communication in therapeutic users.

Concerned that MDMA would become an illegal substance like LSD and mescaline, early advocates tried unsuccessfully to restrict the available information and use of MDMA while they conducted informal research on its properties. By the late 1970s, there was a small recreational market for MDMA. By the early 1980s, it began to take hold as a “club drug” in places like Studio 54.

In 1984, Michael Clegg put together some financial backing, coined the term “Ecstasy” for MDMA, and mass-produced it in a Texas lab. “Ecstasy parties” were advertised at bars and discos. MDMA use quickly became a common sight on college campuses. “By May 1985, MDMA use was widespread in California, Texas, southern Florida, and the northeastern United States.”

Concern over the recreational use of MDMA resulted in its temporary placement as a Schedule I controlled substance on July 1, 1985. As a result of a hearing challenging the placement of MDMA as a Schedule I controlled substance, it was removed from its Schedule I status because of an improper procedure when it was originally scheduled on December 22, 1987. Within a short period of time, the DEA administrator reclassified MDMA as Schedule I, and it was permanently placed as a Schedule I controlled substance on March 23, 1988.

Ecstasy has remained a common recreational substance, particularly at dance clubs and raves. But it also persisted as a potential psychotherapeutic agent. The non-profit organization MAPS—Multidisciplinary Association for Psychedelic Studies—is currently funding clinical trials of MDMA as a “tool to assist psychotherapy” in the treatment of PTSD. Rick Doblin, the executive director of MAPS, founded it in 1986. His pre-MAPS organization, Earth Metabolic Design, held a conference on MDMA in March of 1985, in the midst of the fight over whether MDMA should become an illicit controlled substance.

MAPS is undertaking a roughly $20 million plan to make MDMA into a Food and Drug Administration (FDA)-approved prescription medicine by 2021, and is currently the only organization in the world funding clinical trials of MDMA-assisted psychotherapy. For-profit pharmaceutical companies are not interested in developing MDMA into a medicine because the patent for MDMA has expired. The idea of using MDMA to assist psychotherapy of any kind for any specific clinical indication has long been in the public domain.

The development of psychoactive substances like MDMA, LSD, Ibogaine and Ayahusca as psychotherapeutic “tools” has gained momentum in recent years. In part, this is because of the growth of concerns over the adverse effects and long-term use of FDA approved medications like antidepressants and antipsychotics. MAPS supports research into the therapeutic use of each of the above-named psychoactive substances. The following quote illustrates how MAPS presents the therapeutic benefits of MDMA-assisted psychotherapy: “MDMA is only administered a few times, unlike most medications for mental illnesses which are often taken daily for years, and sometimes forever.”

Along with Erowid, MAPS cautions that substances sold as “Ecstasy” or “molly” may not be pure MDMA. “Substances sold on the street under these names may contain MDMA, but frequently also contain unknown and/or dangerous adulterants.” The rise of novel or new psychoactive substances (NPS) such as “bath salts” has meant that many partygoers who think they are using MDMA aren’t. Media outlets such as Newsweek and The Fix have reported on a recently published study in the journal Drug and Alcohol Dependence that tested hair samples from ecstasy users for the presence of NPS. The lead author of the study, Joseph Palmer, said in an NYU press release on his research that:

Given the sharp rise in poisonings and recent deaths at dance festivals related to ecstasy use, research was needed to examine whether nightclub/festival attendees who use ecstasy or Molly have been unintentionally or unknowingly using “bath salts.”

The researchers surveyed young adults outside of nightclubs and dance festivals in the summer of 2015 about their use of ecstasy and other drugs.  The participants were asked if they had knowingly used any of a list of more than 35 NPS; and whether or not they had knowingly used ecstasy, MDMA or “molly.” Then they were asked if they would submit a lock of their hair for the researchers to test for NPS. “We collected hair samples from about a quarter of the survey sample to be tested for novel drugs.”

A lot of people laughed when they gave us their hair saying things like “I don’t use bath salts; I’m not a zombie who eats people’s faces.”

However, the researchers found that among individuals who reported they had not knowingly used bath salts or some unknown substance, 40% tested positive for “bath salts” and other NPS. Among participants reporting they had used ecstasy, half the samples tested positive for MDMA and half tested positive for bath salts and other NPS. One sample tested positive for alpha-PVP, flakka.

Ecstasy wasn’t always such a dangerous drug, but it is becoming increasingly risky because it has become so adulterated with new drugs that users and the scientific community alike know very little about. . . .   Users need to be aware that what they are taking may not be MDMA.

04/22/16

Holding Fast to God

© Karel Miragaya | 123rf.com

© Karel Miragaya | 123rf.com; Two Assyrian warriors

Sometimes the interaction of world history with biblical events can be confusing, as with the reign of Hezekiah, king of Judah. Assyria was the dominant Near Eastern power and Babylon was just an Assyrian vassal state, like Judah. But like a season of the reality TV show, Survivor, a series of alliances were made and then broken when it seemed to be to the advantage of the power brokers of the time—including Hezekiah.  Putting the biblical events within their historical context will help in understanding events described in Scripture regarding Hezekiah’s reign.

During the middle period of the Assyrian Empire, the Assyrian king Adad Nirari I (1307-1275 BC), began a policy of deporting large segments of a conquered population to other areas of the empire. This became a standard policy under the Assyrian Empire. “Adad Nirari I decided the best way to prevent any future uprising was to remove the former occupants of the land and replace them with Assyrians.” We see this done in 2 Kings 17: 24 and 18:11, after a later Assyrian king took over Samaria and conquered Israel in 722 BC.

Those who had actively rebelled against the Assyrians were either killed or sold into slavery. But not everyone else was deported; and families were never separated. Those who were deported were carefully selected for their abilities and sent to where their talents were most needed. They were absorbed into the expanding empire and were thought of as Assyrians once they had submitted to central authority.

It was within the later period of the Neo-Assyrian Empire that the events of Hezekiah’s time occurred. Tiglath Pileser III (745-727 BC) revitalized the empire by reorganizing the military and restructuring the governmental bureaucracy. In 2 Kings 16, Ahaz the king of Judah, agreed to become an Assyrian vassal if Tiglath Pileser would take his side against the kings of Syria and Israel, which he did. Under Tiglath Pileser’s reign, the Assyrian army became the most effective military force of the era.

Shalmaneser V was the Assyrian king who conquered Samaria in 722 BC, the same year of his death. His successor, Sargon II (722-705 BC) improved the existing policies and expanded the kingdom even further through his military exploits. Sargon made the mistake in one of his last campaigns against Babylon of sparing the life of the king Merodach-Baladan when he defeated him and his allies in 710 BC.

While he was away on military campaigns, Sargon entrusted his son Sennacherib to maintain the administration of the empire. Because he had been relegated to the role of a governmental official under his father, it seems that when he ascended to the throne, Sennacherib (705-681 BC) was thought to be a potentially weak ruler. He had never gone with his father on campaign and never proved himself in battle. This perceived weakness led others, including Merodach-Baladan and Hezekiah to begin taking stands against him.

Shortly after Sennacherib ascended to the Assyrian throne, Merodach-Baladan returned to Babylon at the head of an army, assassinated the sitting ruler and again took the throne. The first army sent by Sennacherib was easily defeated, so he led a second one in 703 BC, causing Merodach-Baladan to flee the battle field and seek sanctuary in Elam. Merodach-Baladan then attempted to forge another coalition against Sennacherib with Judah, Egypt and other powers in the west of the empire.

Hezekiah became king of Judah in 715 BC after a period of co-regency with his father, Ahaz from 729 BC. As the sole king of Judah, Hezekiah began to make religious reforms, undoing the syncretism that had been practiced by Ahaz. He removed the high places, which had become places of pluralistic worship for Yawveh and other Canaanite gods. He tore down the pillars, and cut down the Asherah poles and broke up the bronze serpent made by Moses into pieces. All these had also become idolatrous objects of worship for the people. 2 Kings 18:5 said there was none who trusted the Lord like Hezekiah among all the kings of Judah—either before or afterwards. These actions of reform seem to have taken place in the earlier days of Hezekiah’s reign, before he rebelled against the king of Assyria.

It seems that while Sennacherib was busy with Merodach-Baladan and Babylon in the east of the Assyrian empire, Hezekiah and others in the west had decided to rebel against Sennacherib as well. Other powers in the area that attempted to throw off the yoke of Assyrian rule shortly after Sennacherib took Babylon included: Tyre and Sidon, as well as the Philistine cities of Ekron and Lachish.

Hezekiah’s revolt (2 Kings 18:7) consisted of withholding his required tribute from Assyria and attempting to extend his regional influence over neighboring territory. 2 Kings 18:8 reports that Hezekiah stuck down the Philistines as far as Gaza. Remember that while not mentioned as such in Scripture, the Philistine city-states were part of the Assyrian Empire. The Assyrian-appointed king of Ekron was taken to Jerusalem in chains and imprisoned by Hezekiah.

Politically, Hezekiah’s expansionist agenda turned out to be a bad idea. In 701 BC, Sennacherib brought his armies into the region to put down the revolts. While Sennacherib himself was busy besieging Lachish, he sent his envoys, including his field commander, to Jerusalem to deal with Hezekiah. They wanted Hezekiah to release the imprisoned king and surrender the city to them. In 2 Kings 18, Hezekiah is reported to have responded to Sennacherib by saying he had done wrong. He released the King of Ekron and vowed to pay whatever tribute Sennacherib imposed if he would withdraw.

But Hezekiah would only sent tribute; he wouldn’t depose himself, as Sennacherib wanted. The chief Assyrian envoy returned to Jerusalem after consulting with Sennacherib and asked whom Hezekiah was relying on for delivery? Egypt? The Lord? Did he think that mere words were enough power and strategy for war? If he was trusting in Egypt to save him, it was a “broken reed of a staff” that would pierce the hand of whomever would lean upon it. Then the Rabahakeh said:

But if you say to me, “We trust in the Lord our God,” is it not he whose high places and altars Hezekiah has removed, saying to Judah and to Jerusalem, “You shall worship before this altar in Jerusalem”? (2 Kings 18:22)

He suggested a wager. He would provide two thousand horses if Hezekiah could provide two thousand riders for them. How could they hope to defeat even one of the Assyrian captains if they were relying upon Egypt for chariots and horsemen? He then claimed it was the Lord who told him to go against Judah and destroy it. Had the gods of any other city delivered them from Assyria?

Then the Rabshakeh proposed that if the people did not listen to Hezekiah, but surrendered to him, they would live and remain with their current property until he returned to take them to another land like their own land. While this negotiation went on, “Lachish was taken and the population slaughtered. Those who were spared were deported to regions in Assyria.”

Hezekiah was required to pay three hundred talents of silver (worth about $4.95 million in today’s currency) and thirty talents of gold (worth about $37.5 million in today’s currency). He stripped the temple of its gold and gave all the silver of the temple and the king’s treasury to Sennacherib. The Assyrian army did withdraw, but only because of an advancing force of Egyptians (2 Kings 19:9) . Sennacherib defeated the Egyptians near the city of Ekron. He then returned to Jerusalem after subduing Ekron, Tyre and Sidon, and resumed the siege. Judah now stood alone against the Assyrians. How had Hezekiah dug himself into such a hole?

About three years before, in 704 BC while Sennacherib was busy subduing the Babylonian rebellion under Merodach-Baladan, Hezekiah became deadly ill. The prophet Isaiah was sent by the Lord to tell him to put his house in order; he was going to die of his illness. But Hezekiah prayed and asked the Lord to remember his faithfulness, how he had “done what is good in your sight.” Then the Lord sent Isaiah back to Hezekiah with another word: the Lord had heard his prayer and granted him another fifteen years of life. Moreover, he would deliver Hezekiah and Jerusalem out of the hand of Sennacherib.

After Merodach-Baladan fled to Elam when Sennacherib defeated him in Babylon, he approached Hezekiah about an alliance to rebel against Sennacherib. Seemingly under the guise of celebrating the good news of Hezekiah’s healing, he sent envoys and presents to Hezekiah. This occurred in 703 BC, shortly before the death of Merodach-Baladan in Elam. Hezekiah stupidly showed the envoys of his new “ally” all that he had—his treasure house; his storehouses; his whole armory. “There was nothing in his house or in all his realm that Hezekiah did not show them” (Isaiah 39:2).

Then Isaiah said to Hezekiah, “Hear the word of the Lord of hosts: Behold, the days are coming, when all that is in your house, and that which your fathers have stored up till this day, shall be carried to Babylon. Nothing shall be left, says the Lord. And some of your own sons, who will come from you, whom you will father, shall be taken away, and they shall be eunuchs in the palace of the king of Babylon.” Then Hezekiah said to Isaiah, “The word of the Lord that you have spoken is good.” For he thought, “There will be peace and security in my days.” (Isaiah 39:5-8)

There was peace from the Babylonians in his days, but he was about to experience the wrath of Sennacherib in two short years.

Hezekiah may have been faithful in doing what was good before the Lord, but he was a terrible leader and politician. It would seem that Hezekiah saw the opportunity of throwing off Assyrian rule as a slam-dunk because of the prophesied protection. But his actions brought the wrath of the most powerful nation of his time down upon him and his people. And it set the stage for the one that replaced it, Babylon, to return and take up where Assyria had to leave off.

Hezekiah prayed once more to the Lord for deliverance and the Lord heard his prayer (Isaiah 37). Again, through the prophet Isaiah, the Lord said: “He shall not come into this city or shoot an arrow there, or come before it with a shield or cast up a siege mound against it. By the way that he came, by the same he shall return, and he shall not come into this city, declares the Lord.” During the night, 185,000 Assyrians were struck down. Sennacherib withdrew to Nineveh and never attempted to take Jerusalem again. In 681 BC, he was assassinated.

The lesson here from Hezekiah is that God doesn’t judge us by what we accomplish in his name; or how successful we are in our lives. Rather, do we trust him with our whole heart?  Will we “hold fast” to God—stay close or cling to him in affection and loyalty—as Hezekiah did? What stood Hezekiah apart from all the other kings of Judah was the way he trusted the Lord. In him we see a living embodiment of the truth that would be spoken by Jesus in John 14:14, over 700 years in the future: “If you ask me anything in my name, I will do it.”

04/19/16

Ketamine to the Rescue?

© albund |Stockfresh.com

© albund |Stockfresh.com

Enthusiasm for using ketamine to treat depression has been growing. The interest in the fast action effects of ketamine for treatment-resistant depression began with the publication of a study by Zarate et al. in 2006 that found “Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection.” Since then, dozens of studies have been done and thousands of people have been treated for depression off label with ketamine. Now the American Psychiatric Association has a ketamine task force and is seriously considering an endorsement of ketamine for treatment-resistant depression.

An NPR story featured psychiatrist David Feifel’s work in treating depression with ketamine. Feifel began treating people with low dose ketamine in 2010. After reading the papers on ketamine, he said he was electrified. People were getting better in hours. “It became clear to me that the future of psychiatry was going to include ketamine, or derivatives of ketamine, or the mechanism of action in some way.”

He said it was hard for him to take the “wait and see” approach suggested by other psychiatrists when people are desperate for help. It didn’t make sense to him. Sara Solovitch, writing for The Washington Post, said some experts are calling it the most significant advance in mental health treatment in fifty years.

Ketamine has been around since the 1960s. It is regularly used as an ER anesthetic because it can rapidly stop pain without affecting vital functions like breathing. It’s often the go-to painkiller for children who come to the ER, say with a broken bone. It’s used in veterinary medicine and is an important tool in burn centers. It’s also been used as date-rape drug, because of some of the self-same properties that make it an attractive ER anesthetic. It will quickly numb and render someone immobile.

A single dose of ketamine costs under $2. The drug is easily available in any pharmacy; and doctors are free to prescribe it for off-label use. But ketamine treatment for depression is expensive. Dr. Feifel charges $500 for an injection and $1,000 for an intravenous infusion. The high cost is attributed by practioners to the medical monitoring and IV equipment required during an infusion.

It isn’t an approved depression treatment, so the costs are out-of-pocket, placing it out-of-reach for many people. But clinics are going up everywhere. A directory found 19 different centers in the US as of the beginning of February, in 2016. Dr. Feifel is afraid something will happen to a depressed patient at one of these unregulated clinics that could set back efforts to make the drug more widely available.

Sara Solovich reported there a growing number of academic medical centers that are offering ketamine treatments off-label for severe depression. These medical centers include: Yale University, the University of California at San Diego, the Mayo Clinic and the Cleveland Clinic. A San Francisco psychiatrist, Alison McInnes, thinks this is the next big thing in psychiatry. Psychiatry has “run out of gas” in trying to help depressed patients. “There is a significant number of people who don’t respond to antidepressants, and we’ve had nothing to offer them other than cognitive behavior therapy, electroshock therapy and transcranial stimulation.”

Dr. McInnes reported a 60% success rate for people with treatment-resistant depression who try ketamine. Dr. McInnes is also a member of the APA’s ketamine task force. She expects the APA to support ketamine treatment in 2016.

Ryan, Marta and Koek did a literature review on ketamine as a treatment for depression in a 2014 issue of the International Journal of Transpersonal Studies,Ketamine and Depression: A Review.”  They acknowledged that the largest challenge with ketamine was extending its benefit for the longer term. Repeated infusions of ketamine showed some promise, but it is far from clear what the optimum dose, frequency and number of infusions should be. “It also worth noting that some patients do not benefit from ketamine, despite multiple treatments.”

Ready for the drawbacks? “Even low-dose ketamine infusion can cause intense hallucinations.” Patients experience a kind of lucid dreaming or dissociative state where they lose track of time and have out-of-body experiences. Many people enjoy it; but others don’t. The treatment effects are often temporary. Dr. Feifel reported one patient whose depression remission would begin to fade within twenty-four hours. With others, the remission can be longer; even weeks. The fleeting remission effect means that many patients return for booster infusions. A business executive from Seattle flies back-and-forth to New York for bimonthly infusions. Sometimes his remission periods will last six months.

Gerald Sanacora, the director of the Yale Depression Research Program, said ketamine infusion is an extremely important treatment. His concern is that people may begin using it as a first-line treatment—before CBT (cognitive behavioral therapy) or antidepressants like Prozac. “Maybe someday it will be a first-line treatment. But we’re not there yet.”

It’s a medication that can have big changes in heart rate and blood pressure. There are so many unknowns, I’m not sure it should be used more widely till we understand its long-term benefits and risks.

There isn’t a registry yet for tracking ketamine patients treated for depression. So the number of people treated, the frequency of those treatments, the dosage levels, follow up care—and importantly—adverse effects from ketamine treatment aren’t known. Carlos Zarate, the NIMH’s chief of neurobiology and treatment of mood disorders, said: “We clearly need more standardization in its use.”  In his opinion, it should still be sued in a research setting or a highly specialized clinic.

There also seems to be a turf war or sorts brewing. Ketamine was once almost exclusively a drug known to anesthesiologists. Psychiatrists are now saying that with the use of ketamine for depression growing, it should be left for psychiatrists to prescribe. David Feifel said:

The bottom line is you’re treating depression. . . . And this isn’t garden-variety depression. The people coming in for ketamine are people who have the toughest, potentially most dangerous depressions. I think it’s a disaster if anesthesiologists feel competent to monitor these patients. Many of them have bipolar disorder and are in danger of becoming manic. My question [to anesthesiologists] is: “Do you feel comfortable that you can pick up mania?”

Six of the providers in the above-linked directory are specialists in anesthesiology. Six are psychiatric specialists. The rest are a mixture of specialists in emergency medicine, neurology, internal medicine and even family medicine. Enrique Abreu, A Portland Oregon anesthesiologist who began treating depressed patients with ketamine in 2012, said: “Most anesthesiologists don’t do mental health, and there’s no way a psychiatrist feels comfortable putting an IV in someone’s arm.”

Ketamine in larger doses than are being used in the above discussed depression research is a club drug known as “Special K,” “K,” of Ket.” It is a Schedule III Controlled Substance, meaning it is classified as having an addictive potential. Current depression research has not indicated dependence as an adverse effect, likely because of the low doses currently being used. When used with other sedating drugs like alcohol, the potential of slowing or shutting down the central nervous system are increased. And it is possible to overdose on ketamine. While some clinicians like Drs. Feifel and McInnes would like to see ketamine treatment revolutionize the psychiatric treatment of depression, caution in waiting for the results of further research seems advisable.

Unfortunately, I don’t think that will happen. Psychiatric treatment of depression is in crisis. Even the articles and researchers cited here seemed to acknowledge this. Dr. McInnes said psychiatry has “run out of gas” in trying to help depressed patients. Dr. Fiefel said he found it hard to “wait and see” what further research found regarding ketamine, when so many people were desperate for help.

Pharmaceutical companies stopped doing research into new antidepressants. The chemical imbalance theory of depression is now referred to as more of an urban myth than a true description. Pharma and psychiatry need an antidepressant savior and it seems they hope it will be ketamine.

04/15/16

Drunkenness Disease

© Vlada Grechko | 123rf.com

© Vlada Grechko | 123rf.com

Okay, I’ve heard a few wild stories over the years from individuals trying to explain why they really didn’t use drugs or alcohol, despite what the urine screen or breathalyzer said. The tennis star, Richard Gasquet, claimed his positive drug test for cocaine was because he kissed a woman. And he was believed! So when someone insisted they didn’t drink any alcohol when they were arrested for a DUI with a BAL over .30—verified by blood work at a hospital—I was convinced that was a lie. The person insisted they only drank Gatorade. Their best guess was there must have been alcohol in the Gatorade bottle, although why they didn’t taste any as they chugged it was never explained. But then I heard about Auto-Brewery Syndrome.

The condition has been known to exist for several decades. The first cases reported in the scientific literature appeared in the 1970s. There have been sporadic reports of Auto-Brewery Syndrome or Gut Fermentation Syndrome over the years. A google search I did for “auto brewery syndrome pubmed” drew over 28,000 hits. There was a 2013 article by Cordell and McCarthy in the International Journal of Clinical Medicine that reviewed the history of the disorder and then presented a well-documented case of a 61 year-old man who had Auto-Brewery Syndrome.

This disorder has a few other names besides the two noted above. It is also called Drunkenness Disease and Endogenous Ethanol Fermentation. I like Auto-Brewery, with Drunkenness Disease as a close second. It is a syndrome where patients become intoxicated without ingesting alcohol. Cordell and McCarthy said: “The underlying mechanism is thought to be an overgrowth of yeast in the gut whereby the yeast ferments carbohydrates into ethanol.”

There is some evidence that unusual fermentation can occur with high fiber diets, the use of ampicillin and the ingestion of a dietary supplement, prebiotic inulin. An experiment by Bivin and Heinen combined five infant food formulas with four common yeasts and found that all the mixtures produced ethanol. The yeast producing the highest ethanol content was Saccharomyces cerevisiae, also known as brewer’s yeast.

In January of 2010, a 61 year-old man presented with a five-year history of unexplained intoxication. After surgery for a broken foot in 2004 and treatment with antibiotics, he began to seem excessively intoxicated after only having two beers. His wife, who is a nurse, began to use a breathalyzer to measure this phenomenon. His blood alcohol percent was as high as .33 to .40. The episodes of intoxication were more frequent when he missed a meal, after exercising, or when he had ingested alcohol the night before. Over time, his episodes of intoxication increased in severity and frequency.

In November of 2009, the subject was taken to the Emergency room on a day when he had not ingested alcohol. In the ER, his blood alcohol concentration was 371 (0.37%). He was admitted to the hospital for 24-hour observation and treated for severe alcohol intoxication. The physicians were not aware of any way that a person could be intoxicated without ingesting alcohol and therefore believed he must be a “closet drinker”.

In April of 2010 he was admitted to the hospital for a 24-hour observation period. His belongings were searched to verify that he didn’t have any alcohol with him and no visitors were allowed during the 24-hour period. A glucose challenge test was done and he was fed a high carbohydrate diet. His blood alcohol levels were checked regularly threw blood being drawn and the use of a breathalyzer. At one point, his BAC rose to .12 in this controlled condition. The authors believe he had “Gut Fermentation Syndrome.” Although it is rare, they urged that it be recognized because of social implications, such as potential job loss, relationship problems, and even possible arrest and incarceration.

It would behoove health care providers to listen more carefully to the intoxicated patient who denies ingesting alcohol. Gut Fermentation Syndrome warrants additional investigation to determine which organisms induce symptoms and what definitive tests should be conducted to confirm diagnosis.

So you can see where this is going, right? Recently a New York State judge dismissed a drunk driving charge against a 35-year old teacher who lives in Hamburg, a town south of Buffalo. A U.S. News & World Report article indicated the woman had a .33 BAC at the time of her arrest. She spent $7,000 working with a specialist, Dr. Anup Kanoda of Ohio, to show her body could meet the legal definition of drunkenness without actual alcohol intake. The local prosecutor’s office plans to appeal the judge’s decision.

The woman’s lawyer had her monitored by a physician and two nurses for a full day to prove she drank no alcohol, yet she had a .36 BAC, according to a report in The Fix, about the same case. The woman also bought a breathalyzer and blew into it for 18 straight nights, recording an average of .20 BAC each night. Jonathan Turley, a law professor at George Washington University said it’s not really a get-out-of-jail-free card, although it seems so at first glance. “Courts tend to be skeptical of such claims. You have to be able to document the syndrome through recognized testing.” Turley added that the woman’s defense was only valid because she was not aware that she had auto-brewery syndrome.

Dr. Kanoda said he thought between 50 and 100 people have been diagnosed with the disorder. He thought it likely that up to 95% of those who have Auto-Brewery Syndrome don’t know they have it. “I would say it is not safe to drive a car if you are in an auto brewery syndrome flare.”

So back to my possible close encounter with Auto-Brewery Syndrome. It just so happened that I first heard about this syndrome before the person was sentenced for DUI. I told them about it and urged them to tell their attorney and have some tests done. Their attorney supposedly didn’t think the claim would be worth investigating and the individual was found guilty of DUI. Yet to this day, they have asserted they did not drink any alcohol before passing out at a park and waking up at the hospital.

04/12/16

No One Knows

© Bram Janssens | 123rf.com

© Bram Janssens | 123rf.com

On December 7, 1834, at the age of 42, Edward Irving died of consumption—tuberculosis. He was laid to rest in the crypt of Glasgow Cathedral and most of the ministers of Glasgow were at his funeral. Reportedly, a group of young women dressed in white kept vigil around his tomb, “expecting to see him arise from the dead.” They believed he had not been healed of his illness in order that God would do a mightier work—that of raising Irving from the dead. Succinctly reported by his biographer, Arnold Dallimore, “With the passing of some days they were forced to recognize that their hope was in vain.”

Edward Irving served as a Presbyterian minister in London from 1822 until the time of his death in 1834. During his last five years of ministry, his doctrinal position was almost the same as that of modern Pentecostals and Charismatics. He believed that God was restoring the apostolic gifts, especially those of tongues, healing and prophecy. Ministering over sixty years before Azusa Street, and almost one hundred and thirty years before the modern Charismatic movement, Irving has only recently begun to receive recognition as a forerunner of the modern Charismatic Movement.

Irving was born in Annan Scotland, on August 4th, 1792. By the age of twelve, he had decided to be a minister. At the age of thirteen, he left Annan with his fifteen year-old brother John to attend the University of Edinburgh. At seventeen, he completed the Masters of Arts degree. For the next six years he taught school fulltime to support himself while he continued as a part time divinity student. When he did not immediately receive a call to a church, Irving continued teaching for four more years. In 1819, at the age of twenty-seven, he received a call as the assistant to the most celebrated minister in Scotland at the time: Doctor Thomas Chalmers of St. Johns Church, Glasgow.

Their relationship was an easy one for either of them. Chalmers was frequently concerned that Irving would do or say something too extreme or erratic—and thus cause problems. Irving disliked being merely an assistant; he chafed at standing in Chalmers shadow. Eventually Irving was considered for a call to a large congregation in Jamaica, and a prestigious church in New York. But before these possibilities could bear fruit, he was asked to preach as a supply minister at the Caledonian Chapel in London. Irving was so well received, that he was called to be the Chapel’s new minister in 1822. He quickly accepted.

Within six months of coming to London, success and popularity overcame Irving. Every Sunday, three times the seating capacity (500) of the Chapel sought entrance. Long before the service began, the building was filled—every seat was taken, even the aisles were packed. Outside the streets became impassable with carriages and a crowd of would-be hearers vainly attempted to get in. People from all walks of life flocked to hear Irving: laborers as well as titled gentlemen. Lawyers, physicians, actors, artists, and diplomats were drawn in large numbers to his ministry.

By the end of his first year in London, he was always newsworthy in the eyes of the press. Some praised him, some belittled him, but no one ignored him. Public opinion about him was also mixed. Some people felt he was a charlatan, while others saw him as an example of the nineteenth century’s version of our cultures fifteen minutes of fame: only briefly famous, and soon to be forgotten. Yet many others regarded him as a mighty man of God; the greatest orator of the age.

One of those who was drawn to Irving was the celebrated English critic, poet and philosopher, Samuel Taylor Coleridge.  He said: “I hold that Irving possesses more of the spirit and purpose of the first Reformers, that he has more of the Head, and Heart, the Life, the unction and the general power of martin Luther, than any man now alive.” Irving was quite flattered by Coleridge’s words and became close to him. A friend, who accompanied Irving on one of his visits to Coleridge, said he sat at Coleridge’s feet and “drinks in the inspiration of every syllable.”

Dalimore said Irving formed his belief that humankind was moving quickly towards a period of terrible judgment and suffering from listening to Coleridge. Nevertheless, he thought there was still the possibility of spiritual transcendence over this time through the direct work of the Holy Spirit. This was the ‘deeper truth’ and ‘higher style of Christianity’ that Irving had been seeking. These beliefs were firmly entrenched in him by the time Irving was asked to address the London Missionary Society in 1824.

As the guest speaker, he was expected to extol the past accomplishments of the Society, highlight its recent ones, and then point out areas of particular need. The aim was to arouse his listeners to a greater devotion to the Society and to liberally support it work. But Irving said the exact opposite. He described the apostles as constantly followed by miracles and as independent of all earthly assistance. He said the Church had drifted from the purity and practices of that day. As a result, it now relied upon human devices and earthly organizations.

He implied that missionary societies were both unnecessary and the result of apostasy. They should go to foreign lands without human support, trusting that God would sustain them. Returning to this apostolic practice would usher in the return of apostolic power. His statements created a furor. Opponents said they always believed he was unbalanced and his address to the London Missionary Society proved they were right. But Irving went even further—he published the address and dedicated it to Coleridge, saying:

You have been more profitable to my faith in orthodox doctrine, to my spiritual understanding of the Word of God, and to my right conception of the Christian church, than any or all the men with whom I have entertained friendship. . . . Your many conversations concerning the revelations of the Christians faith have been so profitable to me . . . and your high intelligence and great learning have at all times so kindly stooped to my ignorance and inexperience, that . . . with the gratitude of a disciple to a wise and generous teacher, . . . I do presume to offer you the first fruits of my mind since it received new impulse towards truth, and a new insight into its depths from listening to your discourse.

In his book, Counterfeit Miracles, B.B. Warfield commented how the religious atmosphere of the early nineteenth century was very unsettled and filled with a restless desire for change. “In particular, premillenarian extravagances were rife, and men were heatedly looking for the early coming of the Lord.” Dallimore agreed, saying that the national upheavals at the end of the previous century had confirmed that conviction for the students of prophecy. The events were, of course, the American and French Revolutions. The rise of the military dictatorship of Napoleon was the icing on the premillennial prophetic cake. Many Christians at the time were convinced he would prove to be the Antichrist of the book of Revelations.

Two additional influences on Irving were to come into his life in 1824, Hatley Frere and Henry Drummond. Frere’s thoughts were a continuation of Coleridge’s, believing that the world was about to enter a period of great suffering. However, where Coleridge based his on a human assessment of the political and moral state of the world, Frere based his on an interpretation of the biblical books of Daniel and Revelation. Frere believed that by 1824, almost all the biblical prophecies contained in those two books had been fulfilled, “and that the coming of Christ could not be more than a few years away.” Irving would eventually tell Frere, “I had no rest in my spirit until I waited upon you and offered myself as your pupil, to be instructed in prophecy according to your ideas.”

Henry Drummond was a major figure in the European missionary work of The Continental Society. Despite the reaction to Irving’s address before the London Missionary Society, Drummond invited him to speak at the Continental Society’s 1825 rally. Irving said their missionary work had no hope of success. He described a cataclysmic judgment, which he said was about to fall, especially on the target of their missionary work, southern Europe. Again, people were highly upset. Some even walked out while he was speaking. As he did before, Irving published his address, titling it: Babylon and Infidelity Foredoomed.  Babylon was the term he used for all of Christendom.

Moved by Irving’s emphasis on prophecy, Drummond announced that a conference on prophecy would be held at his country estate south of London in November of 1826. The views espoused at the conference were essentially those of Frere. But the zeal with which these ideas were discussed led the men in attendance to return to their homes proclaiming that the end times had come. Irving now devoted his ministry almost entirely to the interpretation of prophecy. The second coming of Jesus Christ was not far off. Dallimore commented:

He was equally sure that before that time arrived, God would grant the special ‘outpouring of the Holy Spirit’, and indeed, that at any moment he might witness the beginning of that outpouring—the ‘signs and wonders’ of ‘the latter rain.”

Irving’s ministry was about to take another radical shift in emphasis (See “In Spite of Delusions”), but the first phase was dominated by his interest in prophecy as well as the influence of Samuel Coleridge and Hatley Frere. He was in many ways at the right place and the right time with his message on the soon-coming Christ, except that he was wrong. Like many who are captivated by the lure of prophetic interpretation, what seems so clear to them is not the way it actually turns out to be… as it was true of Harold Camping.

While in seminary, I heard Harold Camping speak about his conjecture that Christ would return in September of 1994. As the theologian John Walvoord predicted, when the date came and went, he had another theory. Camping then predicted Christ would return on May 21, 2011. After the predicted return, Camping said the saved would be taken up into heaven and then there would follow five months of fire, brimstone and plagues. October 21, 2011 would then be the final destruction of the world. Camping largely avoided press interviews after his failed prophecy on May 21st. Then he had a stroke in June of 2011.

In a letter to the listeners of his Family Radio show, he acknowledged he was wrong about the May 21st date. “Events within the last year have proven that no man can be fully trusted. Even the most sincere and zealous of us can be mistaken.” However he said the “incorrect and sinful” prediction that Christ would return on May 21st and that true believers would be raptured, still allowed God to get the attention of a great many people. Sounds like he was still trying the get a positive out of his stubborn pursuit of an erroneous interpretation of Scripture.

Harold Camping died on December 15, 2013. Maybe he and Irving are comparing notes to see where they went wrong. Or perhaps they realize a better approach would have been to remember the truth of Matthew 24:36, “But concerning that day and hour no one knows, not even the angels in heaven, nor the Son, but the Father only.”

The above discussion was largely taken from: The Life of Edward Irving: The Forerunner of the Charismatic Movement, by Arnold Dallimore.

04/8/16

Foxes in the Henhouse

© Juan Auni’n | 123rf.com

© Juan Auni’n | 123rf.com

On February 24, 2016, 2015 the FDA announced that Robert Califf MD was confirmed as the new Commissioner of the FDA by an 89 to 4 vote in the Senate. There seems to be opposing opinions regarding his role as the new FDA Commissioner. Presidential candidate Bernie Sanders opposed his appointment because of his extensive ties to the pharmaceutical industry and lack of commitment to lowering drug prices. Writing for Forbes, Matthew Herper said: “Any senators who slow his path to the job he [Califf] deserves should be accused of practicing the basest kind of partisanship.”

Herper said it was no shock that Califf was nominated. His nomination seems to have been the culmination of a leadership transition at the FDA beginning before Califf was appointed as the FDA Deputy Commissioner for Medical Products and Tobacco in January of 2015. Herper said Califf’s departure from Duke University was a clear sign this transition was already in the works. Herper wasn’t alone in seeing this potential nomination and appointment.

Also writing for Forbes, David Kroll commented that Califf’s position as Deputy Commissioner for Medical Products and Tobacco was second in scope to being commissioner of the FDA. Massimo Calabresi, in his article for Time in February of 2015, also suggested Carliff could be the next FDA Commissioner. Then the serving FDA Commissioner, Margaret Hamburg announced she would step down at the end of March 2015. According to Herper, Califf’s name had been in circulation six years ago when Hamburg was nominated. But he was widely seen at the time as having too many links with industry. So instead, the Obama administration went with Hamburg.

Herper acknowledged Califf’s ties with the medical industry, but felt he worked with drug companies “in the best possible way”—convincing them to do large, expensive clinical trials. Not only were these trials profitable for Duke, but they helped prove the effectiveness of major medicines like Plavix, Vytroin, and Zarelto. But he hasn’t been a pushover. “His goal has always seemed to be to make sure that doctors and patients have the best evidence possible for deciding what drugs to give to patients. He has not always been easy on industry.”

Massimo Calabresi gave a more nuanced portrayal of Califf. At Duke, he was the founding director of the Duke Clinical Research Institute, which is considered to be one of the world’s largest academic research organization, with an annual budget of $320 million. Califf himself estimated that 50 to 60% of this annual research funding comes from industry. Calabresi captured the controversy nicely about Carliff when he noted that Carliff sees collaboration between industry, academia and the government as the way of the future: “The greatest progress almost certainly will be made by breaking out of insular knowledge bases and collaborating across the different sectors.”

Carliff went on to say there was a tension that cannot be avoided between the industry and creating the conditions where the industry can thrive. “The FDA’s got to do both.” He thought it would be useful to have someone leading the FDA who understood how companies operate, “because you’re interacting with them all the time.” Calabresi said the tension over Callif’s collaboration with industry gets at the heart of the FDA at a pivotal moment. “While FDA defenders see the collaboration as a threat to its independence, others see close relationships between government, industry and academia as the model for the future.”

Diana Zuckerman, President of the National Center for Health Research, which advocates for FDA regulatory authority, says such ties “should be of great concern.” Dr. Califf is “a very accomplished, smart physician who’s been an important name in the field,” Zuckerman says, but his “interdependent relationships” raise questions about his “objectivity and distance.” She cites several studies suggesting the medical products industry uses such ties to influence the behavior and decision making of doctors and researchers, even when the scientists don’t realize it.

Senator Sanders said he strongly believed “We need a leader at the FDA who is prepared to stand up to the drug companies.” Someone who will strive to substantially lower drug prices, to develop rules to safely import brand-name drugs from Canada “and hold companies accountable who defraud our government.” Carliff’s extensive ties to the pharmaceutical industry did not give him reason to believe he would make “the FDA work for ordinary Americans rather than the CEOs of pharmaceutical companies.”

Whether or not Senator Sanders’ reservations about Robert Carliff come true remain to be seen. But there is a more troubling tie between the pharmaceutical industry and our government to consider. Reporting for The New York Times, Nicholas Kristof said the pharmaceutical industry spent $272,000 in campaign contributions per member of Congress in 2015. And there are more pharma lobbyists than there are members of Congress. One of the key issues at stake is to keep the government from bargaining for lower drug process with Medicare. “That amounts to a $50 billion annual gift to pharmaceutical companies.”

Reporting for STAT News, Sheila Kaplan and Ike Swetliyz said that around 30% of US Senators and 20% of US Representative hold assets in biomedical and health-care companies. Johnson & Johnson, Merck and Pfizer were favored investments for members of the House and the Senate. Some of the most aggressive congressional investors in the biomedical sector served on key committees. The House Energy and Commerce Committee for example, which oversees the FDA and works on issues of importance to the industry such as drug regulation, research funding and taxes on medical devices.

Members of Congress owned more stock in health-related companies last year than in the defense and construction sectors combined, according to the Center for Responsive Politics. Their investments in the sector topped $68 million.

They described legislators who had financial investments and even ownership stakes in companies that Congress was regulating. One Congressman who sits on the Energy and Commerce Committee co-sponsored a bill to repeal taxes on medical devices. If passed, this bill would help two companies in which he has heavily invested. He also proposed that the FDA loosen requirements for drug companies to track the safety and effectiveness of their products once they are on the market. Not only would that provision help many drug companies, it would benefit a biotech company in which he is the largest single stockholder.

Dr. Michael Carome, the director of a nonprofit health advocacy organization, Public Citizen’s Health Research Group, said: “Even if the lawmakers aren’t personally picking and choosing each stock, knowingly holding stocks in pharmaceutical and medical device companies creates obvious financial conflicts of interest.”

Members of Congress are not required to recuse themselves from voting on bills that could effect their personal finances, unless they would be the primary beneficiary of the legislation.

Yet across most of the federal government, employees are required to recuse themselves from working on issues that could influence the value of their investments. Within the Department of Human Services, employees are barred from owning stock in drug companies or other industries that the agency closely regulates.  STAT said they called dozens of lawmakers for their story, but none would comment in detail about their investments.

Matthew Herper’s opening comment about partisan politics blocking Califf’s appointment seems to have been baseless. He almost had unanimous support. Whether or not he will be tough on the industry remains to be seen. And with regard to partisanship, it was Democratic Senators who held up his nomination; and three of the four opposing votes were from Democrats. So only 20 to 30 percent of U.S. Member of Congress have a financial stake in biomedical and health-care companies. But it is disturbing that several of those legislators are on committees making regulatory decisions for those companies. And when you consider that the number of pharma lobbyists outnumbers the sitting legislators, it seems we have a situation where the foxes have been invited into the henhouse.

04/5/16

I Smell a RAT

© antonihalim | Stockfresh.com

© antonihalim | Stockfresh.com

Medication Assisted Treatment (MAT) for addiction comes in various forms that are often (unhelpfully) lumped together into one category. Replacement or substitution methods, like methadone or Suboxone maintenance are radically different from using naltrexone to treat alcohol or opioid use disorders. Yet they are combined into the single category of MAT. While naltrexone is not a cure for addiction, it has been shown to help minimize cravings for urges for both alcohol and opioids. And there is some evidence emerging that it could be useful to blunt cravings for methamphetamine.

In 2010 Karlia et al. did a literature review on pharmacological approaches to treat methamphetamine use disorders. They concluded there was no substantial evidence for effective treatment at the time. “Clinical trials using aripiprazole [Abilify], GABA agents (gabapentin [Neurontin], baclofen, vigabatrin), SSRIs, ondansetron and mirtazapine [Remeron] have failed to show efficacy.” They noted where there was some indication where “agonist replacement medications” like d-amphetamine and modafinil may hold some promise.

The unavoidable problem with “treating” methamphetamine addiction with d-amphetamine is you are using a similarly addictive substance to “treat” methamphetamine addiction. Again, it repeats the error of opioid substitution/replacement therapy. While methamphetamine and amphetamine are Schedule II controlled substances, Modafinil still has an addictive potential as a Schedule IV. It is used to treat narcolepsy and shift work disorder, and it is touted as a “life hack” on Wall Street or “smart pill”—until you decide to stop taking it.

They also pointed to the work of Swedish researcher, Nitya Jayaram-Lindström, who showed in a 2005 study where naltrexone significantly reduced the subjective effects of dexamphetamine and blocked cravings in dependent patients. Additionally, the frequency and amount of amphetamine use was significantly reduced. A double blind study by Jayaram-Lindström in 2008 again showed the efficacy of naltrexone in reducing cravings and self-reported use of amphetamine. A further double-blind, placebo-controlled study by Jayaram-Lindström again demonstrated a significant reduction in cravings and self-reported use of amphetamine. “Naltrexone therefore appears to be a highly promising medication for amphetamine dependence.”

Now there is a study by UCLA researchers on naltrexone as a treatment for methamphetamine addiction. Here is a link to a pre-publication manuscript of the study by Ray et al. Again it was found that naltrexone blunted cravings for methamphetamine and lowered self-reports of subjective effects. Lara Ray, a UCLA psychology professor said: “The results were about as good as you could hope for.” The UCLA press release on the study and an article on The Fix by Zachary Siegel noted where clinical trials into the efficacy of naltrexone to treat methamphetamine addiction have already begun.

One clinical trial with naltrexone was completed and last updated in May of 2013 but no results are posted yet; and another study is ongoing. Although results for the complete trail by California Pacific Medical Center Research Institute were not posted on Clinicaltrails.gov, it does seem to be reported in a 2015 study by Pal et al. reported in the Journal of Addictive Medicine. There was not an improved treatment response found in this study. The Pal et al. study was quite small and does not really argue against further clinical trials into the potential use of naltrexone to treat methamphetamine addiction. The replication of Jayaram-Lindström’s results by Ray et al. are sufficient to see further research into this potential treatment.

The side effects from naltrexone are minimal, making it a viable medication to assist addicts trying to establish and maintain abstinence from dependence upon alcohol, opioids, and now—apparently—methamphetamine. Substitution or replacement medications for addiction need to be distinguished from other medications such as naltrexone within the catchall category of MAT. Perhaps they would be better labeled as SAT—Substitute Addiction Treatment—or RAT—Replacement Addiction Treatment—instead of MAT, Medication Assisted Treatment. Personally, I’m partial to RAT.

04/1/16

Faithful Through the Heat

Copyright: irisphoto18 / 123RF Stock Photo

© Alex Postovski | 123rf.com

The Pony Express is a fixture of American history. William “Buffalo Bill” Cody’s time as a Pony Express rider initiated his eventual branding as a legend of the American West. Despite the obstacles it had to overcome, the Pony Express was remarkably efficient. During its short life of 18 months of operation, only one bag of mail was reported lost. As daring as the idea of an overland mail delivery route was in 18th century America, it has two historical precedents; one which has a biblical connection.

With war on the horizon and the traditional Southern mail route by stagecoach in jeopardy, there was an urgent need for a fast central-route mail service. “It was this demand that gave rise to the idea of the Pony Express.” There are several YouTube videos that describe the Pony Express. Here is one made from stock footage from a 1950s educational film. It has an illustrated map of the route and some helpful descriptions of what went into the operation of the Pony Express route.

In April of 1860, the Central Overland California & Pike’s Peak Express Company established an overland deliver route of mail from St. Joseph Missouri to Sacramento California that took about ten days. Each rider rode 75 to 200 miles and changed horses every 10 to 15 miles. The route was almost 2,000 miles long and had about 190 stations. Then on October 24, 1861, the East and West coasts were connected by the transcontinental telegraph system. Two days later, the Pony Express announced it would close down its services. It couldn’t compete with the almost instantaneous communications of the telegraph.

During the short time of its operation, the Pony Express completed a total of 308 runs and delivered 34,753 letters; only losing the one bag of mail. The recruitment poster for Pony Express riders read: “WANTED. Young, skinny wiry fellows; not over eighteen. Must be expert riders, willing to risk death daily. Orphans preferred.”  When hired, the riders were required to take the following pledge. Those who violated the oath were terminated.

I [name], do hereby swear, before the Great and Living God, that during my engagement, and while I am an employee of Russell, Majors & Waddell, I will, under no circumstances, use profane language; that I will drink no intoxicating liquors; that I will not quarrel or fight with any other employee of the firm, and that in every respect I will conduct myself honestly, be faithful to my duties, and so direct all my acts as to win the confidence of my employer. So help me God.

Genghis Khan was noted for a horse relay postal system that covered the expanse of his empire. It has been said that this system “was instrumental in the expansion of the Mongolian Empire.” A letter could travel from the eastern end of the route near the Caspian Sea to the far western edge in two weeks, a distance of 4,225 miles. In Mongolia, postal riders continued to deliver the mail until 1949, when the former Soviet Union shut down the system while attempting to erase the memory of Genghis Khan from the history of Mongolia.

However, before Genghis Khan in 1224, the Persian Empire of the 5th century BCE was renowned for its communication system, one with striking similarities to the Pony Express. The Greek historian Herodotus said there was no swifter form of human communication at the time than the Persian system. There were men and horses stationed along the route so that each horse and man would be responsible for the interval of a day’s journey. The first rider delivered his charge to the second rider, the second to the third, and so on.

These are stopped neither by snow nor rain nor heat nor darkness from accomplishing their appointed course with all speed.

The biblical connection occurs in the book of Esther. We first see where King Ahasuerus (Xerxes) sent letters to all the royal provinces with a decree regarding conduct within a man’s household. This was after Queen Vashti refused to be paraded in front of Xerxes’s banquet guests (Esther 1:10-22). Haman later successfully convinced Xerxes to issue an edict calling for the destruction of all the Jews in the Persian Empire, and sent it by courier (Esther 3:9-13) to all the provinces of the kingdom. After Haman’s plot was uncovered and he was put to death, Xerxes sent letters “by mounted couriers riding on swift horses that were used in the king’s service, bred from the royal stud” (Esther 8:10) saying that the king permitted the Jews to defend themselves by whatever means necessary and destroy anyone who would attack them.

Although God is not explicitly mentioned anywhere in Esther, it is clear from the story that he was always with his people. And the message for us today is that he continues to guide and protect us even as he defended his people in the time of Esther. Neither snow nor rain will stop him. He is faithful through heat and darkness.